Data fails to support routine use of doxorubicin and ifosfamide combination for soft tissue sarcoma

In the oncology community, it is common knowledge that sarcomas are rare tumours. Indeed, their overall incidence is approximately five per 100,000 people every year, making the feasibility of conducting statistically powered clinical trials a significant challenge. Adding to this is the fact that sarcomas are made up of several different histological types, so conducting a clinical trial in one specific histological type of sarcoma is virtually impossible!

Considering our current knowledge, survival data from the EORTC Soft Tissue and Bone Sarcoma Group presented at ESMO 2012 Presidential Symposium was received with great interest. This was a randomized phase 3 trial (EORTC 62012), designed to evaluate single agent doxorubicin versus doxorubicin plus ifosfamide as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma. Professor Winette van der Graaf from Nijmegen, The Netherlands, explained that “the study was initiated to address concerns that previous studies comparing these agents in soft tissue sarcomas had used suboptimal doses of ifosfamide”, adding that “non-randomized data had suggested that a higher dose of this drug could increase response rate and progression-free survival”.

In this trial, 455 patients aged 18−60 years with locally advanced or metastatic, grade 2 or 3 soft tissue sarcoma, were randomized to receive either doxorubicin (75 mg/m2, bolus or 72h IC) alone or in combination with ifosfamide (10 g/m2 over 4 days with mesna and pegfilgrastim) as first- line treatment. Randomization was stratified by performance status, age, presence or absence of liver metastases and histological grade. Patients were treated every 3 weeks until either disease progression or a maximum of 6 cycles had been administered. Professor van der Graaf advised that after a median follow-up of 56 months, no significant difference in overall survival (OS) was seen between the treatment arms. Median OS was 14.3 months with doxorubicin/ifosfamide and 12.8 months with doxorubicin (HR 0.83; 95% CI: 0.67−1.03, p=0.076), and OS at 1 year was 60% with doxorubicin/ifosfamide and 51% with doxorubicin. However, doxorubicin/ifosfamide was associated with a longer progression-free survival (median: 7.4 months versus 4.6 months; HR 0.74; 95% CI: 0.60−0.90, p=0.003) and higher overall response rate (26.5% versus 13.6%) compared with doxorubicin alone, but this was at the cost of increased toxicity.

Professor van der Graaf concluded that the lack of a significant improvement in OS means that the routine use of this intensive combination of doxorubicin and ifosfamide is not supported for soft tissue sarcoma in the palliative setting – the standard treatment remains single-agent doxorubicin. However, she added that that combination therapy could be an option for selected patients aged <60 years if tumour shrinkage was critical, although the toxicity profile of this treatment combination should also be considered. “As always, the pros and cons of combination therapy should be discussed with the patient”, she added.