A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma

Talbot, Susan; Keohan, Mary Louise; Hesdorffer, Mary; Orrico, Russell; Bagiella, Emilia; Troxel, Andrea B.; Taub, Robert N.

doi:10.1002/cncr.11730

Cited by 83 publications

(55 citation statements)

References 16 publications

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“…Published studies on single-agent treatments, such as high-dose ifosfamide or temozolamide, reported a limited efficacy (17,18). Trabectedin, which has been approved in Europe for second-or further-line treatment of advanced STS, achieved response rates of ≤10%, with significant clinical benefit almost exclusively in LMS and liposarcoma patients (19).…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine in combination with paclitaxel for advanced soft-tissue sarcomas

Sonnenblick

Eleyan

Peretz

et al. 2015

Molecular and Clinical Oncology

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Abstract.A limited number of chemotherapeutic agents have been found to be active against advanced soft-tissue sarcomas (STSs), particularly sarcomas that have progressed following doxorubicin treatment. The aim of this retrospective study was to determine the response to treatment with gemcitabine plus paclitaxel in patients with STSs. Data were collected on all patients with advanced non-resectable STS who were treated with a fixed dose 700 mg/m 2 gemcitabine in combination with 70 mg/m 2 paclitaxel on days 1 and 8 every 3 weeks. A total of 30 patients were included, with a median age of 56.4 years (range, 40-70 years). The gemcitabine/paclitaxel combination was well tolerated, with an overall response in 27% and a clinical benefit in 57% of the patients. The median progression-free survival was 6.1 months and the overall survival was 14.3 months. In conclusion, gemcitabine plus paclitaxel was found to be tolerable and effective in patients with advanced STSs. IntroductionSoft-tissue sarcomas (STSs) are a heterogeneous family of malignancies originating from mesenchymal tissues. Patients who present with advanced-stage STS or develop disease recurrence following initial resection carry a poor prognosis, since the majority of chemotherapeutic agents have not achieved any survival benefit in this disease. However, ~30% of patients treated with doxorubicin achieve an objective response and the response rates may increase to 35-40% when doxorubicin is combined with ifosfamide (1,2). The combination of gemcitabine and docetaxel was also proven to be effective in advanced STS, particularly in patients with uterine leiomyosarcoma (LMS) (3). While single-agent gemcitabine exhibited only modest activity, the overall response rates in phase II trials combining gemcitabine with docetaxel were in the range of 16-53% in this patient group (3-6). A higher efficacy with superior progression-free survival (PFS) and overall survival (OS) was also demonstrated with this combination in several comparative trials (3,7,8). Therefore, it became common practice in several sarcoma centers to initiate combination treatment, hypothesizing synergy between gemcitabine and docetaxel. Myelosupression is the primary toxicity (grade 3-4 neutropenia in 17%, grade 3 anemia in 25% and severe thrombocytopenia in 10% of the patients) associated with this type of treatment (9). In addition, grade 3 non-hematological toxicities, including fatigue and myalgia, developed in 25% of the patients. Patients with advanced sarcoma are usually heavily pretreated, with limited bone marrow tolerance and impaired quality of life. Paclitaxel and docetaxel share the same mechanisms of action and were found to exhibit similar efficacies in certain types of cancer, such as breast and lung cancer. Paclitaxel has been proven to be more tolerable when administered weekly, according to studies on breast cancer (10-12). For example, in a prospective randomized trial assessing different schedules and regimens of paclitaxel vs. docetaxel in adjuvant therapy for breast ca...

