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Phase III Trial of Two Investigational Schedules of Ifosfamide Compared With Standard-Dose Doxorubicin in Advanced or Metastatic Soft Tissue Sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study

Paul Lorigan, Jaap Verweij, Zsuzsa Papai, Sjoerd Rodenhuis, Axel Le Cesne, Michael G. Leahy, John A. Radford, Martine M. Van Glabbeke, Anne Kirkpatrick, Pancras C.W. Hogendoorn, Jean-Yves Blay

From the Weston Park Hospital, Sheffield; Christie Hospital, Manchester; St James's University Hospital, Leeds, United Kingdom; Erasmus University Medical Center, Rotterdam; The Netherlands Cancer Institute, Amsterdam; University Medical Centre, Leiden, the Netherlands; National Institute of Oncology; National Medical Center, Budapest, Hungary; Institut Gustave Roussy, Villejuif; Centre Léon Bérard, Lyon, France; and the European Organisation for Research and Treatment of Cancer (EORTC) Data Center, Brussels, Belgium

Address reprint requests to Paul Lorigan, MB, FRCP, Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Rd, Manchester M20 4BX, United Kingdom; e-mail: Paul.Lorigan{at}christie-tr.nwest.nhs.uk

	ABSTRACT

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Purpose Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin.

Patients and Methods This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m² every 21 days, ifosfamide 9 g/m² over 3 days continuous infusion, or ifosfamide 3 g/m² per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity.

Results The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown).

Conclusion Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma.

	INTRODUCTION

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Progress in the treatment of advanced soft tissue sarcoma over the last 10 years has been slow, with the notable exception of imatinib in gastrointestinal stromal tumors (GIST). Patients with metastatic or locally advanced, inoperable disease are generally considered incurable and are treated with palliative intent. While a small proportion of these may be long-term survivors, the majority die of their disease with a median survival of 51 weeks.^1,2 Anthracyclines and ifosfamide have been established as the most active agents for metastatic soft tissue sarcoma, with reported single-agent response rates of between 10% and 36%.³ However, treatment with doxorubicin is limited because of cumulative cardiotoxicity. A randomized comparison of two doses of epirubicin and doxorubicin showed no difference in response rate, but higher myelotoxicity for epirubicin.^4,5 The use of pegylated doxorubicin in liposomes showed equivalent activity in a randomized phase II trial but at the expense of greater skin toxicity.⁶ It has been suggested that the response rate to ifosfamide is both dose and schedule dependent.^7,8 A randomized phase II study comparing standard-dose ifosfamide 5 g/m² over 24 hours, with ifosfamide 3 g/m² daily for 3 days, reported a response rate of 10% for the lower-dose treatment and 25% for the higher dose.⁹ In contrast, a phase II study using a higher ifosfamide dose of 12 g/m² reported a response rate of only 16%, at the cost of excessive toxicity.¹⁰ However, as a result of dose reductions due to toxicity, the achieved dose intensity was only 75%. This is not unexpected as the pharmacokinetics of ifosfamide are saturable, and further dose escalation results in increased toxicity without increased levels of the active metabolite. Eight studies have compared single-agent doxorubicin with doxorubicin-based combinations.^11-18 None showed a survival advantage for combination therapy over single agent doxorubicin, and this was confirmed in a subsequent meta-analysis.¹⁹ Many studies have compared various doxorubicin-based regimens, with no clear evidence of a benefit.^20-22 A recent phase II study comparing doxorubicin 60 mg/m² plus ifosfamide 6 g/m² or 12 g/m², both given with granulocyte colony-stimulating factor support, showed significantly higher toxicity, and yet a trend toward inferior survival for the high-dose arm.²³

Single-agent chemotherapy with doxorubicin remains, therefore, the standard first-line treatment for the majority of patients. However, there had never been a formal comparison of doxorubicin and ifosfamide in first-line treatment for patients with advanced and/or metastatic soft tissue sarcoma. To address this issue, the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Saroma Group (STBSG) initiated the current study using two different schedules of ifosfamide 9 g/m², based on the results of two previous phase II trials.^9,10

