Outcomes of gemcitabine-docetaxel combination in patients of recurrent or metastatic soft tissue sarcoma: a retrospective analysis

Soft tissue sarcomas (STS) are a heterogeneousgroup of malignancies, of mesenchymal origin, encompassing about 50 differentsubtypes, with a wide spectrum of histological patterns and biological behavior(1,2). Subtypes of STS like leiomyosarcoma, liposarcoma, synovial sarcoma,undifferentiated pleomorphic sarcoma and malignant peripheral nerve sheathtumour are the most common (3). STS can arise anywhere in the body, but mostoriginate in the extremities, less frequently in the trunk, retroperitoneum,head and neck and viscera. They can occur at any age, including children andyoung adults, although more common in middle-age and older adults. In recentyears,though there have been important advances in the understanding of thepathology and molecular biology of this group of cancers, the advances in the therapeuticshave been moderate. About 50% of these tumours develop metastatic recurrences,which are usually fatal, with a median survival ranging from 11 to 18 monthsfrom the diagnosis of advanced disease(4-6). As first line, almost 30% ofpatients treated with doxorubicin and 7-38% patients treated with ifosphamideachieve objective response(7-10).Treatment options for patients with relapseddisease are limited. The role of second line chemotherapy for recurrent STS ismuch less well defined and there is no accepted standard regimen.Moreover, inadvanced STS, the intent of therapy mainly focuses on palliation of symptomsand maintaining an acceptable quality of life.Gemcitabine, as a single agentand in combination with docetaxel have often been used in STS, mainly leiomyosarcomas(a subgroup of STS), where there also have been conflicting results in uterineand non-uterineleiomyosarcomas(11-13).The incidence of many of the individualsubtypes of soft tissue sarcoma is too small to permit large-scale prospectiverandomized controlled trials.

 STSare rare,accounting for less than 1% of adult malignancies and 2% of cancerdeaths (14). Gastro-intestinal stromal tumors (GIST) is the most common subtypeof all sarcomas(15), other common subtypes being leiomyosarcoma, liposarcoma,synovial sarcoma, undifferentiated pleomorphic sarcoma and malignant peripheralnerve sheath tumour (3). Survival estimates for primary localized STS depend onmany factors, including anatomic location and tumour grade(16). Despitetreatment almost half of the patients with STS develop recurrent or metastaticdisease(4-6, 17,18). For primary resectable STS, surgery is the mainstay oftreatment(19,20). For patients with unresectable recurrence or metastaticdisease, systemic chemotherapy with conventional cytotoxic agents remains themain treatment modality, the treatment goal being palliation and ameliorationof symptoms. The National Comprehensive Cancer Network(19) and the EuropeanSociety for Medical Oncology(20), recommend anthracyclines (alone or incombination with other agents like ifosphamide) in most cases as first linetreatment for metastatic STS.Almost 30% of patients treated with doxorubicin (7,8)and 7-38% patients treated with ifosphamide achieve objective response (9,10).These two drugs represent the large majority of first line treatments.Therapeuticoptions after failure of doxorubicin and/or ifosphamide are limited and thereare no standard recognized therapies. Options include ifosphamide(high dose),trabectadine, gemcitabine in combination with docetaxel or dacarbazine basedregimens(18). Seddon et al. conducted a phase II trial to assess the activityof gemcitabine and docetaxel as first line chemotherapy and found significant activityof this combination in first line setting in unresectable leiomyosarcoma(21).Promisinganti-tumor activity in patients with metastatic or unresectableSTS has beenreported with gemcitabine alone (22,23) docetaxel alone(24)or in combination (25,26).  Leu et al. confirmedbiological evidence ofsynergistic cytotoxicity(11). The bestresponses have been observed inleiomyosarcoma (LMS) using gemcitabine and docetaxel together, with up to 53%overall response (21, 25). It has often been hypothesized that despite lowerresponse rates, this combinationmight also be efficient with other histologicalsubtypes of sarcomas.The incidence of many of the individual subtypes of softtissue sarcoma is too small to permit large-scale prospective randomizedcontrolled trials.

Current practice:

Forthe majority of STS, there is no evidence that a particular drug sequence isbetter than another and probably most patients with a good performance statusbenefit from exposed to a higher number of available regimens. As alreadymentioned, some STS subtypes are specially sensitive to certain drugs, and thisfact could help in selecting the second line therapy, for example, high-doseifosphamide for synovial sarcoma, trabectedin in myxoidliposarcoma andleiomyosarcoma, gemcitabine with docetaxel or dacarbazine in leiomyosarcoma(27).Studies in the United States(16) and internationally(18) have shown theheterogeneity in treatment patterns in STS following failure of first linetherapy.Consequently, the choice of second line and later-line treatment foradvanced STS should consider these interventions.  These therapies should also be evaluated fortheir efficacy/toxicity ratio and other parameters like median overall survivaland quality of life.

**AIM:**To study the outcomes of gemcitabine-docetaxel combination as second-line systemic chemotherapy in patients of recurrent or metastatic soft tissue sarcomas.

OBJECTIVES:

**PRIMARY:**To study the objective response rate(ORR) of combination of

Gemcitabine-Docetaxel chemotherapy in patients of metastatic/advanced soft

tissue sarcomas.

 **SECONDARY:**To study the toxicity profile, tolerance, progression free

Survival(PFS), and overall survival(OS) in the study population.

STUDY METHODOLOGY

Study design: Retrospective observational Study **(**Analysis of clinical profile and laboratory reports of eligible STS patients treated with during study period. at Tata Memorial Centre(TMC), Mumbai.

 Patient population: The medical records from the Institutional database of patients of advanced/metastatic soft tissue sarcoma diagnosed at TMH between 01.08.2013and 31.10.2016 and completed at least 3 cycles of chemotherapy with Gemcitabine-Docetaxel combination, in the advanced disease/metastatic setting, and undergone/undergoing response evaluation using either CECT/PET-CT/MRI imaging, with at least 2 months of follow-up data.