Soft tissue sarcomas are a heterogeneous group of tumours that can be localised anywhere in the body. They comprise more than 50 different histological tumour entities that exhibit great differences in terms of clinical behaviour, pathogenesis and genetic alterations. Almost 50% of cases will develop metastasis at some point during the disease course, with a median overall survival of about one year in that case.
For almost 20 years, the treatment of soft tissue sarcoma was not changed, consisting mainly of anthracyclines- and/or ifosphamide-based chemotherapy. Gemcitabine and docetaxel had shown also an evolving role especially in second line. Recently, many drugs had shown activity in metastatic soft tissue sarcoma, and the new challenge had become to select the patients that will benefit the best from each protocol.
Recently published retrospective analysis of pooled data from two EORTC trials on pazopanib in soft tissue sarcoma tries to characterise long-term responders and survivors. Patients who were treated with pazopanib in phase II (n = 118) and phase III study (PALETTE) (n = 226) were selected. Patient characteristics were studied for their association with long-term outcomes.
Combined median progression-free survival (PFS) was 4.4 months; the median overall survival (OS) was 11.7 months. Approximately one third (36%) of patients had PFS ≥ 6 months and were defined as long-term responders; 34% of patients survived ≥18 months, and were defined as long-term survivors. A median follow-up was 2.3 years. Patient characteristics were compared among four subgroups based on short-/long-term PFS and OS, respectively. In total, 76 patients (22.1%) were both, long-term responders and long-term survivors. The investigators identified 12 patients (3.5%) who remained on pazopanib for more than 2 years: 9 aged younger than 50 years, 9 females, 4 with smooth muscle tumours and 9 with low or intermediate grade tumours at initial diagnosis. The median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years. This retrospective analysis concluded that good performance status, low/intermediate grade of the primary tumour and a normal haemoglobin level at baseline were advantageous for long-term outcome. (1)
Pazopanib is a multikinase angiogenesis inhibitor targeting VEGFR, PDGFR, FGFR, and KIT. In the phase III trial, PALETTE study, pazopanib at 800 mg daily dose was used vs. placebo in patients who had failed at least one prior anthracycline-based regimen. Patients with adipocytic soft tissue sarcoma were excluded. There were 369 patients randomised, and the primary endpoint of PFS per independent review was significantly prolonged with pazopanib (4.6 vs. 1.5 months, p < 0.0001). The OS showed a trend towards improvement, but the difference was not statistically significant (median 12.5 vs. 10.7 months; HR = 0.86 [95% CI 0.67–1.11]). (2)
Another new option for treatment that has evolved in the recent few years is trabectedin, a marine-derived alkaloid that uniquely binds DNA through the minor groove. It is approved in Europe for patients who have failed prior anthracycline-based therapy. Two phase II studies had shown objective response rate of 4% by the WHO criteria with a median PFS of 1.9 months and median OS of 12.8 months. (3)
In another recently published phase III trial, ridaforolimus, an mTOR inhibitor, that shown to prevent cell growth and proliferation in multiple sarcoma cell lines, had shown clinical efficacy in delaying tumour progression to a small but statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. (4)
The new challenge now is to choose the best option of treatment based on the patient and the disease criteria, as well as the choice of the best sequence of treatment in first and second line for metastatic soft tissue sarcoma.
What is the best option for first line treatment in metastatic soft tissue sarcoma?
- Kasper B, , Sleijfer S, Litière S,, et al. Long-term responders and survivors on pazopanib for advanced soft tissue sarcomas: subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072. Ann Oncol 2014; 25(3):719-24.
- van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379:1879–86.
- Yovine A, Riofrio M, Blay JY, et al. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol 2004; 22:890–9.
- Demetri GD, Chawla SP, Ray-Coquard I, et al. Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients After Benefit From Prior Chemotherapy, J Clin Oncol 2013; 31:2485-2492.
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.