Efficacy of trabectedin in malignant solitary fibrous tumors: a retrospective analysis from the French Sarcoma Group

Solitary fibrous tumors (SFTs) are rare soft-tissue sarcomas with an estimated incidence of < 0.1/100,000/year [1]. Initially described in pleura, it is now established that SFTs can occur in almost any extra-pleural site. They develop mainly in people aged 50–70 years, with a gender ratio of 1:1.

Solitary fibrous tumors constitute a heterogeneous group of rare spindle-cell tumors, with an unpredictable course. Morphologically, SFTs are characterized by a combination of alternating hypocellular and hypercellular areas, separated by hyalinized collagen, with hemangiopericytoma-like vessels. It should be noted that hemangiopericytomas (initially described as a distinct neoplasm of pericytic origin) and SFTs actually constitute a single entity with a morphological continuum [2].

A large majority of cases are benign neoplasms which have an excellent outcome after complete surgical resection [3]. However, a small proportion of cases follow an aggressive course (recurrence after local treatment or metastatic progression). Increased mitotic activity (≥4 mitoses per 10 high-power fields), greater cellularity, cellular polymorphism, and the presence of necrosis are associated with malignant behavior [4].

The standard treatment for localized SFTs is complete surgical resection. No consensus exists on the treatment of advanced stages of this disease. Anthracycline-based chemotherapy or dacarbazine achieve variable response rates, ranging from 0 to 50 % [5‐8]. In addition, interesting results have been reported in small retrospective series of patients who had received temozolomide plus bevacizumab [9] or tyrosine kinase inhibitors (sunitinib [10], sorafenib [11], pazopanib [12], and imatinib [13]).

Trabectedin (Yondelis(®) [PharmaMar S.A., Madrid, Spain]) is one of the most promising agents to have been developed over the last two decades, and is now an approved treatment for patients with anthracycline/ifosfamide-resistant soft-tissue sarcoma and for those unsuited to these treatments [14, 15]. Objective responses have already been documented in two case reports [16, 17].

This retrospective study describes the efficacy and toxicity of trabectedin in advanced SFTs.

This study is the first to specifically report on the efficacy of trabectedin in a relatively large sample of patients with an advanced malignant solitary fibrous tumor.

We found very interesting results with an overall response rate of 9.1 % and a DCR of 81.8 %. The clinical benefit rate was 72.7 %. However, it should be noted that there is no standard definition of the duration of DCR required to qualify as “clinical benefit” in retrospective studies. The median PFS of 11.6 months (95 % CI = 2.0; 15.2 months) and the median OS of 22.3 months (95 % CI = 9.1 months; not reached) were favorably compared with almost all previous results obtained using conventional chemotherapy or a targeted therapy (Table 4).

The strength of this work was the use of the Growth-Modulation Index, a relevant parameter which takes into account the natural course of solitary fibrous tumors. Based on the fact that SFTs are usually slowly progressive diseases, and the fact that TTPs tend to be shorter with successive lines of treatment, a high GMI strongly suggests drug activity.

Cousin et al. showed that GMI was strongly correlated with OS in pre-treated advanced soft-tissue sarcomas [22]. More recently, Penel et al. have shown that a GMI >1.33, as reported in our study, was strongly correlated with improved PFS and even OS in advanced soft-tissue sarcoma patients receiving trabectedin as a salvage therapy [23].

Interestingly, we found long-lasting responses with trabectedin, even with non-indolent disease. Indeed, two patients had a long-lasting response in disease that had been rapidly progressive before introducing trabectedin (PFS of 11.0 months and 12.3 months after trabectedin, with a GMI of 3.61 and 4.12, respectively), thus highlighting the impact of trabectedin on the natural course of this disease. A further patient had non-progressive disease for 30 months after starting trabectedin therapy (which lasted 9 months) despite presenting with disease progression only 7 months after starting anthracycline-based chemotherapy. In this patient, the predictive GMI was at least 4.28.

Several sources of data suggest the antitumor activity of trabectedin in translocation-related sarcoma. This has been clearly established in the case of myxoid round-cell liposarcoma, where the characteristic chromosomal translocations of t(12;16)(q13;q11) and t(12;22)(q13;q12) code for the fusion transcripts FUS-DDIT3 and EWS-DDIT3, which bind to specific DNA and act as transcription factors for oncoproteins [24]. It has been shown that the antitumor activity of trabectedin in myxoid round-cell liposarcoma was correlated with the expression of the fusion transcript FUS-DDIT3 by interfering with the DNA-binding site of the transcript and by then displacing the transcription factors [25]. Extrapolation of such mechanisms led to the hypothesis that other translocation-related sarcomas (TRS) that express other fusion transcripts may have a particular sensitivity to trabectedin. Thus Le Cesne et al. have provided results from a retrospective pooled analysis of 81 patients with TRS treated with trabectedin in eight phase II trials. They reported an overall control rate of 59 %, a median PFS of 4.1 months, and a median OS of 17.4 months [26]. Promising results have also been reported among TRS patients pretreated with conventional chemotherapy in a randomized phase II trial [27].

As regards SFT of the pleura specifically, a recent study assessed the multimodal management of such tumors (all stages included). Twenty-six of the 68 patients had recurrence after first-line treatment. Nine received trabectedin (as a second- or third-line treatment) with a disease control rate of 78 % and a median TTP of 3.4 months [28]. However, responses were not confirmed at 3 months and, above all, no data were available for TTP on the previous line of treatment. Therefore, in contrast to our study, it is not possible to take into account the natural course of the disease.

Lastly, recent data have highlighted NAB2–STAT6 fusion, which is a result of inversion within chromosome 12, as a distinct molecular feature of SFTs [29, 30]. In the context of SFTs, NAB2 gains an activation domain from the signaling molecule STAT6, which converts a transcriptional repressor (NAB2) into a potent transcriptional activator (NAB2–STAT6) of EGR1 (Early Growth Response 1), a zinc-finger transcription factor. This leads to the constitutive activation of EGR-mediated transcription target genes such as IGF2, FGF2, PDGFD, or FGFR, which are implicated in the differentiation or proliferation pathways.

By analogy with myxoid liposarcoma, we can hypothesize that trabectedin interferes with the physical interaction of the NAB2–STAT6 fusion protein with EGR1 to ensure its specific anti-tumor activity in SFTs. However, no experimental data exist to suggest this specific effect of trabectedin in SFTs.

Even though an important gap remains between progress in diagnosis and advances in therapy, we are now better able to relate specific sarcoma subtypes to specific treatments [14, 31‐34]. Trabectedin could become standard of care in the narrow field of advanced SFTs.

Our data suggest that trabectedin is a very promising systemic treatment for malignant solitary fibrous tumors and should be strongly considered as an option along with other evidence-based therapies such as anthracyclines, dacarbazine, bevacizumab + temozolomide, sunitinib, and pazopanib.

However, we need further clinical investigations along with the experimental data associated with dedicated phase-II trials to understand the mechanisms of action of trabectedin in this rare sarcoma subtype and to validate this treatment prospectively in larger series of patients.