	PATIENTS AND METHODS

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Eligibility Criteria
Patients between the ages 16 and 65 years with histologically confirmed locally advanced or metastatic soft tissue sarcoma were eligible for inclusion in this study. Patients were required to have measurable disease, WHO performance status less than 2, and no prior chemotherapy. All soft tissue sarcoma subtypes were allowable, but patients with Ewing sarcoma, chondrosarcoma, osteosarcoma, and embryonal rhabdomyosarcoma were excluded. GIST had not been defined as a distinct sarcoma subgroup when the study was begun, therefore many GIST patients were not excluded. Other baseline eligibility criteria were adequate renal, hepatic, and bone marrow function (measured creatinine clearance > 70 mL/min, albumin > 25 g/L, billirubin < 30 µmol/L, neutrophils > 2 x 10⁹/L, platelets > 100 x 10⁹/L). Exclusion criteria included a history of other malignancy, prior radiotherapy to a solitary measurable lesion, and active cardiac disease. The study was approved by the institutional review board of each participating institution. All patients gave written informed consent.

Follow-Up Studies
All patients were required to have a physical examination, performance status assessment, measured creatinine clearance, CBC and biochemistry, and tumor assessment before starting treatment. CBCs were repeated weekly.

Treatment
Doxorubicin 75 mg/m² was administered by intravenous bolus every 3 weeks. The ifosfamide short infusion (Ifos 3*3) was administered as follows: a bolus of mesna 0.6 g/m² was followed by ifosfamide 3 g/m² and mesna 1.5 g/m² in 1,000 mL of saline 0.9% over 4 hours, followed by mesna 1.2 g/m² either orally at 2 and 6 hours, or intravenously at 4 and 8 hours, repeated daily for 3 days. Ifosfamide 9 g/m² infusion (Ifos 9) was given as follows: a bolus of mesna 0.6 g/m² was followed by ifosfamide 3 g/m² in 3 L normal saline with mesna 3 g/m² infused intravenously over 24 hours, repeated for 3 days in total followed by either a further 1.8 g/m² of mesna in 1 L of dextrose saline over 12 hours, or 1.2 g/m² mesna orally at 0, 2, and 6 hours. Patients receiving ifosfamide also received sodium bicarbonate 150 mmol intravenously daily during the 3-day infusion. Treatment was continued every 3 weeks until documented disease progression, unacceptable toxicity, or patient refusal, to a maximum of six cycles of chemotherapy. Treatment was delayed by 1 week in the event of incomplete recovery of CBC. In the event of neutropenic fever requiring hospitalization and antibiotics, subsequent treatment was given with a 20% dose reduction. Treatment was discontinued if the serum creatinine rose above 2.5x the upper limit of normal between cycles of treatment, or the measured creatinine clearance was less than 60 mL/min. Treatment was discontinued in the event of grade 3/4 neurotoxicity or if the left ventricular ejection fraction decreased to less than 45%. Patients who experienced somnolesence or other signs of encephalopathy when receiving ifosfamide were treated with methylene blue 50 mg intravenously every 4 hours until symptoms resolved, and subsequently, prophylactively starting 4 hours before the start of the next cycle of treatment until 72 hours after completion.

Evaluation of Response and Toxicity
Response to treatment was assessed after every two cycles of treatment. All responses were confirmed at least 1 month after the initial date of response. WHO criteria were used for the evaluation of response.²⁴ All responses were subject to EORTC STBSG peer review. In case of discrepancy between reviewers the response was down-graded. Progression-free survival (PFS) was measured from the date of registration to disease progression or last contact. Duration of survival was calculated from the date of registration to the date of death. Overall survival (OS) and PFS were estimated by the Kaplan-Meier method; differences between curves were assessed using the log-rank test. Toxicity was evaluated according to the National Cancer Institute Cancer Common Toxicity Criteria.²⁵

Statistical Design and Independent Data Monitoring Committee
The study was designed to detect a 10% (ie, from 15% to 25%) difference in PFS at 1 year. Patients were stratified by institution, grade, and histological subtype (leiomyosarcoma v synovial sarcoma v others). To take into account the multiple comparisons and keep an overall value of .05, each comparison was performed to an of .02; ß was taken to be .2. A total of 780 patients was required. An independent data monitoring committee was to review the data after 163 treatment failures. In addition, an interim analysis of toxicity was planned and carried out after the first 42 patients were treated, with a plan to stop the study if the incidence of neutropenic sepsis or prolonged grade 4 hematologic toxicity (> 7 days) exceeded 25%.

