help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ryan, D. P.
Right arrow Articles by Demetri, G. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ryan, D. P.
Right arrow Articles by Demetri, G. D.
The Oncologist, Vol. 7, No. 6, 531–538, December 2002
© 2002 AlphaMed Press

A Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients with Gastrointestinal Stromal Tumors

David P. Ryana, Thomas Puchalskia, Jeffrey G. Supkoa, David Harmona, Robert Makib, Rocio Garcia-Carboneroa,c, Caroline Kuhlmana, Jennifer Winkelmana, Priscilla Merriamc, Travis Quigleyc, Jose Jimenod, Judith Manolac, George D. Demetric

a Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; b Division of Adult Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; c Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA; d Pharma Mar, S.A., Madrid, Spain

Correspondence: David P. Ryan, M.D., MGH Cancer Center, 100 Blossom Street, Cox 640, Boston, Massachusetts 02114, USA. Telephone: 617-724-4000; Fax: 617-724-3166; e-mail: dpryan{at}partners.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
After completing this course, the reader will be able to:

  1. Describe the mechanism of action, administration, and pharmacokinetics of ecteinascidin 743.
  2. Recognize the classification and pathophysiology of gastrointestinal stromal tumors.
  3. Appreciate that conventional cytotoxic chemotherapy has no efficacy in patients with gastrointestinal stromal tumors and that STI571 has dramatic efficacy.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Purpose. To assess the efficacy, tolerability, and pharmacokinetics of ecteinascidin 743 (ET-743) in patients with advanced gastrointestinal stromal tumors (GISTs).

Patients and Methods. The study was confined to adult patients with radiographically measurable GISTs. ET-743 was administered as a 24-hour continuous i.v. infusion at a dose of 1.5 mg/m2 repeated every 3 weeks. Pharmacokinetic blood sampling was performed during the first cycle of therapy. Tumors were restaged after every second cycle of therapy.

Results. A total of 20 patients was enrolled in the study, 19 of whom were treated with 47 cycles of ET-743 (median 2, range 1-10). Severe toxicities were limited to reversible grade 3 transaminitis in 10 patients and grade 3 fatigue in one patient. There were no objective responses, and disease stabilization occurred in two patients lasting for periods of 4 and 10 months. The 1-year survival rate was 71.1%. Mean ± standard deviation values of the maximum plasma concentration and total plasma clearance were 1.1 ± 0.4 ng/ml and 44 ± 16 l/h/m2, respectively, for 19 of the 20 patients.

Conclusion. This study is the first report of a prospective phase II trial to evaluate a cytotoxic agent in patients with GISTs. This study underscores the primary resistance of GISTS to chemotherapy and stands in stark contrast to the encouraging results recently achieved with STI571. The lack of response may be associated with a therapeutically ineffective exposure to the drug based upon the lower incidence of severe toxicities and greater clearance than described in phase I and II trials of ET-743.

Key Words. Cancer • Chemotherapy • Clinical trials • Human studies • c-kit


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, having an estimated incidence of 10-20 per million. The incidence rate of these tumors is similar between genders and peaks at an age of approximately 60 years. The majority of GISTs, detected when they are of small size (<2 cm), pursue a benign course and are curable by surgical resection [1]. The malignant potential of GISTs cannot be predicted accurately by histopathology alone. Until recently, there was no effective therapy for patients with metastatic disease.

Malignant GISTs, a type of sarcoma, represent spindle cell and/or epithelioid neoplasms of the gastrointestinal tract that characteristically express the c-kit proto-oncogene (CD117) in almost all cases. Recent work has shown that KIT is universally activated in GISTs even in the absence of a demonstrable mutation in the c-kit gene [2]. Mutations of the c-kit gene occur with an overall frequency of greater than 50% in GISTs and at a substantially greater prevalence in malignant disease [3–6]. These mutations can cause constitutive activation of the KIT tyrosine kinase, resulting in ligand-independent tyrosine kinase activity, which appears to be an early and critical pathogenetic event contributing to the malignant phenotype of these cells. Several reports have now demonstrated that STI571 is a potent inhibitor of KIT tyrosine kinase and can lead to benefit in patients with GISTs [7].

