Response rate (complete plus partial response: CR+PR) has traditionally been used to assess the efficacy of cytotoxic agents. However, for a tumour such as STS with limited sensitivity to chemotherapy, and in patients with metastatic disease, chemotherapeutic response (complete and partial) is not predicted by the same factors when analysed retrospectively and, therefore, response should not be the only endpoint for the evaluation of new agents and combinations in this disease. It is now increasingly recognised that progression-free survival (PFS) and PFS rates at 3 and 6 months may well be more meaningful measures of the benefit of therapy than objective response rate [Van Glabbeke 2002, Le Cesne ECCO 2003].

The European Organization for Research and Treatment of Cancer (EORTC) has estimated progression-free rates (PFR) for various groups of soft-tissue sarcoma patients from their clinical trials database, to provide reference values for conducting phase II studies with PFR as the principal end-point. Consequently, for second-line therapy, a 6-month PFR of >14% would suggest a drug activity, and >8% would suggest inactivity [Van Glabbeke 2002, Le Cesne ECCO 2003]. In addition, stable disease (SD) including minor shrinkage not qualifying as partial response (PR) may also be clinically meaningful for such patients. Thus tumour control rate, which includes patients who achieve CR, PR, and SD, and clinical benefit rate, defined as CR+PR+SD >24 weeks are additional measures of clinical efficacy that may be more meaningful than response rate in the assessment of agents for the treatment of STS. This is especially the case when assessing treatments in patients whose disease has already progressed on at least one previous therapy.

Many patients will experience progression of the STS despite these current agents. When current chemotherapy agents (i.e. doxorubicin, ifosfamide and dacarbazine) are used in second-line, response rates are generally lower than when used as first-line treatment and clinical benefit is unproven [van Oosterom 2002]. Phase II studies with other drugs as single agents have not reported evidence or moderate evidence of antitumour activity [Le Cesne 2009]. Gemcitabine and docetaxel are frequently used in combination as salvage therapy despite the fact that both drugs, when administered in monotherapy, are considered inactive or minimally active for STS [Fleming 2008, Sleifjer 2008]. To date, 4 articles have been published on gemcitabine plus docetaxel as second-line therapy for STS: 1 randomised phase II trial in metastasic disease [Maki 2007], 1 phase II uncontrolled study in uterine leiomyosarcoma [Hensley 2008] and 2 retrospective series [Ebeling 2008, Bay 2006]. Results of another randomised phase II study conducted in patients with metastatic or relapsed leiomyosarcoma were presented at the 2008 meeting of the American Society of Clinical Oncology (ASCO). The authors concluded that no advantage over gemcitabine alone was found as median PFS was 5.5 months with gemcitabine alone vs. 3.4 months with gemcitabine/docetaxel [Duffaud 2008]. In contrast, in the other randomised phase II study median PFS was 3.0 months with gemcitabine alone vs. 6.2 with gemcitabine/docetaxel [Maki 2007].