Methods
To achieve our stated objectives, we reviewed and discussed data from clinical studies of pazopanib, trabectedin, and eribulin. When selecting prospective clinical studies, the level of evidence was considered to avoid positional bias and maintain objective impartiality. In accordance with our review criteria, from reports published up to December 2016 of clinical studies of the three drugs that enrolled patients with advanced STS who had received previous treatment, we used data from phase III studies (highest evidence level), subgroup analyses of phase II and III studies according to histologic subtype, and prospective clinical studies in Japanese. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.
In the first section, “
Review of Key Evidence”, we assess the efficacy of each drug by using data from the main analyses of the relevant phase III studies, which have the highest level of clinical evidence. In the second section, “
Review of Histologic Subtypes”, we evaluate the efficacy of each drug for different histologic subtypes of STS. Because the numbers of patients with each histologic subtype were limited and we aim to maximize the data collected, we reviewed the relevant data from subgroup analyses of both phase II and phase III studies. In the third section, “
Safety Considerations”, we review the safety of each drug. To include prospective information on safety of each drug in Japanese patients, we used safety data from the phase III studies, subgroup analyses of data from Japanese patients included in the international phase III study, and two phase II studies conducted in Japan. In addition, we discuss the safety issues to be considered when selecting patients for treatment with pazopanib, trabectedin, and eribulin, based on our combined clinical experience.
Discussion
In light of new treatment options that have been developed with the aim of improving OS in patients with advanced STS, we propose in this article an optimal treatment approach to the use of pazopanib, trabectedin, and eribulin based on current evidence from the relevant clinical studies. In addition, regarding the safety profiles of each drug, the review of clinical study data and our experience in clinical practice may be useful for the selection of appropriate patients for treatment with these drugs. The primary end points of pivotal studies were used in this article. However, because the primary end point of trabectedin and eribulin was OS, and that of pazopanib was PFS, the results of these studies were not directly comparable. For this reason, in this article we have described, in an objective manner, the characteristics of these drugs.
In Japan, pazopanib, trabectedin, and eribulin can be used for all histologic subtypes of STS. However, each drug has a different profile. For the proper use of these drugs, and to maximize their benefit to patients, it is necessary to understand the efficacy and safety profiles of each drug, and to provide treatment in accordance with evidence-based medicine. To achieve these objectives in clinical practice, first, anticancer drugs should be selected according to their sensitivity to histologic subtypes and safety profile on the basis of the findings of clinical trials, as described in this article. In addition, consideration of expert opinions based on clinical experience is recommended. For instance, when choosing an anticancer drug for second-line treatment of liposarcoma and leiomyosarcoma, in addition to the clinical evidence, safety issues such as the onset or worsening of cardiac dysfunction caused by doxorubicin should be considered. Furthermore, retrospective studies from Japan have shown the inferior efficacy of pazopanib in the treatment of liposarcoma compared with other subtypes [
35,
36]. Ifosfamide can also be an option for second-line and later treatment for metastatic STS, especially in cases of fibrosarcoma and synovial sarcoma. However, the response rate for leiomyosarcoma has been shown to be lower than for fibrosarcoma and synovial sarcoma [
37‐
39]. In addition, this treatment requires hospitalization, and attention should be paid to the possibility of renal dysfunction. The efficacy of gemcitabine, given alone or in combination with other drugs, has been studied. In a randomized phase II study in patients with metastatic soft tissue sarcoma, the combination of gemcitabine and docetaxel resulted in superior PFS and OS compared with gemcitabine alone, but with increased toxicity [
40]. However, the combination regimens of gemcitabine with dacarbazine or vinorelbine have not been approved in Japan.
For other histologic subtypes, pazopanib may be effective for synovial sarcoma on the basis of the results of the subgroup analysis of the international phase III study, although the number of patients was limited (
n = 30) [
16]. Predictive analysis, using Cox models, of PFS according to histologic subtype also showed the effectiveness of pazopanib against synovial sarcoma, with no significant interaction between histologic subtypes [
16]. The number of STS patients with histologic subtypes other than liposarcoma and leiomyosarcoma is small, and it is therefore difficult to evaluate the efficacy of each drug in clinical studies. The phase III studies of trabectedin and eribulin included patients with leiomyosarcoma and liposarcoma but not undifferentiated pleomorphic sarcoma [
17,
18]. In contrast, the phase III study of pazopanib included patients with undifferentiated pleomorphic sarcoma [
16]. Therefore, it is inappropriate to discuss in this article the treatment of undifferentiated pleomorphic sarcomas. The phase II studies of pazopanib, trabectedin, and eribulin included patients with undifferentiated pleomorphic sarcoma, but the data are insufficient to enable us to make specific recommendations for treatment [
20,
29,
41,
42]. A more practical approach to evaluation of the effectiveness of pazopanib, trabectedin, and eribulin against specific histologic subtypes of STS is recommended, namely to generate evidence by obtaining clinical data retrospectively. For example, the Japanese Musculoskeletal Oncology Group have conducted a study to evaluate the effects of pazopanib in Japanese STS patients, based on safety data gathered by post-marketing surveillance and efficacy data obtained at the study group sites [
35]. It is expected to accumulate real-world data including information on various histologic subtypes.
To provide more effective treatment, it is preferable to identify biomarkers. Trabectedin has been shown to reduce the risk of progressive disease or death in patients with advanced translocation-related sarcoma [
22]. In addition, tumor biomarkers for safety and efficacy end points have been incorporated into the phase III study of eribulin as a planned exploratory analysis [
18]; the results are awaited with interest.
It may be necessary in future clinical studies to evaluate sequential therapy, for example the efficacy in terms of OS of trabectedin after eribulin or OS of eribulin after trabectedin in the treatment of liposarcoma. In a phase III study, eribulin monotherapy resulted in no significant difference in PFS but significantly improved OS compared with dacarbazine, suggesting that eribulin might have induced biological effects on tumor vascularization, microenvironment, and metastasis [
18].
We have proposed treatment strategies for advanced STS by histologic subtype as well as safety considerations based on our clinical experience in the use of pazopanib, trabectedin, and eribulin. These would benefit patients by maximizing the therapeutic effects and enhancing the proper use of these drugs.
Acknowledgements
Sponsorship for this article, including processing charges, was funded by Eisai Co., Ltd (Tokyo, Japan).
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Medical writing assistance was provided by Hiroki Matsushita of ShiftZero K.K. (Tokyo, Japan) and editorial assistance was provided by Rie Ishibashi on behalf of inScience Communications, Springer Healthcare (Tokyo, Japan). Support for these assistances was funded by Eisai Co., Ltd.