Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine lelomyosarcoma: A Gynecologic Oncology Group phase II trial

Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Gynecologic Oncology (Impact Factor: 3.77). 07/2008; 109(3):329-34. DOI: 10.1016/j.ygyno.2008.03.010
Source: PubMed


Fixed-dose rate gemcitabine plus docetaxel is active as second-line therapy for metastatic uterine leiomyosarcoma. We sought to determine the activity of this regimen as first-line treatment.
Eligible women with advanced uterine leiomyosarcoma were treated with gemcitabine 900 mg/m(2) over 90 min, on days one and eight, plus docetaxel 100 mg/m(2) on day eight, with granulocyte growth factor support on day nine of a 21-day cycle. Patients with prior pelvic radiation received lower doses. Patients were treated until progression or unacceptable toxicity. Response was assessed every other cycle by RECIST.
Forty-two women enrolled, with 39 evaluable for response. Objective responses were observed in 15 of 42 patients (35.8% overall; complete response 4.8%, partial response 31%, 90% confidence interval 23.5 to 49.6%), with an additional 11 (26.2%) having stable disease. Nineteen of 38 (50%) received six or more cycles of study treatment. Myelosuppression was the major toxicity: neutropenia grade 3 in 5%, grade 4 in 12%; anemia grade 3 in 24%; thrombocytopenia grade 3 in 9.5%, grade 4 in 5%. One patient had a grade 3 allergic reaction, 17% had grade 3 fatigue. One possibly-related grade 4 pulmonary toxicity was observed. The median progression-free survival (PFS) was 4.4 months (range 0.4 to 37.2+ months). Among 15 women with objective response, median response duration was 6 months (range 2.1 to 33.4+ months). Median overall survival was 16+ months (range:.4-41.3 months).
Fixed-dose rate gemcitabine plus docetaxel achieves high objective response rates as first-line therapy in metastatic uterine leiomyosarcoma.