Prior to the advent of STI571, GISTs were typically treated according to the same principles that are applied to the clinical management of patients with soft tissue sarcomas (STSs). Complete resection remains the only curative treatment. However, most patients with malignant GISTs either present with unresectable disease or develop recurrences after resection [8, 9]. GISTs are notoriously unresponsive to the conventional chemotherapy regimens devised for STSs [10]. Nevertheless, there are no reports of prospective clinical trials undertaken to evaluate the efficacy of cytotoxic chemotherapy specifically against GISTs in the existing literature.

Ecteinascidin 743 (ET-743) is a cytotoxic tetrahydroisoquinoline alkaloid with potent broad spectrum antiproliferative activity isolated from a marine organism [11, 12]. It binds to DNA in a sequence-specific manner and forms a covalent adduct with the N-2 amino group of guanine bases in the minor groove, which bends the double helix toward the major groove [13, 14]. Recognition of these drug-associated lesions by the transcription-coupled nucleotide-excision repair system, resulting in the generation of lethal single-strand breaks in DNA, appears to be the principal mechanism of cell death [15]. ET-743 also interferes with transcription including the transcriptional activation of the multiple drug resistance (MDR)1 gene [16, 17].

In recently completed phase I studies performed in the U.S. and Europe, patients with leiomyosarcoma, liposarcoma, osteosarcoma, melanoma, mesothelioma, and ovarian and breast cancer responded to treatment with ET-743 [18–21]. In the initial phase I study and compassionate use program of ET-743, four patients with chemorefractory STSs had partial responses, and three patients with GISTs had stable disease among a cohort of 29 patients treated with 1.5 mg/m2 of ET-743 given as a 24-hour continuous i.v. infusion every 21 days [19]. A phase II trial to evaluate the activity of ET-743 was undertaken based upon this promising activity in patients with STSs. The primary objective of the study was to prospectively assess the clinical activity of ET-743 in patients with unresectable advanced or metastatic GISTs. Secondary objectives were the determination of the toxicity and pharmacokinetic behavior of the drug.


   PATIENTS AND METHODS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patient Selection
This prospective multicenter phase II clinical trial was conducted at the Dana-Farber Cancer Institute (Boston, MA), Massachusetts General Hospital (Boston, MA), and Memorial Sloan-Kettering Cancer Center (New York, NY). The study protocol was approved by the Scientific Review Committee and Human Protection Committee of each institution. Patients with a diagnosis of unresectable advanced or metastatic GISTs, which was proven histologically, were eligible for the study. Patients were evaluated by a physical examination, performance status determination, a complete blood count with differentials and platelets, and a standard serum chemistry panel that included creatinine, total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and alkaline phosphatase, within 14 days of entering the study. Radiographic assessment of measurable disease by computed tomography (CT) was performed not more than 4 weeks before initiating treatment. Eligibility criteria included the following: age >=18 years; life expectancy >=3 months; World Health Organization (WHO) performance status <=1 or Karnofsky performance status >=80%; a lesion >=20 mm in at least one diameter, located in a nonirradiated region, as determined by CT; and complete recovery from toxicity due to prior chemotherapy with the exception of peripheral neuropathy of grade <=2 (National Cancer Institute Common Toxicity Criteria [NCI-CTC]). The following laboratory parameters were required: neutrophil count >=1,500/µl; platelet count >=100,000/µl; serum creatinine <=1.5 mg/dl or creatinine clearance >=40 ml/min; total bilirubin and serum alkaline phosphatase within the upper limits of normal; SGOT and SGPT <2.5 times the upper limits of normal. Patients were excluded if they had a history of any other neoplastic disease during the previous 5 years, symptomatic brain or leptomeningeal involvement of the tumor, or other serious illness, such as heart failure, significant liver disease, and uncontrolled hypertension. Patients who were pregnant, had an active infection, had a history of neurologic or psychiatric disorders, or were otherwise unable to adhere to a regular follow-up schedule were also excluded. Participation in another clinical trial concomitantly or within 30 days of entering this study was not permitted. Immunohistochemical analysis of kit expression staining was performed by the pathology departments at the Brigham and Women’s Hospital, Massachusetts General Hospital, and Memorial Sloan-Kettering Cancer Center.