	RESULTS

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Between February 1998 and October 2001, 326 patients were randomized by 40 institutions. Twenty-eight patients (9%) were ineligible—26 due to the delay between the baseline computed tomography scan and the start of treatment, and two had no target lesion.

This study was closed early following the advice of an independent data monitoring committee.

Patient and Tumor Characteristics
Patient characteristics are presented in Table 1. Treatment arms were well balanced for age, sex, performance status, liver involvement, and site of primary tumor. There were more patients with a retroperitoneal primary in the doxorubicin arm.

Safety and Toxicity
Clinically relevant toxicities are presented in Table 3. A higher proportion of patients in the ifosfamide arms had grade 4 neutropenia, leucopenia, and febrile neutropenia. Twenty-one episodes of grade 3 or 4 encephalopathy were recorded in 20 patients receiving ifosfamide, with none being reported for doxorubicin treated patients. Other toxicities were not different between the three groups. There were five toxic deaths (1.5%)—one in the doxorubicin arm (0.9%), three in the Ifos 3*3 arm (2.75%); and one (0.9%) in the Ifos 9 arm. There were four more deaths where the cause was unassessable—one in the Ifos 3*3 arm and three in the Ifos 9 arm.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Progression-free survival (PFS). Doxo, doxorubicin; Ifos 3*3, ifosfamide 3 g/m2 per day in 3 hours over 3 days; Ifos 9, ifosfamide 9 g/m2 over 3 days continuous infusion. N, total number of cases; O, number of observed events.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival (OS). Doxo, doxorubicin; Ifos 3*3, ifosfamide 3 g/m2 per day in 3 hours over 3 days; Ifos 9, ifosfamide 9 g/m2 over 3 days continuous infusion. N, total number of cases; O, number of observed events.

View larger version (28K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Consort diagram; clinical trial flow chart. Ifos 3*3, ifosfamide 3 g/m2 per day in 3 hours over 3 days; Ifos 9, ifosfamide 9 g/m2 over 3 days continuous infusion; CT, chemotherapy; Rx, treatment/additional treatment.

	DISCUSSION

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The standard first-line treatment of advanced soft tissue sarcoma remains single-agent doxorubicin. Combination chemotherapy has not been shown to increase survival in this population of patients despite the higher response rates reported by several randomized trials. Single-agent high-dose ifosfamide is active in soft tissue sarcoma. This is the first study to directly compare doxorubicin and ifosfamide, the two most active single agents in soft tissue sarcoma. The group planned to enroll a total of 760 patients. However, the study was stopped early, on the advice of the data monitoring committee, for futility reasons; that is, a lack of superiority of either of the ifosfamide arms to doxorubicin—a conclusion that was reached after prolonged follow-up.

Response rates were low for all treatment arms. This is likely to be due in part to the stringent response evaluation used including independent verification. Furthermore, 30% of patients registered had leiomyosarcoma; in 49% of these, the primary tumor was gastrointestinal or retroperitoneal in origin, and central pathology review identified 8.6% of patients to have GIST.

Treatment with doxorubicin was better tolerated than either ifosfamide schedule. More patients completed six cycles of doxorubicin (33%) than either ifosfamide arm (20% and 29% for Ifos 3*3 and Ifos 9, respectively), and only 3% of patients receiving doxorubicin stopped treatment due to toxicity or withdrawal of consent, compared with 15% and 21% in the ifosfamide arms. Leucopenia and neutropenia were less marked with doxorubicin than in the two ifosfamide regimens, and this resulted in less febrile neutropenia with this treatment (8%) than in the ifosfamide arms (18% and 20% for Ifos 3*3 and Ifos 9, respectively). Neurotoxicity was a problem in the patients receiving ifosfamide, with 11% of patients experiencing grade 3 or 4 encephalopathy. Stomatitis was more common with doxorubicin, but was rarely worse than grade 2.

