Objective. In the era of oral molecular kinase inhibitors, cytotoxic chemotherapy agents are somewhat overlooked, but remain the backbone of treatment for most cancers. Patients with non-gastrointestinal stromal tumor sarcomas, such as leiomyosarcoma, liposarcoma, and undifferentiated high-grade pleomorphic sarcoma (formerly called malignant fibrous histiocytoma), have received doxorubicin and ifosfamide as the backbone of their treatment for over 15 years or more. The goal of this article is to review the data that have led to the use of gemcitabine and docetaxel as a useful combination for patients with metastatic sarcomas, and to comment on possible synergy of the combination. Methods and results. The literature regarding the use of gemcitabine, docetaxel, or both, is reviewed, with emphasis on patients with metastatic sarcoma. Results. Activity of gemcitabine and docetaxel is observed in leiomyosarcoma and undifferentiated high-grade pleomorphic sarcoma. There is apparent schedule dependence of the combination in other cancers; it is unclear if schedule matters in patients with sarcomas. The dose and schedule of gemcitabine and docetaxel examined in phase II studies are probably too high for routine practice. Conclusions. The combination of gemcitabine and docetaxel is an effective option for patients with metastatic sarcoma, increasing the armamentarium for the practicing oncologist in treating this heterogeneous group of diseases. Given the low response rate to docetaxel as a single agent, it is likely that there is true clinical synergy of the combination. Disclosure of potential conflicts of interest is found at the end of this article.

Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future.

Gemcitabine is largely used in the management of sarcomas. We have systematically reviewed all of the fully published trials that investigated a gemcitabine-based regimen in the management of sarcomas and then provided a grade of recommendations and a level of evidence for every recommendation. Because of conflicting results from successive non-randomized phase II trials, gemcitabine activity alone in unselected pretreated soft tissue sarcomas could not be properly assessed. Gemcitabine alone and gemcitabine-docetaxel appeared to both be active in pretreated uterine and non-uterine leiomyosarcoma (1B;I). Gemcitabine-dacarbazine appeared to be active in pretreated unselected soft tissue sarcomas (1B;I). According the GeDDIS phase III trial (not yet fully published), gemcitabine-docetaxel appeared slightly less active than doxorubicine and more toxic than doxorubicine in chemo-naive metastatic soft tissue sarcoma patients. Because of the absence of controlled randomized trials, the benefit of gemcitabine-docetaxel as an adjuvant treatment in high-grade uterine leiomyosarcoma could not be appropriately assessed. The level of activity of gemcitabine/docetaxel in bone sarcomas cannot be ascertained with the available data. The level of evidence supporting the use of gemcitabine-based regimens in sarcoma management is limited. Confirmatory phase III trials are warranted when phase II trials suggest some preliminary activity.

Gemcitabine-based chemotherapy in sarcomas: A systematic review of published trials.

Liposarcoma is one of the most common adult soft tissue sarcomas and consists of three histologic subtypes (well and dedifferentiated, myxoid/round cell, and pleomorphic). Surgery is the mainstay of treatment for localized disease; however for unresectable or metastatic disease, effective treatment options are currently limited. In the past decade, a better understanding of the distinct genetic and molecular aberrations for each of the three histologic subtypes has led to the development of several novel systemic therapies. Data from phase I and early phase II clinical trials have been reported. Despite challenges with conducting clinical trials in liposarcoma, preliminary results for several of these novel, biology-driven therapies are encouraging.

https://www.mdpi.com/2072-6694/5/2/529/pdf

Novel Systemic Therapies in Advanced Liposarcoma: A Review of Recent Clinical Trial Results

Future treatment of soft tissue sarcomas will be driven by histological subtype and molecular abberations

BACKGROUND.

For patients with advanced soft tissue sarcoma (STS), no standard treatment is established after previous chemotherapy with anthracyclines and ifosfamide. Bendamustine hydrochloride is a bifunctional alkylating agent that is not cross-resistant to other DNA-interacting substances including anthracyclines and oxazaphosphorines. It has shown single-agent activity in refractory lymphoma, myeloma, and some solid tumors. A phase 2 study was initiated to evaluate the efficacy of bendamustine in previously treated patients.



METHODS.

Thirty-six of 44 screened patients were included and received a total of 101 cycles (median, 2 cycles; range, 1–8 cycles), 21 as second-line treatment and 15 as third-line treatment. The median age was 55 years (range, 18–79 years). Bendamustine was given as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on 2 consecutive days and repeated every 28 days. Eighty-eight percent of cycles could be given without dose or schedule modification.



RESULTS.

The toxicity profile was mild, consisting of National Cancer Institute Common Toxicity Criteria (CTC) grade 3 neutropenia in 11% and grade 3 anemia in 9% of patients. Nonhematologic toxicities were noticed with CTC grade 3 fever in 3% of patients. No other grade 3 toxicity and no treatment-related toxic deaths were observed. The best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 1 partial remission (3%) and disease stabilizations in 31% of patients. Six of 15 patients (40%) with leiomyosarcoma histology achieved stable disease. The estimated 3-month and 6-month progression-free survival rates were 35.3% and 23.5%, respectively, for all histologic subtypes included.



CONCLUSIONS.

In patients with refractory STS, bendamustine is well tolerated and appears moderately effective, particularly in patients with leiomyosarcoma histology. Cancer 2007. © 2007 American Cancer Society.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.22846

Bendamustine hydrochloride in patients with refractory soft tissue sarcoma: a noncomparative multicenter phase 2 study of the German sarcoma group (AIO-001).

Background: The number of effective cytotoxic agents for the treatment of patients with metastatic adult type soft tissue sarcoma (STS) is limited, when patients have failed anthracyline-based chemotherapy. The aim of this trial was to evaluate the efficacy of gemcitabine in this setting. Methods: Between August 2001 and March 2003 19 patients were eligible to enter. Gemcitabine was administered as a 30-minutes infusion at a dosage of 1 g/m2 on day 1, 8 and 15 every 4 weeks. All patients had progressive disease during (n = 12) or shortly after an anthracycline-based regimen (n = 3). Results: Four of 19 patients did not start study treatment because of fulminant progression. Fifteen patients with a median age 47 years (32–72) were assessable. All patients had received at least one prior treatment regimen (range, 1–6) for metastatic disease containing anthracyclines (n = 15) and ifosfamide (n = 11). To date, a total of 72+ cycles have been applied (median; 3, 1–28+). Seven patients (47%) had progressive disease after completion of two cycles at the first response assessment. One patient (6%) attained a partial remission, and 7 patients (47%) achieved disease stabilisations. One patient is still on treatment after more than 2.5 years. The calculated progression-free rate at 3 and 6 months was 46.7% (CI95%, 21.4–71.9) and 13.3% (CI95%, (0–30.5). 95% of the cycles have been applied without any dose modification or treatment delay. Conclusions: Considering response and progression-free rate as the primary endpoints for phase II trials in pretreated STS, gemcitabine has moderate efficacy.

An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated adult type soft tissue sarcoma

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An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated adult type soft tissue sarcoma