Drug Administration, Toxicity Assessments, and Dose Modifications
ET-743 was supplied by Pharma Mar, S.A. (Madrid, Spain) as a sterile lyophilized powder in glass vials containing 0.25 mg of ET-743, 250 mg of mannitol, 34 mg of monopotassium phosphate, and phosphoric acid to adjust the pH to 4.0 upon reconstitution with 5 ml of sterile water for injection, United States Pharmacopeia (USP). An appropriate volume of the 50 µg/ml reconstituted solution was loaded into the 100 ml medication cassette reservoir of a computerized ambulatory drug delivery programmable ambulatory infusion pump (SIMS Deltec; St. Paul, MN) and diluted with normal saline for injection, USP to deliver the intended dose in a total volume of 96 ml. The dosing solution was administered through a central venous catheter without an inline filter.

Support with hematopoietic colony-stimulating factors was not permitted. All patients received a seratonin receptor antagonist for antiemetic prophylaxis with additional doses given on subsequent days as needed. Initially, the use of dexamethasone to control nausea and vomiting was precluded due to theoretical concerns about inducing the hepatic metabolism of ET-743. However, because of the severity of nausea and vomiting encountered in other phase II trials involving this dosing regimen of ET-743, dexamethasone prophylaxis was instituted on a routine basis shortly after starting this study. A total of 14 patients were treated with dexamethasone, typically a 10-mg i.v. dose, beginning on the first day of the ET-743 infusion, with a single additional dose given on the following day.

Patients were scheduled to receive 1.5 mg/m2 of ET-743 by 24-hour continuous i.v. infusion once every 3 weeks on an outpatient basis until disease progression was documented, as long as the pretreatment eligibility criteria continued to be satisfied. Physical examinations, complete blood counts, and serum chemistry tests were performed on a weekly basis. During subsequent cycles of therapy, the dose was reduced to 1.2 mg/m2 in the event of grade 4 neutropenia (platelet count <500/µl) associated with fever or persisting for more than 5 days. The dose was also reduced to 1.2 mg/m2 for thrombocytopenia with a nadir platelet count less than 25,000/µl. The dose was not reduced in the event of a grade 3 or 4 increase in transaminase levels that fully resolved by day 21. A 1-week delay in treatment was permitted to allow grade 3-4 elevations in serum transaminase levels to return to baseline values, in which case, the dose of ET-743 was reduced to 1.2 mg/m2; otherwise, the patient was withdrawn from study. A further reduction in the dose to 1.0 mg/m2 was permitted in patients experiencing nonhematologic toxicity following treatment with 1.2 mg/m2 under the same provisions as described in the above for the full dose.

Response Assessment
CT scans of measurable disease were performed after every two cycles. Response criteria were as follows: complete response required disappearance of all measurable disease, signs, symptoms, and biochemical changes related to the tumor for >=28 days, during which no new lesions could appear; partial response required reduction of >=50% in the sum of the products of the perpendicular diameters of all measurable lesions lasting for >=28 days, during which no new lesions could appear; stable disease required reduction of <50% or an increase of <25% in the sum of the products of the perpendicular diameters of all measurable lesions lasting for >=28 days, during which no new lesions could appear; and progressive disease required an increase of >=25% in the sum of the products of the perpendicular diameters of all measurable lesions or development of any new lesions.

Pharmacokinetic Studies
The plasma pharmacokinetics of ET-743 were characterized during the first cycle of therapy using a minimally intensive sampling schedule. Blood specimens (7 ml) were drawn from an arm vein into a Vacutainer brand tube with freeze-dried sodium heparin anticoagulant (Becton Dickinson; Franklin Lakes, NJ) at the following times relative to the start of drug infusion: 0, 2, 23.5, 24.5, 25, 48, and 72-96 hours. Sample tubes were mixed by inversion, placed on wet ice until centrifuged (1,800 g for 10 minutes at 4°C) within 15 minutes, after which the plasma was transferred into a polypropylene cryovial and stored at -70°C until assayed. The beginning and ending times of the drug infusion and sample collection intervals were monitored with a digital timer and recorded.

A validated analytical method involving isolation of the drug and an added internal standard from plasma by solid-phase extraction followed by isocratic reversed-phase high-performance liquid chromatography with electrospray ionization mass spectrometric detection was used to measure the concentration of ET-743 in study specimens, as previously described [18]. During its application to the present study, the between-day accuracy and precision of the assay were assessed by analyzing the interpolated drug concentrations from 16 standard curves run over a 57-week period. Grand mean ± standard deviation (SD) values of the between-day accuracy and precision for standard solutions of ET-743 in plasma at concentrations ranging from 50 to 1,000 pg/ml were 101.0% ± 6.8% (range 90.7%-109.7%) and 12.1 ± 5.3% (range 4.8%-18.9%), respectively. ET-743 was measured with an accuracy of 109.7% and precision of 14.1% at the lowest concentration included in the standard curves (50 pg/ml).