The Ifos 9 schedule seemed slightly better than the 3*3 schedule in terms of higher response rate and less toxicity. However, this should be interpreted with care; response rate was not a primary end point, and the higher response rate did not translate into better PFS and OS. A higher proportion of Ifos 9 patients completed six cycles of therapy (31.8% v 20.1% for Ifos 3*3 and Ifos 9, respectively) and fewer discontinued treatment due to toxicity (10.3% v 15.6% for Ifos 3*3 and Ifos 9, respectively). However, grade 3 and 4 anemia was more common with this schedule (17.6% v 11.5%) as was grade 2 and 3 nausea (43.1% v 33.4% for Ifos 3*3 and Ifos 9, respectively).

Many studies have compared single-agent doxorubicin with doxorubicin-based combinations.^11-18 None has shown a survival advantage for combination therapy over single-agent doxorubicin. Two studies showed a higher response rate for the combination.^16,17 However a large study from the EORTC that randomly assigned patients to doxorubicin 75 mg/m²; doxorubicin 50 mg/m², and ifosfamide 5 g/m²; or cyclophosphamide, vincristine, doxorubicin, and dacarbazine; reported no difference in response rate, remission duration, or OS between the three arms, though myelosuppression was more common in the doxorubicin plus ifosfamide–treated patients.¹⁸ A subsequent meta-analysis carried out by the Cochrane Group showed no significant difference in response rate or survival for combination therapy over single-agent doxorubicin.¹⁹

Many studies have compared various combination regimens. Antman compared the combination of doxorubicin and dacarbazine and the same regimen with the addition of ifosfamide and mesna. While response rates and time to progression were better with ifosfamide and mesna, there was a trend toward improved survival for the doublet (13.3 v 11.9 months).²⁰ A study comparing doxorubicin and dacarbazine with the same combination plus either cyclophosphamide or actinomycin showed no difference in outcome for the triplet regimens.²⁰ A randomized study comparing the combination of doxorubicin, dacarbazine, cyclophosphamide, and vincristine with an alternating schedule of doxorubicin and dacarbazine with cyclophosphamide and vincristine showed a lower response rate for the alternating combination, but no significant difference in OS.²²

The role of dose intensification in patients with advanced sarcoma is unclear. A pilot study comparing doxorubicin (60 mg/m²) and ifosfamide either at a dose 6 g/m² or 12 g/m² with granulocyte colony-stimulating factor was too small to draw any reliable conclusions.²³ However, the dose-intensified arm was associated with significantly worse toxicity and a trend toward worse survival. A phase III trial comparing standard-dose doxorubicin 50 mg/m² and ifosfamide 5 g/m², or an intensified arm combining doxorubicin 75 mg/m² and ifosfamide 5 g/m² with granulocyte-macrophage colony-stimulating factor support showed no difference in response rate or OS, though the PFS rate was higher in the dose-intensified arm.²⁶ Whether the doses used in the dose-intensified arm were still too low is being addressed in the current EORTC phase III study randomly assigning patients to either doxorubicin 75 mg/m² or doxorubicin 75 mg/m² + ifosfamide 10 g/m². High response rates have been reported for ablative therapy with ifosfamide 12 g/m², etoposide 800 mg/m², cisplatin 200 mg/m², and hematopoietic stem-cell support as consolidation therapy in the phase II setting, and this strategy is being evaluated in an ongoing study.²⁷

A number of studies have examined prognostic factors in soft tissue sarcomas. A review of 2,185 patients from the EORTC showed that absence of liver metastases, young age, and high-grade tumor were associated with a higher response to treatment, whereas performance status, low histologic grade, and a long disease-free interval were associated with an improved OS.² There is evidence that some histologic subtypes are more sensitive to chemotherapy than others. Response rates for leiomyosarcoma are generally accepted as being lower than for synovial sarcoma, with the series from the EORTC reporting PFS rates at 3 months of 44% and 77%, respectively.^28-31 Because of the small numbers of patients in each subgroup in this study, it is not possible to comment reliably on whether individual histologic subtypes responded differently to chemotherapy, or were more likely to be long-term survivors (> 3 years; Appendix Table A1, online only). A meta-analysis of all first-line ifosfamide-based regimens is ongoing.

