Phase II Clinical Investigation of Gemcitabine in Advanced Soft Tissue Sarcomas and Window Evaluation of Dose Rate on Gemcitabine Triphosphate Accumulation

Patel, Shreyaskumar; Gandhi, Varsha; Jenkins, Jan; Papadopolous, Nicholas; Burgess, Michael A.; Plager, Carl; Plunkett, William; Benjamin, Robert S.

doi:10.1200/jco.2001.19.15.3483

Cited by 232 publications

(148 citation statements)

References 11 publications

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“…Thus, it was logical to examine a fixed-dose rate of gemcitabine in patients with sarcomas. The pharmacodynamics of gemcitabine in patients with sarcoma were consistent with those found in the pancreatic cancer study [20].…”

Section: Gemcitabinesupporting

confidence: 71%

“…These have generally involved gemcitabine with the U.S. Food and Drug Administration-approved bolus schedule, and have shown only low response rates [20,[22][23][24][25][26][27][28][29][30][31] (Table 1). Collectively, it is clear that uterine leiomyosarcoma is more sensitive to gemcitabine than other histologies and even leiomyosarcomas from other sites, and that other histologies can occasionally respond as well.…”

Section: Gemcitabine In Sarcoma Patients: Clinical Observationsmentioning

confidence: 99%

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Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

Maki

2007

The Oncologist

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Objective. In the era of oral molecular kinase inhibitors, cytotoxic chemotherapy agents are somewhat overlooked, but remain the backbone of treatment for most cancers. Patients with non-gastrointestinal stromal tumor sarcomas, such as leiomyosarcoma, liposarcoma, and undifferentiated high-grade pleomorphic sarcoma (formerly called malignant fibrous histiocytoma), have received doxorubicin and ifosfamide as the backbone of their treatment for over 15 years or more. The goal of this article is to review the data that have led to the use of gemcitabine and docetaxel as a useful combination for patients with metastatic sarcomas, and to comment on possible synergy of the combination.Methods and results. The literature regarding the use of gemcitabine, docetaxel, or both, is reviewed, with emphasis on patients with metastatic sarcoma.Results. Activity of gemcitabine and docetaxel is observed in leiomyosarcoma and undifferentiated highgrade pleomorphic sarcoma. There is apparent schedule dependence of the combination in other cancers; it is unclear if schedule matters in patients with sarcomas. The dose and schedule of gemcitabine and docetaxel examined in phase II studies are probably too high for routine practice.Conclusions. The combination of gemcitabine and docetaxel is an effective option for patients with metastatic sarcoma, increasing the armamentarium for the practicing oncologist in treating this heterogeneous group of diseases. Given the low response rate to docetaxel as a single agent, it is likely that there is true clinical synergy of the combination. The Oncologist 2007;12: 999 -1006 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Gemcitabinesupporting

confidence: 71%

Section: Gemcitabine In Sarcoma Patients: Clinical Observationsmentioning

confidence: 99%

Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

Maki

2007

The Oncologist

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“…A study by Touroutoglou and colleagues showed that FDR gemcitabine (1,200 -2,800 mg/m 2 ) was safe and well tolerated [61]. Once-weekly administration of gemcitabine for 7 weeks of an 8-week cycle and FDR dosing of 1,000 mg/m 2 in 150 minutes demonstrated that intracellular levels of dFdCTP in peripheral blood mononuclear cells (PBMCs) increased linearly with infusion duration [69]. The maximum concentration (C max ) of dFdCTP was 1.4-fold higher after FDR than after standard gemcitabine.…”

Section: Phase I/ii Dose-finding Studies Investigating Prolonged (Fdrmentioning

confidence: 99%

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

2008

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After completing this course, the reader will be able to:1. Describe the molecular pharmacology of nucleoside analogues.2. Explain transport, metabolism, and elimination in relation to the activity of gemcitabine.3. Describe the clinical pharmacology of gemcitabine in relation to its rate of administration.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTGemcitabine is frequently used in the treatment of patients with solid tumors. Gemcitabine is taken up into the cell via human nucleoside transporters (hNTs) and is intracellularly phosphorylated by deoxycytidine kinase (dCK) to its monophosphate and subsequently into its main active triphosphate metabolite 2,2-difluorodeoxycytidine triphosphate (dFdCTP), which is incorporated into DNA and inhibits DNA synthesis. In addition, gemcitabine is extensively deaminated to 2,2-difluorodeoxyuridine, which is largely excreted into the urine. High expression levels of human equilibrative nucleoside transporter type 1 were associated with a significantly longer overall survival duration after gemcitabine treatment in patients with pancreatic cancer.Clinical studies in blood mononuclear and leukemic cells demonstrated that a lower infusion rate of gemcitabine was associated with higher intracellular dFdCTP levels. Prolonged infusion of gemcitabine at a fixed dose rate (FDR) of 10 mg/m 2 per minute was associated with a higher intracellular accumulation of dFdCTP, greater toxicity, and a higher response rate than with the standard 30-minute infusion of gemcitabine in patients with pancreatic cancer.In the current review, we discuss the molecular pharmacology of nucleoside analogues and the influence of hNTs and dCK on the activity and toxicity of gemcitabine, which is the basis for clinical studies on