Actual sample times were calculated from the beginning of the infusion of drug to the midpoint of each sample collection interval. Individual patient plasma concentration-time data were analyzed by noncompartmental methods using routines supplied in the WinNonlin Version 1.1 software package (Scientific Consulting; Apex, NC). Area under the curve from time zero to infinity (AUC) for the plasma profiles was estimated by the logarithmic-linear trapezoidal algorithm to the last data point, with extrapolation to time infinity using the estimated value of the slope of the terminal logarithmic-linear phase. Total plasma clearance (CL) was calculated as the dose divided by the AUC. Mean values of the pharmacokinetic variables were calculated as the geometric mean of the individual patient values [22]. SDs of the geometric mean values were estimated by the jackknife method [23]. Parametric statistical tests using log-transformed values of the maximum concentration (Cmax), AUC, or CL of ET-743 were performed to identify differences among subgroups of patients categorized according to demographic characteristics or toxicity. p < 0.05 (two-tailed) was considered to be significantly different.


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient Characteristics
A total of 20 patients with a clinicopathologic diagnosis of GIST were enrolled into the study and treated with ET-743, beginning in August 1999. All were determined to be eligible at the time of study entry. One patient was withdrawn from the study prior to receiving any treatment due to rapidly progressing disease. Demographic characteristics of the patients are presented in Table 1Go. Only nine patients had received prior chemotherapy. Patients had been treated with a variety of regimens but all pretreated patients had received prior adriamycin, and five patients had received prior ifosfamide. Immunohistochemical detection of KIT was not considered an entry criterion for participation in the study, as the performance of this test to diagnose GISTs did not become standard practice until early 2000. However, KIT expression by tumor samples was assayed retrospectively whenever possible in these study patients. Sixteen of the 20 patients were confirmed to have positive immunohistochemical staining for KIT, and only one patient was found to be KIT negative by immunohistochemistry. Unstained tumor samples were not available for KIT immunoassay in three patients.


View this table:
[in this window]
[in a new window]
  		Table 1. Patient characteristics
 
Toxicity
A total of 47 cycles (median 2, range 1-10) of therapy were administered. The full 1.5-mg/m2 dose was delivered in 44/47 (94%) of the cycles, and the dose was reduced to 1.2 mg/m2 in only three patients. All 19 patients entered into the study who received protocol treatment were evaluable for toxicity. Hematologic toxicity was mild, with 47% of patients experiencing grade 3 neutropenia; there were no occurrences of more severe neutropenia or thrombocytopenia greater than grade 2 (Table 2Go). Among the nonhematologic toxicities, there were no grade 4 events, and the only grade 3 events were transaminitis in 10 patients and fatigue in a single patient (Table 2Go). There was only one patient in which the time to fully recover from grade 3 transaminase elevations required more than 21 days.


View this table:
[in this window]
[in a new window]
  		Table 2. Most severe toxicities observed over all cycles of therapy
 
Efficacy and Survival
One patient, who withdrew from the study due to toxicity, was unevaluable due to the absence of repeat scans. There were no complete or partial regressions among the 18 treated patients who were evaluable for response. Only two patients (one patient with no prior therapy and one patient previously treated with an adriamycin-based regimen) exhibited stable disease as the best response to therapy with ET-743, with one patient receiving four cycles of therapy and another 10 cycles of therapy. All other patients were removed from the study due to disease progression when evaluated soon after receiving the second cycle of therapy. There were no discernible differences between the characteristics of the two patients who had stable disease and those of the 16 patients who progressed on therapy. The median time to progression was 1.25 months (Fig. 1Go). Due to the dramatic change in the control of GISTs for those patients after STI571 in our clinical study in July 2000, overall survival is shown with and without censoring for patients who were subsequently treated with STI571 (Figs. 2 and 3GoGo). All the patients who went on to STI571 were alive at 1 year, as opposed to only 18% of the patients who did not receive STI571.



View larger version (14K):
[in this window]
[in a new window]
  		Figure 1. Time to progression. Abbreviation: CI = confidence interval.

 


View larger version (10K):
[in this window]
[in a new window]
  		Figure 2. Overall survival.