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    • "The combination of gemcitabine and docetaxel has recently emerged as a promising treatment for U-LMS, thus representing a valuable addition to doxorubicin and ifosfamide in the treatment of metastatic U- LMS (Table 1) [41]. In three prospective phase II studies the combination of gemcitabine and docetaxel has demonstrated efficacy as first-or second-line therapy for advanced U- LMS associated with a high ORR ranging from 27% to 53%, median PFS from 4.4 to 6.7 months, and median OS from 14.7 to 17.9 months [42] [43] [44]. However, for the combination of Sarcoma gemcitabine plus docetaxel as the second-line therapy, 50% of patients received red blood cell transfusions, 13% received platelet transfusion, and 8% of patients had pulmonary toxicity [42]. "
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    ABSTRACT: The treatment of advanced uterine leiomyosarcomas (U-LMS) represents a considerable challenge. Radiological diagnosis prior to hysterectomy is difficult, with the diagnosis frequently made postoperatively. Whilst a total abdominal hysterectomy is the cornerstone of management of early disease, the role of routine adjuvant pelvic radiotherapy and adjuvant chemotherapy is less clear, since they may improve local tumor control in high risk patients but are not associated with an overall survival benefit. For recurrent or disseminated U-LMS, cytotoxic chemotherapy remains the mainstay of treatment. There have been few active chemotherapy drugs approved for advanced disease, although newer drugs such as trabectedin with its pleiotropic mechanism of actions represent an important addition to the standard front-line systemic therapy with doxorubicin and ifosfamide. In this review, we outline the therapeutic potential and in particular the emerging evidence-based strategy of therapy with trabectedin in patients with advanced U-LMS.
    Sarcoma 06/2015; 2015:1-14. DOI:10.1155/2015/704124
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    • "Furthermore API regimen demonstrated to be extremely toxic, with high incidence of severe adverse effects and two deaths. A better tolerated regimen, characterized by the association of gemcitabine plus docetaxel, achieved high objective response rates as in first-line therapy for metastatic uterine leiomyosarcoma (36%) and in second line treatment (27%) [25] [26]. The same combination has been studied also in patients with localized disease: the recent 3-year follow-up update of SARC 005, using four cycles of gemcitabine/ docetaxel followed by four cycles of doxorubicin in 47 patients with high-risk uterine leiomyosarcoma, showed a progression-free survival rate of 78% at 2 years and 57% at 3 years, which compares favorably with historical controls without adjuvant chemotherapy [27]. "
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    ABSTRACT: Objective: About 50-60% of patients with stage I-II uterine leiomyosarcoma (ULMS), primarily treated with surgery, relapse and die from progressive disease. In this retrospective study we describe the impact of adjuvant chemotherapy in this subset of patients. Methods: 140 women treated from 1976 to 2011 were included in the study. Univariate and multivariate analysis were used to test the association of clinical features and adjuvant treatments with overall survival (OS) and disease-free survival (DFS). Results: 62 women did not receive any further treatment after hysterectomy, 14 had radiotherapy (RT), 52 chemotherapy and 12 chemo-radiotherapy. Chemotherapy based on doxorubicin and ifosfamide combination was used in 54 cases. After a median follow-up of 63months, 87 women (62%) have relapsed, and 62 (44%) have died. The vast majority of patients who relapsed had distant recurrences (72%). The 5year median DFS and OS were 43% and 64% respectively. After 5years of follow up 68.7% of women treated with chemotherapy (±RT) vs 65.6% of patients only observed were alive (p=0.521). In the univariate analysis no factors had a statistical impact on DFS, while number of mitosis (>20×10HPF), age (>60years) and adjuvant radiotherapy were found as negative prognostic factors for OS. In the multivariate analysis only mitosis and age remained significant for OS. Conclusion: Adjuvant chemotherapy was not associated with a significant survival benefit and should not be considered as standard of care for patients with stage I-II ULMS until randomized clinical studies will give further information.
    Gynecologic Oncology 06/2014; 133(3). DOI:10.1016/j.ygyno.2014.03.001 · 3.77 Impact Factor
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    • "surgical margins, size, grade etc.) adjuvant chemotherapy, radiotherapy or combined treatment are sometimes offered [3-5]. For women with advanced, unresectable ULMS, chemotherapy is given with palliative intent; however, the median duration of response is limited to 6–8 months [6-8]. Therapeutic options are limited for patients who progress following standard chemotherapeutic regimens, although recently the multitargeted tyrosine kinase inhibitor pazopanib has been approved for this indication [9]. "
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    ABSTRACT: Background Aromatase inhibitors (AIs) have not been used consistently as part of the management of hormone receptor positive uterine leiomyosarcomas (ULMS). As a result, the published data regarding the efficacy of AIs in this subtype of ULMS are sparse. Methods We performed a retrospective electronic medical record review of patients with ULMS treated with an AI, in the 1st or the 2nd line setting, at the Sarcoma Unit of the Royal Marsden Hospital between 2001 and 2012. We assessed progression-free survival (PFS), objective response and toxicities and explored the correlation of the intensity of the hormone receptor status, as well as of the grade with PFS. Results Sixteen patients with measurable advanced ULMS were treated with an AI in our unit. All of them were oestrogen receptor (ER) and progesterone receptor (PgR) positive. Letrozole was used in all patients as 1st line endocrine therapy, while exemestane was mainly prescribed as 2nd line (83%). Median PFS in 1st line was 14 months (95% CI: 0 – 30 months), and prolonged PFS was more likely to be observed in patients with low grade compared to high grade ULMS (20 months vs. 11 months), and in moderately/strongly ER positive compared to weakly ER positive ULMS (20 months vs. 12 months). Best response was partial response (PR) in 2/16 patients (12.5%) and clinical benefit (CB), defined as complete response (CR) + PR + stable disease ≥6 months, was observed in 10/16 patients (CB rate (CBR) 62.5%). Median duration of 2nd line was 3 months and median PFS was not reached. The 1-year progression-free rate for the 2nd line AI was 80%. Best response was PR in one patient and CBR was 50%. AIs were well tolerated in both lines of treatment. Conclusions In this population of patients with hormone positive ULMS, AIs achieved a significant CBR (62.5%) in 1st line, which was retained in 2nd line (CBR: 50%). The relatively prolonged median PFS (14 months), along with the favourable toxicity profile could place AIs among the first choices of systemic treatment in hormone positive ULMS, preferably in strongly positive (>90%), and/ or low grade and low volume disease.
    06/2014; 4(1). DOI:10.1186/2045-3329-4-5
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