Abstract
OBJECTIVE Promising anti-tumor activity in patients with metastatic or unresectable soft tissue sarcomas has been reported with gemcitabine and/or docetaxel.
METHODS Forty patients with advanced soft tissue sarcomas refractory to first-line chemotherapy treatment were enrolled. They received combination of gemcitabine at dose of 900 mg/m2 on days 1 and 8 and docetaxel at dose of 100 mg/m2 on day 8, and had this regimen repeated every 3 weeks. If the patients had received the pelvic irradiation in advance, gemcitabine dose was reduced to 675 mg/m2 on days 1 and 8 and docetaxel to 75 mg/m2 on day 8, and had it repeated every 3 weeks.
RESULTS Gemcitabine/docetaxel combination was well tolerated by the patients with an overall response of 20%. After median follow-up of 15 months, a median overall survival time was 12 months (95% CI 7.042–16.958) and a median progression free survival time was 6 months (95% CI 5.445–6.545). The most common hematologic toxicity was neutropenia (47.5%) while mucositis was the most common non- hematologic toxicity (45%). The 1- and 2-year survival rates were 50% and 15%, respectively.
CONCLUSION This regimen of gemcitabine/docetaxel combination as second-line treatment for the patients with advanced soft tissue sarcomas is effective with acceptable toxicities. These results should be evaluated in a large phase III trial.
keywords
Introduction
Soft tissue sarcomas (STSs) are malignant tumors of connective tissues that account for 1% of all human cancers[1]. The STSs consist of approximately 50 different histological subtypes which have different clinical behavior and response to chemotherapy. In the advanced disease setting, (locally advanced or metastatic) palliative chemotherapy is the mainstay of treatment[2], although in a small subset this treatment may be curative[3].
Docetaxel is an agent that stabilizes tubulin, inhibits the dynamic reorganization of the microtubular network of the cell, and as a result inhibits the mitotic and interphase cellular functions[4,5]. Gemcitabine is a fluorinated analogue of the nucleoside deoxycytidine (dCTP). Though it is inactive in its parent form, successive intracellular phosphorylation of the parent drug yields active di- and tri-phosphate metabolites[6]. The di-phosphate form inhibits ribonucleotide reductase and the tri-phosphate form is incorporated into DNA and competes with dCTP as a fraudulent base (dFdCTP).
The inhibition of ribonucleotide reductase may allow for a self-potentiating mechanism to increase nucleotide incorporation in cells[7]. Once the gemcitabine tri-phosphate metabolite is incorporated into DNA, one additional nucleoside is incorporated after which DNA chain synthesis is terminated. This “masked chain termination” leaves the fraudulent base resistant to excision repair by DNA repair enzymes and may overcome an important mechanism of drug resistance[8].
Promising anti-tumor activity in patients with metastatic or unresectable STSs has been reported with gemcitabine (G) alone[9,10], docetaxel (D) alone[11] or in combination[12,13]. As no standard second line chemotherapy has been developed for advanced STSs, we conducted this study to assess response, toxic effects and survival of the patients applied with G/D regimen.
Patients and Methods
Patients
All the patients were provided with written informed consent before entering the trial. Finally, 40 patients were included in this study. Inclusion criteria were as follows: patients with locally advanced or metastatic soft tissue sarcoma had received first line chemotherapy with no response or with evidence of disease progression within 6 weeks prior to the trial entry; World Health Organization (WHO) performance status was up to (PS) 0–2; aged greater or equal to 18 years, and were histologically confirmed as soft tissue sarcoma. Other inclusion criteria were: patients had measurable disease which was evaluable for response based on the WHO criteria; their life expectancy was at least 3 months, and had adequate organ function including: neutrophil greater than 1.5/L, hemoglobin ≥ 10 g/dL, platelets greater than 100/L, bilirubin less than or equal to 1.5 × upper limit of normal (ULN), asparate aminotransferase (AST) ≤ 3 × ULN, ejection fraction greater than or equal to 50%. Exclusion criteria were: patients were diagnosed as Ewing’s sarcoma family of tumors; rhabdomyosarcoma; gastrointestinal stromal tumors; known active central nervous system metastases; pregnancy or lactation; active uncontrolled infection, and any serious and/or unstable pre-existing medical condition. Initial pre-treatment evaluation included: medical history; physical examination; computerized tomography (CT) scan or magnetic resonance imaging (MRI) detecting the primary lesion or the site of metastasis; biochemical test; complete blood count; electrocardiogram; chest X-ray; liver ultrasound, and bone scan. Laboratory and clinical evaluations were repeated after each cycle, and radiological evaluations were repeated after 3 cycles, then every 2 months after the end of the treatment.