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“…Until recently, the differentiation between these two entities had not been thought to be clinically relevant. Chemotherapeutic agents, such as doxorubicin and ifosfamide used in the treatment of soft-tissue sarcomas have resulted in response rates of 0-10% in patients with advanced GIST (3)(4)(5). However, the use of the selective tyrosine kinase inhibitor imatinib mesylate [also known as STI571 (Gleevec; Novartis Pharmaceuticals Corp., East Hanover, NJ)] has resulted in response rates of Ͼ50% for patients with GIST (6, 7, **).…”

mentioning

confidence: 99%

Highly accurate two-gene classifier for differentiating gastrointestinal stromal tumors and leiomyosarcomas

Price

Trent

El‐Naggar³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

139

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Gastrointestinal stromal tumor (GIST) has emerged as a clinically distinct type of sarcoma with frequent overexpression and mutation of the c-Kit oncogene and a favorable response to imatinib mesylate [also known as STI571 (Gleevec)] therapy. However, a significant diagnostic challenge remains in the differentiation of GIST from leiomyosarcomas (LMSs). To improve on the diagnostic evaluation and to complement the immunohistochemical evaluation of these tumors, we performed a whole-genome gene expression study on 68 well characterized tumor samples. Using bioinformatic approaches, we devised a two-gene relative expression classifier that distinguishes between GIST and LMS with an accuracy of 99.3% on the microarray samples and an estimated accuracy of 97.8% on future cases. We validated this classifier by using RT-PCR on 20 samples in the microarray study and on an additional 19 independent samples, with 100% accuracy. Thus, our two-gene relative expression classifier is a highly accurate diagnostic method to distinguish between GIST and LMS and has the potential to be rapidly implemented in a clinical setting. The success of this classifier is likely due to two general traits, namely that the classifier is independent of data normalization and that it uses as simple an approach as possible to achieve this independence to avoid overfitting. We expect that the use of simple marker pairs that exhibit these traits will be of significant clinical use in a variety of contexts.cancer ͉ classification ͉ diagnostic ͉ machine learning ͉ molecular signature G astrointestinal stromal tumors (GISTs) and leiomyosarcomas (LMSs) are common mesenchymal tumors with remarkably similar phenotypic features (1, 2). Until recently, the differentiation between these two entities had not been thought to be clinically relevant. Chemotherapeutic agents, such as doxorubicin and ifosfamide used in the treatment of soft-tissue sarcomas have resulted in response rates of 0-10% in patients with advanced GIST (3-5). However, the use of the selective tyrosine kinase inhibitor imatinib mesylate [also known as STI571 (Gleevec; Novartis Pharmaceuticals Corp., East Hanover, NJ)] has resulted in response rates of Ͼ50% for patients with GIST (6, 7, **). Conversely, patients with advanced LMS expect response rates of 27-53% when treated with doxorubicin or newer regimens combining gemcitabine with docetaxel (8, 9) but do not benefit from imatinib therapy (10, 11, † †). Thus, there is clear clinical importance in distinguishing between these two entities to guide the most effective therapy. Currently, the best marker to differentiate GIST from LMS is Kit immunostaining, which is subjective and variable due to cellular heterogeneity that may result in false-negative diagnoses. Kitnegative GISTs and Kit-expressing LMS have been reported on the basis of tumor cell morphology and other markers such as CD34, desmin, and smooth muscle actin ( ‡ ‡). The occurrence of Kit-negative GIST in the literature is Ϸ4-10% (2, 12). We used whole human genome microarray d...

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Phase II Clinical Investigation of Gemcitabine in Advanced Soft Tissue Sarcomas and Window Evaluation of Dose Rate on Gemcitabine Triphosphate Accumulation

Abstract: Given the limited therapeutic armamentarium for STS, the activity of gemcitabine is encouraging. Its potential for combination therapy in the salvage setting should be studied with pharmacologically guided fixed dose-rate infusion.

Cited by 232 publications

References 11 publications

Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

Highly accurate two-gene classifier for differentiating gastrointestinal stromal tumors and leiomyosarcomas

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