 


View larger version (11K):
[in this window]
[in a new window]
  		Figure 3. Overall survival among patients not receiving STI571.

 
Pharmacokinetics
Complete sets of plasma specimens were obtained during treatment with the first 1.5 mg/m2 dose of ET-743, given as a 24-hour continuous i.v. infusion, from 19 of the 20 patients entered into the study. The mean ± SD AUC of ET-743 was 34.2 ± 8.9 ng•h/ml (range 16.4-52.1 ng•h/ml), and the mean CL was 43.9 ± 15.8 l/h/m2. The mean ± SD of the observed Cmax of the drug was 1.10 ± 0.44 ng/ml. The AUC and Cmax values were used to evaluate associations between ET-743 pharmacokinetics and pretreatment pathophysiological characteristics of the patients. There were no statistically significant differences in the mean AUC for patients grouped according to gender, age (<=50 years versus >50 years), and performance status. Values of the AUC or Cmax in patients experiencing any severe toxicity (i.e., grade >=3) during the first cycle of therapy were not significantly different from values in other patients.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Malignant GISTs are the most common mesenchymal malignancy of the gastrointestinal tract and are characterized immunohistochemically by the expression of the KIT transmembrane receptor tyrosine kinase (CD117) [1]. Most malignant GISTs have mutations in c-kit that lead to constitutive expression of the KIT tyrosine kinase. Downstream effects of this tyrosine kinase include signaling cascades, which promote resistance to apoptosis, uncontrolled cell proliferation, and the malignant phenotype of this disease [6, 24–26]. Until recently, GISTs were treated according to the same principles as those applied to STSs. Standard chemotherapeutic agents, such as doxorubicin and ifosfamide, which can lead to objective responses in 16%-34% of patients with STSs [27–32], have been virtually useless against GISTs [10]. Due to the lack of available treatment options for GISTs, prior to the recent introduction of STI571, we undertook this study as the first prospective phase II trial of an investigational or approved chemotherapeutic agent to specifically target this highly resistant disease.

There was no evidence of any significant antitumor activity in this patient population. Disease progression was evident in 16/18 patients who were evaluable for efficacy after two cycles. These results confirm the retrospective and largely anecdotal evidence that GISTs do not respond to conventional chemotherapy. Moreover, these results stand in stark contrast to the recently described clinical findings of STI571 in patients with GISTs, where 59% and 26% of the cohort had responding or stable disease, respectively [33]. The overall survival of patients in our study should be viewed cautiously, since this was likely impacted significantly by the subsequent clinical trial at our institution studying STI571 in GIST. Eleven patients from this study subsequently received STI571. The 1-year survival declined from 71% to 18% when these patients were censored from survival analysis at the time of starting STI571.

Toxicity in this study was moderate, since there were no grade 4 hematologic toxicities. In contrast, grade 4 neutropenia was noted in 10%-18% of cycles, and grade 4 thrombocytopenia occurred in 1.7%-3.8% of cycles when this regimen was administered to patients with soft tissue sarcomas [19]. Mean values of the AUC (34.2 ± 12.5 ng•h/ml) and Cmax (1.10 ± 0.44 ng/ml) of ET-743 in GIST patients were also substantially lower than the AUC (55 ± 25 ng•h/ml) and Cmax (1.8 ± 1.1 ng/ml) reported for 25 patients treated with a dose of 1.5 mg/m2 during the initial phase I trial of ET-743 given as 24-hour continuous i.v. infusion [34]. Moreover, the highest AUC value observed in this study was lower than the mean AUC for this same dose in the phase I trial. The lower apparent systemic exposure of GIST patients to ET-743 may account for the better-than-anticipated tolerability of the drug.

It has been suggested that the ineffectiveness of the chemotherapy against GISTs may be associated with MDR, and in particular, overexpression of the MDR gene product, P-glycoprotein (PGP). Such PGP overexpression was found in 68% of clinically defined GISTs compared with only 31% in leiomyosarcomas [35]. Greater expression of PGP has been associated with resistance to ET-743 in tumor cell lines [36]. Thus, it would appear possible that the lack of activity of ET-743 in GIST patients may be the combined result of MDR and enhanced systemic clearance by an unclear mechanism. Since 79% of patients in this study had hepatic involvement of their disease, it may be postulated that these metastases affected clearance, e.g., increased hepatic blood flow. It is unlikely that the enhanced CL of ET-743 observed is related to the concurrent administration of dexamethasone as a prophylactic antiemetic. The mean AUC in the subset of patients that received dexamethasone (33.0 ± 12.7 ng•h/ml, n = 13) did not differ significantly (p = 0.53) from that of those who did not receive dexamethasone (36.9 ± 13.2 ng•h/ml, n = 6).