Treatment
Regimen that the patients received consisted of gemcitabine 900 mg/m2 in 500 mL of 0.9% normal saline administered through IV over 90 minutes on days 1&8 and docetaxel 100 mg/m2 in 500 mL of 0.9% normal saline through IV over 1 hour on day 8. This regimen was repeated every 3 weeks. Pre-medication was composed of 5-HT antagonists given 30 minutes prior to treatment and dexamethasone at the dose of 8 mg taken orally b.i.d. for 5 days starting 1 day before docetaxel administration. If the patients had received pelvic radiotherapy in advance, the regimen consisted of gemcitabine 675 mg/m2 given through IV over 60–75 minutes on days 1&8 and docetaxel 75 mg/m2 given through the same way mentioned above on day 8. This regimen was repeated every 3 weeks. Dose modification was performed in subsequent cycles of the therapy with 25% reduction in each agent for those of the patients experiencing febrile neutropenia (temperature > 38°C with neutrophil count < 400/μL), grade ≥ 3, non-hematologic toxicity or thrombocytopenia. G-CSF (Filgrastrim 5 mg/kg daily for 5 days) was applied for the cases developing neutropenia, grade ≥ 3. If hemoglobin value was < 9 g/dL, chemotherapy was administered on time along with red blood cell transfusion or erythropoietin administration. Three weeks after the 3rd cycle of G/D, the patients were reassessed for tumor responses according to the WHO criteria[14]. Toxicity induced by this regimen was assessed using the NCI Common Terminology Criteria for Adverse Events V3.0[15]. Overall survival was calculated from the date when disease progression was diagnosed to the date of death or the date of last follow up and progression-free survival was calculated from the date when the treatment was just finished to the date of the progression. Statistical method: statistical calculations were performed using SPSS version 15. Kaplan and Meier method was used to estimate OAS and PFS.
Results
Between November 2006 and December 2009, 40 patients with advanced soft tissue sarcoma (locally advanced and/or metastatic), who failed to respond to first line chemotherapy (with or without surgery or radiotherapy) were eligible for entering the study. The median age of the patients was 48 years, and male to female ratio was 1.35:1. Liposarcoma was the commonest histological type (22.5%) among these patients followed by leiomyosarcoma (17.5%) and fibrosarcoma (17.5%), and 50% of the patients presented single organ metastasis, in which lung was the commonest site (60%). PS in most of the patients was 1 (47.5%). Limbs were the commonest involved site (35%). Most of the patients (45%) had received combined chemotherapy (ifosfamide plus adriamycin) prior to gemcitabine and docetaxel protocol. Only 25% of the patients were operable before first line chemotherapy (Table 1).
Patients’ Characteristics.
All the patients received G/D combination. The median of chemotherapy courses delivered was 3, with a total of 165 courses. No major complications induced by the G/D regimen, which can cause discontinuation of the courses occurred. Dose reduction was required in 4 patients (10%) because of hematologic toxicity and mucositis. As shown in Table 2, neutropenia was the commonest hematologic toxicity (47.5%) with grade ≥ 3 in 10% of the patients who received G-CSF, followed by thrombocytopenia (37.5%) with grade 3 in (7.5%), while mucositis was the commonest non hematologic toxicity (45%) followed by fatigue (42.5%) at grade 1 and 2 only.