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Section: Discussionmentioning

confidence: 99%

Gemcitabine in combination with paclitaxel for advanced soft-tissue sarcomas

Sonnenblick

Eleyan

Peretz

et al. 2015

Molecular and Clinical Oncology

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“…This therapeutic benefit was associated with silencing of the O6-methylguanine-DNA methyltransferase (MGMT) expression as determined by immunohistochemistry. All the above mentioned studies revealed good tolerance to TMZ (6)(7)(8)(9)(10)(11). The MGMT gene has been shown to be epigenetically downregulated in several solid tumors.…”

Section: Introductionmentioning

confidence: 99%

“…The trial involving patients with soft tissue sarcomas not subjected to standard chemotherapy revealed only minimal efficacy of TMZ (7). Another trial on TMZ demonstrated a modest activity against previously treated unresectable or metastatic soft tissue sarcomas (8). Notably, all responding patients had leiomyosarcoma (of uterine or non-uterine origin) (8).…”

Section: Introductionmentioning

confidence: 99%

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The promoter methylation and expression of the O6-methylguanine-DNA methyltransferase gene in uterine sarcoma and carcinosarcoma

et al. 2012

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Abstract. O6-methylguanine-DNA methyltransferase (MGMT) gene promoter hypermethylation is observed in a number of solid tumors and is correlated with the silencing of MGMT expression. In glioblastoma patients treated with the alkylating agent temozolomide, MGMT gene methylation status was shown to have predictive value in terms of prolonged overall survival. Recently, temozolomide has demonstrated promising activity in the treatment of soft tissue sarcomas, including those of the uterus. The tissue specimens involving tumor samples and normal uterine fragments were obtained from nine patients with smooth muscle uterine sarcoma, 11 with stromal uterine sarcoma and 17 with mixed uterine tumors. MGMT gene promoter methylation was analyzed by combined bisulfite restriction analysis (COBRA) while its expression levels were assessed using the real-time reverse transcription polymerase chain reaction (qRT-PCR). MGMT promoter methylation was observed in 27% of all tumor samples analyzed. When stratified by the disease type, 55.5% (5/9) of smooth muscle sarcomas, 23.5% (4/17) of mixed uterine tumor tissues and 9% (1/11) of stromal sarcomas showed MGMT methylation. The MGMT promoter methylation was associated with lower levels of gene expression in tumors when compared with those with an unmethylated promoter (P=0.0232) or normal tissues (P=0.0141). To conclude, MGMT promoter methylation and downregulation of gene expression is observed in a fraction of carcinosarcomas and non-epithelial malignant tumors of corpus uteri. The assessment of MGMT promoter methylation status may potentially identify patients who would benefit from temozolomide treatment.

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“…Based on its similar mechanism of action to dacarbazine, temozolomide has been evaluated in soft tissue sarcoma using a variety of dosing schedules. In several studies which included a variety of STS subtypes, all of the clinical benefit was seen in patients with leiomyosarcoma [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Phase II study of temozolomide and thalidomide in patients with unresectable or metastatic leiomyosarcoma

Boyar

Keohan

Hesdorffer

et al. 2005

JCO

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We assessed the efficacy of combined temozolomide and thalidomide in patients with unresectable or metastatic leiomyosarcoma in a phase II single-institution trial. Twenty-four patients were enrolled. Temozolomide (150 mg/m 2 /day for 7 days every other week) was administered with concomitant thalidomide (200 mg/day), and continued until unacceptable toxicity or disease progression. There were no complete responses and two (10%) partial responses. Five patients (24%) had stable disease for at least six months. Fourteen patients (67%) progressed after a median of two-month treatment. The median overall survival (twenty-two assessable patients) was 9.5 months [95% CI 7-28 months]. There were no treatment-related deaths or CTC grade 4 toxicities. Thirteen patients were dose-reduced or discontinued thalidomide due to toxicity. In conclusion, this combination of temozolomide and thalidomide provided disease stabilization in a subset of patients with advanced leiomyosarcoma. We hypothesize that temozolomide is the active agent in this regimen, and should be further studied.

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A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma

Cited by 83 publications

References 16 publications

Gemcitabine in combination with paclitaxel for advanced soft-tissue sarcomas

Gemcitabine in combination with paclitaxel for advanced soft-tissue sarcomas

The promoter methylation and expression of the O6-methylguanine-DNA methyltransferase gene in uterine sarcoma and carcinosarcoma

Phase II study of temozolomide and thalidomide in patients with unresectable or metastatic leiomyosarcoma

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