In summary, this study represents the first prospective phase II clinical trial undertaken to evaluate a cytotoxic chemotherapeutic agent in patients with GISTs. The lack of significant activity underscores the chemorefractory nature of this malignancy, which has previously been limited to anecdotal experience and retrospective subset-based analyses of the literature. Therapeutically ineffective exposure to the drug, based upon the lower incidence of severe toxicities and greater CL than described in several recently reported phase I and II trials of ET-743, may have contributed to the inactivity of ET-743 against GISTs. Nevertheless, the survival curves established during the course of this study provide a baseline for evaluating the therapeutic effects of STI571.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
J.J. receives research support from and is a stockholder and employee of Pharma Mar. G.D. receives research support and is a consultant for Pharma Mar and Johnson and Johnson.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Miettinen M, Lasota J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 2001;438:1–12.[CrossRef][Medline]
  2. Rubin BP, Singer S, Tsao C et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 2001;61:8118–8121.[Abstract/Free Full Text]
  3. Ernst SI, Hubbs AE, Przygodzki RM et al. KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors. Lab Invest 1998;78:1633–1636.[Medline]
  4. Lasota J, Jasinski M, Sarlomo-Rikala M et al. Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol 1999;154:53–60.[Abstract/Free Full Text]
  5. Taniguchi M, Nishida T, Hirota S et al. Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res 1999;59:4297–4300.[Abstract/Free Full Text]
  6. Lux ML, Rubin BP, Biase TL et al. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 2000;156:791–795.[Abstract/Free Full Text]
  7. Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052–1056.[Free Full Text]
  8. DeMatteo RP, Lewis JJ, Leung D et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51–58.[CrossRef][Medline]
  9. Pierie JP, Choudry U, Muzikansky A et al. The effect of surgery and grade on outcome of gastrointestinal stromal tumors. Arch Surg 2001;136:383–389.[Abstract/Free Full Text]
  10. Goss GA, Merriam P, Manola J et al. Clinical and pathological characteristics of gastrointestinal stromal tumors (GISTs). Proc Am Soc Clin Oncol 2000;19:2203a.
  11. Sakai R, Rinehart KL, Guan Y et al. Additional antitumor ecteinascidins from a Caribbean tunicate: crystal structures and activities in vivo. Proc Natl Acad Sci USA 1992;89:11456–11460.[Abstract/Free Full Text]
  12. Izbicka E, Lawrence R, Raymond E et al. In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann Oncol 1998;9:981–987.[Abstract/Free Full Text]
  13. Pommier Y, Kohlhagen G, Bailly C et al. DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 1996;35:13303–13309.[CrossRef][Medline]
  14. Moore 2nd BM, Seaman FC, Hurley LH. NMR-based model of an ecteinascidin 743-DNA adduct. J Am Chem Soc 1997;119:5475–5476.[CrossRef]
  15. Takebayashi Y, Pourquier P, Zimonjic DB et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 2001;7:961–966.[CrossRef][Medline]
  16. Jin S, Gorfajn B, Faircloth G et al. Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc Natl Acad Sci USA 2001;97:6775–6779.[Abstract/Free Full Text]
  17. Minuzzo M, Marchini S, Broggini M et al. Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci USA 2000;97:6780–6784.[Abstract/Free Full Text]
  18. Ryan DP, Supko JG, Eder JP et al. Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies. Clin Cancer Res 2001;7:231–242.[Abstract/Free Full Text]
  19. Delaloge S, Yovine A, Taamma A et al. Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients—preliminary evidence of activity. J Clin Oncol 2001;19:1248–1255.[Abstract/Free Full Text]
  20. Taamma A, Misset JL, Riofrio M et al. Phase I and pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors. J Clin Oncol 2001;19:1256–1265.[Abstract/Free Full Text]
  21. Villalona-Calero MA, Eckhardt SG, Weiss G et al. A phase I and pharmacokinetic study of ecteinascidin-743 on a daily x 5 schedule in patients with solid malignancies. Clin Cancer Res 2002;8:75–85.[Abstract/Free Full Text]
  22. Mizuta E, Tsubotani A. Preparation of mean drug concentration—time curves in plasma. A study on the frequency distribution of pharmacokinetic parameters. Chem Pharm Bull (Tokyo) 1985;33:1620–1632.
  23. Lam FC, Hung CT, Perrier DG. Estimation of variance for harmonic mean half-lives. J Pharm Sci 1985;74:229–231.[Medline]
  24. Nakahara M, Isozaki K, Hirota S et al. A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors. Gastroenterology 1998;115:1090–1095.[CrossRef][Medline]
  25. Hirota S, Isozaki K, Nishida T et al. Effects of loss-of-function and gain-of-function mutations of c-kit on the gastrointestinal tract. J Gastroenterol 2000;35(suppl 12):75–79.[CrossRef]
  26. Hirota S, Nishida T, Isozaki K et al. Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours. J Pathol 2001;193:505–510.[CrossRef][Medline]
  27. Baker LH, Frank J, Fine G et al. Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613). J Clin Oncol 1987;5:851–861.[Abstract/Free Full Text]
  28. Borden EC, Amato DA, Rosenbaum C et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987;5:840–850.[Abstract/Free Full Text]
  29. Antman KH, Ryan L, Elias A et al. Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 1989;7:126–131.[Abstract]
  30. Edmonson JH, Ryan LM, Blum RH et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 1993;11:1269–1275.[Abstract/Free Full Text]
  31. Antman K, Crowley J, Balcerzak SP et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 1993;11:1276–1285.[Abstract/Free Full Text]
  32. Le Cesne A, Antoine E, Spielmann M et al. High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas. J Clin Oncol 1995;13:1600–1608.[Abstract/Free Full Text]
  33. Blanke CD, von Mehren M, Joensuu H et al. Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI571, in patients (pts) with unresectable or metastatic gastrointestinal stromal tumors (GISTS) expressing c-KIT (CD117). Proc Am Soc Clin Oncol 2001;20:1a.
  34. van Kesteren C, Cvitkovic E, Taamma A et al. Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study. Clin Cancer Res 2000;6:4725–4732.[Abstract/Free Full Text]
  35. Plaat BE, Hollema H, Molenaar WM et al. Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol 2000;18:3211–3220.[Abstract/Free Full Text]
  36. Erba E, Bergamaschi D, Bassano L et al. Isolation and characterization of an IGROV-1 human ovarian cancer cell line made resistant to Ecteinascidin-743 (ET-743). Br J Cancer 2000;82:1732–1739.[CrossRef][Medline]
Received August 6, 2002; accepted for publication October 17, 2002.