Toxicity of Chemotherapy
Overall response rate (ORR) was 20% with complete response in 5% of the patients, and disease was stable in 17.5% while progression occurred in 62.5% (Table 3). After a median follow-up of 15 months, the median overall survival (OAS) time was 12 months (95% CI 7.042–16.958) and median progression free survival (PFS) time was 6 months (95% CI 5.455–6.545). The 1-year and 2-year survival rates were 50% and 15%, respectively (Fig. 1).
Response to Treatment.
Over all survival of All Patients (OAS).
Discussion
Advanced soft tissue sarcomas are usually resistant to cytotoxic agents, such as doxorubicin and ifosfamide. Single-agent therapy or combination regimens yield occasional or negligible responses. For example, high-dose ifosfamide, DTIC, etoposide, mitoxantrone and platinum have been used in the treatment of STSs, but the response rates these drugs generate are less than 20%[16–20]. Hensley et al.[13] postulated that gemcitabine and docetaxel might be synergistic agents because of their complementary anti-tumor effects. Gemcitabine induces cell cycle arrest while docetaxel promotes cell death. To reach a better apoptosis rate, they suggested using gemcitabine alone on day 1 and adding docetaxel on day 8. In vitro, the synergistic cytotoxicity of G/D sequential combination was demonstrated by Leu et al.[21] who observed 35 patients with STS or bone sarcomas and evaluated the effect of G/D combination in SAOS-2 sarcoma cells and MCF-7 breast cancer cells. They demonstrated in vitro that gemcitabine followed by docetaxel was more effective than the reverse sequence with synergistic antitumor effect.
In the present study, the commonest hematologic toxicity was neutropenia (47.5%) with grade ≥ 3 in 10% of the patients followed by thrombocytopenia (37.5%) with grade 3 in 7.5%. This is comparable to a study conducted by Hensley et al.[12] who reported neutropenia in 44.1%, and thrombocytopenia of grade ≥ 3 in 8.8% of the patients with unresectable leiomyosarcoma (LMS) treated with gemcitabine and docetaxel as second line treatment.
Mucositis (45%) was the commonest non hematologic toxicity followed by fatigue (42.5%) then diarrhea (20%) with grade 3 in 2.5% of the patients. Bay et al.[22] reported mucositis grade ≥ 3 in 0.77% only and diarrhea grade 3 in 1.16%.
In this study, overall response rate (ORR) was 20%, and stable disease occurred in 17.5% and progressive disease in 62.5% of the patients. Expanded initial phase II study of Hensley et al.[13] showed an ORR of 35%, with 40% of ORR being presented in patients with LMS and 10% of ORR in patients with other histological subtypes. However, in this study, G/D was the second line treatment in 51.9% of the patients only. Maki et al.[23] reported an ORR of 17% when G/D was used in the treatment of metastatic STS.
In our study, median OAS time was 12 months and median PFS time was 6 months. The 1-year and 2-year survival rates were 50% and 15%, respectively. These results were comparable to that reported by Bay et al.[22] as they reported median OAS time of 12 months and 1-year and 2-year survival rates of 51% and 15%, respectively, when G/D combination was used as second-line treatment in 84.21% of their patients and as first-line in the remaining patients, while Leu et al.[21] reported a median OAS time of 13 months, a median PFS time of 6.7 months, and a 1-year survival rate of 66% after treating 80% of their patients in which 34.29% had LMS, with G/D combination as second-line treatment.
Conclusion
This regimen of G/D combination as second line treatment for patients with advanced soft tissue sarcomas is effective with acceptable toxicities. These results should be evaluated in a large phase III trial.
Conflict of interest statement
No potential conflicts of interest were disclosed.
- Received May 19, 2011.
- Accepted August 3, 2011.
- Copyright © 2011 by Tianjin Medical University Cancer Institute & Hospital and Springer
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