Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: An exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG)

Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30–June 3, 2008, Chicago, Illinois.
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Abstract

Background

Adult patients with advanced soft tissue sarcomas (STS) are generally treated similarly, regardless of great differences between STS subtypes, disease presentation and patients’ characteristics. As ifosfamide is frequently applied in first line systemic therapy, we aimed to establish prognostic and predictive factors for outcome to ifosfamide-based therapy.

Methods

A retrospective, exploratory analysis was performed on data from 1337 advanced STS patients who received first-line ifosfamide-containing chemotherapy. For predictive factor analysis, 660 patients treated with doxorubicin monotherapy served as comparators.

Results

Independent favourable prognostic factors for overall survival (OS) were good performance status, female gender, low histological grade, extremity primary tumour site and locally advanced disease; for progression-free survival (PFS), the combination of doxorubicin and ifosfamide, locally advanced disease, and tumour entity with a lower risk to progress for synovial sarcoma patients compared to leiomyosarcoma. For response, independent favourable prognostic factors were doxorubicin combined with ifosfamide, higher histological grade, and histology with synovial sarcoma patients having the highest chance to respond. Predictive factor analysis showed that compared to doxorubicin monotherapy, patients who benefited less from ifosfamide-based therapies were leiomyosarcoma patients in terms of OS, and patients with liposarcoma for response. No predictive factors were found for PFS.

Conclusion

In this study, we established an independent set of prognostic and predictive factors for outcome to ifosfamide-based chemotherapy in advanced STS patients. This study provides important information for the interpretation and design of clinical trials for specific STS entities and may contribute to further treatment individualisation of advanced STS patients.

Introduction

Soft tissue sarcomas (STS) form a rare group of tumours comprising over 40 histological entities differing in pathogenesis, clinical behaviour and sensitivity to systemic agents.1, 2, 3, 4 Despite this, together with differences in disease presentation and patients’ characteristics, adult patients with advanced non-gastrointestinal stromal tumours (GIST) STS are in general treated similarly. Palliative chemotherapy can be considered for patients with advanced disease, but until now, only a few agents with consistent anti-tumour activity have been identified. Of these, doxorubicin is regarded first line standard therapy.5

Another drug with anti-tumour activity is ifosfamide. In phase II trials, ifosfamide produced outcomes comparable to those achieved by doxorubicin.6 Moreover, a recent phase III trial comparing two different schedules of ifosfamide to doxorubicin was prematurely stopped as an interim analysis revealed that no statistical differences between the three arms would be shown.7 Apart from its application as monotherapy, ifosfamide is frequently part of combination regimens, in particular with doxorubicin, although evidence is lacking that such combinations yield an overall survival benefit over monotherapy.8

Despite its frequent use in STS patients and in contrast to doxorubicin-containing regimens,9 data on prognostic and predictive factors for outcome to ifosfamide-containing regimens are not available from large series. Identification of such factors is essential for patient management and clinical trial design, in particular for STS given its heterogeneity. In this study, an exploratory, retrospective analysis for prognostic and predictive factors for outcome to ifosfamide-containing treatment in first-line was performed on advanced STS patients treated in prospective trials of the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) aiming to establish independent prognostic and predictive factors for best overall response (RR), progression-free survival (PFS) and overall survival (OS).

Section snippets

Patients

Patients were treated in one of ten prospective EORTC-STBSG trials that included a treatment arm with ifosfamide, doxorubicin, or the combination (Table 1).7, 10, 11, 12, 13, 14, 15, 16, 17, 18 Of 2112 patients captured in our data-set, 115 patients who received prior (neo)-adjuvant chemotherapy were excluded. Details on eligibility criteria, treatment regimens and outcomes have been published.7, 10, 11, 12, 13, 14, 15, 16, 17, 18

End-points

The end-points of this analysis were RR, PFS and OS. Responses

Results

Collectively, 660 patients received doxorubicin alone, 414 ifosfamide alone and 923 a combination of doxorubicin and ifosfamide (Table 1). Table 2 depicts patients’ characteristics.

Predictive factor analysis

Compared to doxorubicin monotherapy, PFS (p = 0.044, log-rank test) (Fig. 2) and RR (20.4% versus 24.7% (p = 0.0415, χ2 test)) were better for ifosfamide-based therapies. OS did not differ (Fig. 1). Predictive factor analyses revealed that compared to doxorubicin monotherapy, patients who benefited less from ifosfamide-based therapies in terms of OS were patients with leiomyosarcomas (p = 0.0247, interaction test) (Fig. 3). There was a trend that patients with liver metastases did better after

Discussion

Doxorubicin and ifosfamide, alone or in combination, are the most widely used first line agents for the treatment of advanced STS patients. Previously, we have determined prognostic factors for outcome to doxorubicin-based regimens.9 As such factors are currently missing for ifosfamide-based, we established a set of independent prognostic and predictive factors for outcome to ifosfamide-based therapy in terms of OS, PFS and RR.

Good performance status, female gender, non-metastatic disease,

Authors’ contribution

Conception and design: Stefan Sleijfer, Monia Ouali, Martine van Glabbeke, Jaap Verweij.

Financial support: none.

Administrative support: all.

Provision of study materials or patients: Stefan Sleijfer, Anders Krarup-Hansen, Sjoerd Rodenhuis, Axel Le Cesne, Pancras C.W. Hogendoorn, Jaap Verweij, Jean-Yves Blay.

Collection and assembly of data: Stefan Sleijfer, Monia Ouali, Martine van Glabbeke, Anders Krarup-Hansen, Sjoerd Rodenhuis, Axel Le Cesne, Pancras C.W. Hogendoorn, Jaap Verweij, Jean-Yves

Conflict of interest statement

None declared.

Acknowledgement

This publication was supported by the EORTC Charitable Trust.

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