Salvage Therapy in Advanced Adult Soft Tissue Sarcoma: A Systematic Review and Meta-Analysis of Randomized Trials

Abstract

There is some evidence that salvage therapies after first-line failure are able to improve outcome in metastatic soft tissue sarcoma (STS). Trabectedin, gemcitabine-based therapy, and pazopanib are currently approved drugs used after conventional upfront treatment. This meta-analysis reviews the benefit of new agents used in randomized trials in comparison with no active treatments or older agents for recurrent/progressed STS. The results show that modern drugs confer a statistically significant 3-month benefit in terms of overall survival, and an increase in response rate. Despite a limited improvement in outcome, currently approved second-line therapy should be offered to patients with good performance status.

Improved survival for extremity soft tissue sarcoma treated in high‐volume facilities

“…noted that higher-volume institutions experienced fewer inpatient deaths than lower-volume institutions in a number of conditions, but with substantial variation in the magnitude, and implied clinical significance, of the survival benefit.For instance, entities such as pancreatic and esophageal cancers demonstrated clear superiority at high-volume centers, 20 likely due to the rarity and complexity of diagnosis and management, while more common and straightforward procedures such as colon cancer showed a difference of much less clinical significance 33. Soft tissue sarcoma compares more favorably to the magnitude of differences seen in rare malignancies requiring multidisciplinary management, and treatment of STS in a high-volume center demonstrated a clear long-term survival benefit, not simply differences in short-term adverse events or treatment decisions.Recent efforts to improve survival in soft tissue sarcoma have generally ended disappointingly with little deviation from the results of standard treatment 34,35. Outcome improvement in sarcoma has traditionally centered on optimizing surgical techniques, introducing adjuvant treatments, and manufacturing new medical therapies.Interestingly, it was the use of radiation, and not chemotherapy, that resulted in a survival benefit in our multivariate analysis, further highlighting the need for effective systemic treatment.…”

Aldoxorubicin: a tumor-targeted doxorubicin conjugate for relapsed or refractory soft tissue sarcomas

“…Salvage therapies in advanced or metastatic STS after initial or first-line treatment have been shown to confer an absolute benefit in OS and PFS by 3.3 and 1.6 months, respectively, and a near doubling of ORR when compared with control. 21 Furthermore, survival after failure of first-line therapy accounts for >70% of the entire OS despite postprogression therapies and crossover to other agents that may potentially dilute the absolute gain – altogether highlighting the activity of new agents even in treatment-refractory STS. 21 However, despite these advances in therapies after initial treatment of advanced STS, prognosis remains dismal with a median OS of 8–12 months.…”

“… 21 Furthermore, survival after failure of first-line therapy accounts for >70% of the entire OS despite postprogression therapies and crossover to other agents that may potentially dilute the absolute gain – altogether highlighting the activity of new agents even in treatment-refractory STS. 21 However, despite these advances in therapies after initial treatment of advanced STS, prognosis remains dismal with a median OS of 8–12 months. 21 To this end, aldoxorubicin shows promise in fulfilling an unmet need for effective treatments in relapsed or refractory advanced STS.…”

“… 1 , 18 – 20 Significant improvements in outcomes (ORR, PFS, and OS) are still seen in previously treated patients with advanced or unresectable STS and good PS; in particular, clinical benefit was seen when modern therapies (single-agent or combination therapies developed during the trabectedin era) were compared with older, conventional agents or best supportive care after failure of first-line therapies. 21 In the modern era, therapies after first-line treatment are increasingly being tailored to histologic and molecular subtypes of advanced STS including high-dose ifosfamide in SS, 22 , 23 gemcitabine and docetaxel in UPS or LMS (particularly uterine LMS), 24 – 27 trabectedin in LMS or LPS (particularly myxoid/round cell LPS), 28 pazopanib in all STS subtypes except LPS, 29 and eribulin in LPS. 30 …”

“…Furthermore, despite the availability of therapies for STS when standard treatments have failed (salvage therapies), prognosis remains poor in relapsed or refractory STS patients with a median OS of 8–12 months. 21 The rational and clinical development of novel agents to improve outcomes in this area of high unmet need is desperately warranted. In this review, we highlight the clinical development of aldoxorubicin, a doxorubicin derivative with promising activity in the treatment of advanced STS.…”