When to Consider Doxorubicin Alone or in Combination With Ifosfamide for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma?
Results of an EORTC Soft Tissue and Bone Sarcoma Group phase III randomised trial
A study conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group and published in the April issue of Lancet Oncology does not support administration of intensified doxorubicin and ifosfamide regimen for palliation of advanced or metastatic soft tissue sarcoma, unless the treatment objective is to shrink the tumour.
For most cases of advanced sarcoma, clinicians rely on conventional chemotherapy for palliation, which is somewhat effective, but only few patients achieve an objective response. Histological diagnosis can be used to guide treatment for some sarcomas: e.g. paclitaxel for angiosarcoma, gemcitabine plus docetaxel for leiomyosarcoma and undifferentiated pleomorphic sarcoma, or ifosfamide is more favoured for synovial sarcoma and less so for leiomyosarcoma.
Doxorubicin and ifosfamide have been used to treat patients with advanced and metastatic soft tissue sarcoma for more than 30 years and still have an important role. But, whether doxorubicin alone or in combination with ifosfamide should be used in routine practice is still controversial.
The EORTC trial 62012 assessed whether the addition of ifosfamide to doxorubicin improves survival compared with doxorubicin alone in that setting. This intergroup phase III randomised controlled study was conducted at 38 hospitals in ten countries: Belgium, Canada, Denmark, France, Germany, Slovakia, Spain, Switzerland, The Netherlands, and the United Kingdom.
Doxorubicin vs. doxorubicin/ifosfamide
Between April 2003 and May 2010, the EORTC researchers randomised 455 patients, aged 18 to 60 years, with unresectable locally-advanced or metastatic high-grade soft tissue sarcoma to receive either doxorubicin alone (228 patients) or intensified doxorubicin plus ifosfamide (227 patients, combination group) as first-line treatment.
At a median follow-up of 56 months in the doxorubicin alone group and 59 months in the combination group, no significant difference was observed in median overall survival, 12.8 months in the doxorubicin alone group and 14.3 months in the combination group (hazard ratio [HR] 0.83; stratified logrank test p = 0.076).
Median progression-free survival was significantly higher in the combination group than for the doxorubicin alone group, 7.4 months vs. 4.6 months (HR 0.74, stratified log-rank test p = 0.003).
More patients in the doxorubicin and ifosfamide group than in the doxorubicin alone group achieved an overall response (26% versus 14%; p < 0.0006).
The most common grade 3 and 4 toxic effects were all more common in the combination than in the doxorubicin alone group: leucopenia (43% vs. 18%), neutropenia (42% vs. 37%), febrile neutropenia (46% vs. 13%), anaemia (35% vs. 5%), and thrombocytopenia (33% vs. <1%).
How can the study data be used to guide clinical practice?
Although, powered to study overall survival as the primary endpoint, this trial failed to show a statistically significant improvement in this outcome. However, the investigators did note a clinically meaningful 2,8 month improvement in median progression-free survival and a greater proportion of patients responded to the combination therapy as well.
The study investigators reasoned, as explained by Dr Ian Judson of the Royal Marsden Hospital in London, UK who coordinated the study, in an accompanied EORTC news published on 28 March “… if the goal of treatment is to control the disease, then administering doxorubicin alone is appropriate. On the other hand, if the goal is to shrink the tumor before another intervention or to relieve symptoms, then combination treatment is justifiable. The observed lack of improvement in overall survival points to the need for better treatments for patients with this disease.” There might be some clinical situations for which delaying disease progression for as long as possible is the priority; for example, in case of nerves involvement.
“However, this study only recruited patients up to age 60 years. Although some older patients can tolerate intensive combination treatment, the regimen used in this study is very myelosuppressive, therefore the data cannot be extrapolated to patients older than 60 years”, the authors wrote in their article.
Individual sarcoma subtypes are being treated increasingly differently. This fact might explain why less than half of the patients in the doxorubicin group received ifosfamide as a second-line treatment.
The investigators also compared their results with results from a recent phase III study that compared doxorubicin in a combination with an alkylating agent palifosfamide, and in which the combination treatment did not also improve progression-free survival. However, pazopanib has recently been approved for the treatment of soft tissue sarcoma on the basis of its effect on progression-free survival.
The EORTC trial 62012 was supported by Cancer Research UK, EORTC Charitable Trust, United Kingdom National Health Service, Canadian Cancer Society Research Institute, and an Educational Grant from Amgen.
The study was presented at ESMO 2012 Congress in Vienna.
Judson I, Verweij J, Gelderblom H, et al. for the European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. The Lancet Oncology 2014; 15(4): 415-423.