This article has been cited by other articles:


Home page
 The OncologistHome page
R. S. Benjamin, C. D. Blanke, J.-Y. Blay, S. Bonvalot, and B. Eisenberg
Management of Gastrointestinal Stromal Tumors in the Imatinib Era: Selected Case Studies
Oncologist, January 1, 2006; 11(1): 9 - 20.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
N. Theou, S. Gil, A. Devocelle, C. Julie, A. Lavergne-Slove, A. Beauchet, P. Callard, R. Farinotti, A. Le Cesne, A. Lemoine, et al.
Multidrug Resistance Proteins in Gastrointestinal Stromal Tumors: Site-Dependent Expression and Initial Response to Imatinib
Clin. Cancer Res., November 1, 2005; 11(21): 7593 - 7598.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
J.-Y. Blay, S. Bonvalot, P. Casali, H. Choi, M. Debiec-Richter, A. P. Dei Tos, J.-F. Emile, A. Gronchi, P. C. W. Hogendoorn, H. Joensuu, et al.
Consensus meeting for the management of gastrointestinal stromal tumors * Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO
Ann. Onc., April 1, 2005; 16(4): 566 - 578.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. Lau, J. G. Supko, S. Blaney, L. Hershon, N. Seibel, M. Krailo, W. Qu, D. Malkin, J. Jimeno, M. Bernstein, et al.
A Phase I and Pharmacokinetic Study of Ecteinascidin-743 (Yondelis) in Children with Refractory Solid Tumors. A Children's Oncology Group Study
Clin. Cancer Res., January 15, 2005; 11(2): 672 - 677.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ryan, D. P.
Right arrow Articles by Demetri, G. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ryan, D. P.
Right arrow Articles by Demetri, G. D.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS