Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group

doi:10.1016/S0959-8049(01)00408-7

European Journal of Cancer

Volume 38, Issue 4, March 2002, Pages 556-559

https://doi.org/10.1016/S0959-8049(01)00408-7 Get rights and content

Abstract

Gemcitabine (2′-deoxy-2′-difluorocytidine monohydrochloride) at a dose of 1250 mg/m² was given as a 30-min intravenous (i.v.) infusion on days 1 and 8 in a 3-weekly schedule to 32 patients with advanced soft-tissue sarcoma (STS) failing first-line chemotherapy. One patient was ineligible due to a delay between the previous chemotherapy and the start of treatment. Of the eligible patients, median age was 53 years (range 23–73 years). The predominant histological subtype was leiomyosarcoma in 12 patients (38%). The median number of cycles was three (range 1–8 cycles) with a median total dose of gemcitabine of 6.25 g/m² (range 1.25–19.97 g/m²). The relative dose intensity of gemcitabine was 96% (range 50–103%). Treatment was tolerated very well with non-complicated haematological toxicity as the most frequently observed side-effect. Only one partial tumour response was documented, giving a response rate of 3.23% (95% Confidence Interval (CI): 0.08–16.2%). The median overall survival was 268 days (95% CI: 129–377) and the median time to progression was 45 days (95% CI: 41–79). These results indicate that gemcitabine given at this dose and schedule is not active as second-line therapy in advanced STS.

Introduction

At present, chemotherapy for patients with advanced soft-tissue sarcoma (STS) is inadequate 1, 2, 3. Patients given chemotherapy for advanced STS have not yet shown a statistically significant prolongation of overall survival. Cure is achieved in less than 4% of advanced sarcoma patients. Few drugs have significant activity in STS and combination chemotherapy is only slightly more active at the expense of more toxicity 3, 4, 5. It has been shown that drugs showing some activity as second-line treatment are likely to be significantly effective first-line, hence the justification for phase II trials in this setting [5].

Gemcitabine (2′-deoxy-2′-difluorocytidine monohydrochloride/beta isomer) was developed as a new deoxycytidine analogue with reduced potential for catabolism by cytidine deaminase 6, 7, 8. Gemcitabine is an antimetabolite that acts as an inhibitor of DNA synthesis, causing chain termination, and also inhibits other targets including ribonucleotide reductase. It is cell cycle specific for S phase, and blocks the progression of the cell through the G1/S phase boundary.

Gemcitabine has been evaluated using a variety of dosages and schedules [9]. In phase I studies, short-lived thrombocytopenia was dose-limiting, granulocytopenia was not so pronounced. Some patients observed maculopapular skin rash with pruritus and flu-like symptoms were also reported. Gemcitabine has shown activity in many solid tumours, both as primary and second-line treatment 10, 11, 12, 13, 14. Of particular note is the activity in patients with advanced and metastatic pancreatic cancer that had progressed despite prior therapy with 5-fluorouracil (5-FU) [11].

Gemcitabine has activity against otherwise refractory solid tumours that suggests that clinical trials in sarcomas are warranted. Therefore, the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group has performed the present phase II study on gemcitabine in advanced STSs.

Section snippets

Patients and methods

Patients with histologically-confirmed STS at central review or after pathology review at the treating centre and with measurable lesions with evidence of progression within 6 weeks prior to treatment were eligible for the study. Patients with prior malignant disease or other serious medical conditions were excluded. Patients were required to have normal haematological function, serum creatinine ⩽120 μmol/l or calculated clearance (Cockroft and Gault method) >1.08 ml/s, bilirubin <30 μmol/l,

Patient characteristics

32 patients were enrolled in the study by eight centres between June and September 1998. One patient was ineligible because of an interval between their previous chemotherapy and the start of the gemcitabine treatment of less than the prescribed 4 weeks. All 31 patients were included in the treatment and toxicity analyses. The median age of the eligible patients was 53 years (range 23–73) Their characteristics are shown in Table 1.

Gemcitabine treatment and toxicity

31 evaluated patients received a median of three cycles (range

Discussion

STSs are rare tumours accounting for approximately 1% of all malignancies. Despite an optimal primary therapy many patients will fail and develop distant metastasis 1, 2, 5. In addition, many patients have locally advanced disease at the time of diagnosis. Only a few drugs have significant activity in STS. Treatment with doxorubicin, ifosfamide and dacarbazine (DTIC) has been reported to result in response rates of approximately 20% 2, 4, 5, 15. New classes of drugs and more effective

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We then applied the level of evidence and grade of recommendations as defined by the U.S. Preventive Services Task Force (Harris et al., 2001) and by the American College of Chest Physicians task force (West et al., 2002) (see online appendixes 1 and 2). Three gemcitabine-based regimens were assessed in patients with soft tissue sarcoma that was previously treated with at least one line of anthracyclin-containing chemotherapy: gemcitabine alone (Spaeth-Schwalbe et al., 2000; Patel et al., 2001; Svancarova et al., 2002; Hartmann et al., 2006; Ferraresi et al., 2008; Pautier et al., 2012), gemcitabine plus docetaxel (Ferraresi et al., 2008; Pautier et al., 2012; Hensley et al., 2002, 2008a) or gemcitabine plus dacabazine (Takano et al., 2014). Two clinical trials were randomized phase II trials: gemcitabine versus gemcitabine plus docetaxel (Ferraresi et al., 2008) and gemcitabine plus dacarbazine versus dacarbazine (Hensley et al., 2008a).
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-naïve 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.
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Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group

Abstract

Introduction

Section snippets

Patients and methods

Patient characteristics

Gemcitabine treatment and toxicity

Discussion

Cancer Treat. Rep.

Eur. J. Cancer Clin. Oncol.

Critical. Rev. Oncol./Hematol.

Eur. J. Cancer

Eur. J. Cancer

Melanomas, soft tissue and bone sarcomas

Eur. J. Cancer Clin. Oncol.

Adjuvant chemotherapy for soft tissue sarcomas

Activity of gemcitabine in human tumours cloning assays as a basis for clinical trials with gemcitabine

Invest. New Drugs

Gemcitabinea cytidine analogue active against solid tumours

Am. J. Health Syst. Pharm.