There was significant discrepancy between the local pathology report and the central review for both histologic subtype and Trojani grade. This shows the importance of independent pathology review in any prospective study of soft tissue sarcoma. These discrepancies may invalidate the initial stratification based on histologic type and grade. New developments will hopefully come with improvement in our understanding of the molecular genetics of sarcoma and identification of targets for new drugs.³²

Standard-dose doxorubicin was as effective as, and better tolerated than the two ifosfamide regimens examined, and remains the treatment of choice for the majority of patients with advanced soft tissue sarcoma.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Paul Lorigan, Jaap Verweij, Zsuzsa Papai, Sjoerd Rodenhuis, Axel Le Cesne, Michael G. Leahy, John A. Radford, Martine M. Van Glabbeke, Anne Kirkpatrick, Pancras C.W. Hogendoorn, Jean-Yves Blay

Administrative support: Martine M. Van Glabbeke, Anne Kirkpatrick

Provision of study materials or patients: Paul Lorigan, Jaap Verweij, Zsuzsa Papai, Sjoerd Rodenhuis, Axel Le Cesne, Michael G. Leahy, John A. Radford, Pancras C.W. Hogendoorn, Jean-Yves Blay

Collection and assembly of data: Martine M. Van Glabbeke, Anne Kirkpatrick

Manuscript writing: Paul Lorigan, Jaap Verweij, Sjoerd Rodenhuis, Anne Kirkpatrick, Jean-Yves Blay

Final approval of manuscript: Paul Lorigan, Jaap Verweij, Zsuzsa Papai, Sjoerd Rodenhuis, Axel Le Cesne, Michael G. Leahy, John A. Radford, Martine M. Van Glabbeke, Anne Kirkpatrick, Pancras C.W. Hogendoorn, Jean-Yves Blay

	Appendix

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	ACKNOWLEDGMENTS

 
We acknowledge the contribution of all the members of the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group, and of the patients who took part in this study.

We are grateful to the participants to EORTC 62971 for recruiting patients [pts] and supplying data for the study: A.T. Van Oosterom, UZ Gashuisberg, Leuven, BE (14 pts), L. Svancarova, National Cancer Institute, Bratislava, SK (14 pts), M. Verrill, General Hospital, Newcastle, GB (13 pts), Q. Van Hoesel, University Medical Centre, Nijmegen, NL (13 pts), I. Judson, Royal Marsden Hospital, London, GB (11 pts), P. Schöffski, Medizinische Hochschule, Hannover, DE, now at UZ Gashuisberg, Leuven, BE (11 pts), O.S. Nielsen, University Hospital, Aarhus, DK (11 pts), J. Whelan, University College Hospital, London, GB (9 pts), C. Kamby, University Copenhagen, Herlev, DK (9 pts), J-B. Vermorken, Universitair Ziekenhuis, Edegem, BE (8 pts), H.T. Mouridsen, Rigshospitalet, Copenhagen, DK (7 pts), W. Ruka, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, PL (7 pts), H.J. Keizer, University Medical Centre, Leiden, NL (5 pts), R. Issels, Klinikum Grosshadern, München, DE (5 pts), P. Woll, City Hospital, Nottingham, GB, now at Weston Park Hospital, Sheffield, GB (5 pts), A. Murias, Hospital Insular de Gran Canaria, Las Palmas, ES (2 pts), W.P. Steward, Royal Infirmary, Leicester, GB (2 pts), W.T.A. Van Der Graaf, University Medical Center, Groningen, NL (1 pt), R.L. Jansen, Academisch Ziekenhuis, Maastricht, NL (1 pt), F. Mayer, Centre G-F. Leclerc, Dijon, FR (1 pt), D. Bissett, University Medical School, Aberdeen, GB (1 pt), O. Merimsky, Sourasky Medical Center, Tel Aviv, IL (1 pt).

	NOTES

 
Supported by Grants No. 5U10-CA11488-27 through 2U10-CA11488-36 from the National Cancer Institute (Bethesda, MD); and by Cancer Research UK.

Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002; Oral Presentation Connective Tissue Oncology Society, San Francisco, CA, October 2002.

This article's contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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

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Submitted November 24, 2006; accepted April 23, 2007.

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