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Randomized Phase III Trial of Pegylated Liposomal Doxorubicin Versus Vinorelbine or Mitomycin C Plus Vinblastine in Women With Taxane-Refractory Advanced Breast Cancer

From US Oncology Inc, Cancer Care Associates, Tulsa, OK; US Oncology, Dallas, TX; University Hospital of Heraklion, Heraklion, Crete, Greece; Cross Cancer Institute, Edmonton, Alberta, Canada; Centro Medico Nacional ISSSTE, Mexico, D.F. Mexico; Hospital Clinico Universitario, Valencia, Spain; Aventura Concorde Center II, Aventura, FL; Department of Gynecology and Obstetrics, Johann Wolfgang Goethe-University, Frankfurt, Germany; University of California San Francisco, San Francisco, CA; Schering-Plough Research Institute, Kenilworth, NJ.

Address reprint requests to Alan M. Keller, MD, US Oncology Inc, Cancer Care Associates, 6151 S Yale, Tulsa, OK 74136, e-mail: alan.keller2{at}usoncology.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
PURPOSE: To compare the efficacy of pegylated liposomal doxorubicin (PLD) with that of a common salvage regimen (comparator) in patients with taxane-refractory advanced breast cancer.

PATIENTS AND METHODS: Following failure of a first- or second-line taxane-containing regimen for metastatic disease, 301 women were randomly assigned to receive PLD (50 mg/m² every 28 days); or comparator-vinorelbine (30 mg/m² weekly) or mitomycin C (10 mg/m² day 1 and every 28 days) plus vinblastine (5 mg/m² day 1, day 14, day 28, and day 42) every 6 to 8 weeks. Patients were stratified before random assignment based on number of previous chemotherapy regimens for metastatic disease and presence of bone metastases only.

RESULTS: Progression-free survival (PFS) and overall survival (OS) were similar for PLD and comparator (PFS: hazard ratio [HR], 1.26; 95% CI, 0.98 to 1.62; P = .11; median, 2.9 months [PLD] and 2.5 months [comparator]; OS: HR, 1.05; 95% CI, 0.82 to 1.33; P = .71; median, 11.0 months [PLD] and 9.0 months [comparator]). In anthracycline-naïve patients, PFS was somewhat longer with PLD, relative to the comparator (n = 44; median PFS, 5.8 v 2.1 months; HR, 2.40; 95% CI, 1.16 to 4.95; P = .01). Most frequently reported adverse events were nausea (23% to 31%), vomiting (17% to 20%), and fatigue (9% to 20%) and were similar among treatment groups. PLD-treated patients experienced more palmar-plantar erythrodysesthesia (37%; 18% grade 3, 1 patient grade 4) and stomatitis (22%; 5% grades 3/4). Neuropathy (11%), constipation (16%), and neutropenia (14%) were more common with vinorelbine. Alopecia was low in both the PLD and vinorelbine groups (3% and 5%).

CONCLUSION: PLD has efficacy comparable to that of common salvage regimens in patients with taxane-refractory metastatic breast cancer, thereby representing a useful therapeutic option.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
The anthracyclines and taxanes are generally considered the most active cytotoxic agents for the management of metastatic breast cancer. During the last 10 years, anthracyclines in particular have become more widely used in adjuvant combination chemotherapy regimens, resulting in greater use of taxanes as first-line treatment at the time of disease progression.¹ However, when patients relapse following taxane-based chemotherapy, there are few therapeutic options. Anthracyclines are often not considered in the metastatic setting because of the risk of anthracycline-induced cardiotoxicity that is associated with high cumulative anthracycline dose and with advanced age.² Efficacious and well-tolerated agents are urgently needed for use in this setting.

Pegylated liposomal doxorubicin (PLD; Caelyx; Schering-Plough Corp, Kenilworth, NJ; Doxil, ALZA Corp, Mountain View, CA) was developed to improve antitumor activity of doxorubicin and to reduce toxicity. In this formulation, doxorubicin-encapsulated liposomes are sterically stabilized by grafting polyethylene glycol onto the liposomal surface (Stealth Liposome). Pegylated liposomal encapsulation reduces plasma levels of free drug as well as drug delivery to normal tissues, potentially decreasing toxicity. PLD has an altered kinetic profile that results in a circulation half-life of approximately 73.9 hours,³ compared with doxorubicin, which has a half-life of less than 10 minutes. Prolonged circulation then permits greater uptake of PLD liposomes by tumor tissues. PLD accumulates selectively in metastatic breast carcinoma tissue, resulting in 10-fold higher intracellular drug concentrations as compared with adjacent normal tissue.⁴

Studies of PLD suggest that a dose of 45 to 50 mg/m² every 4 weeks is well tolerated with little nausea or vomiting, mild myelosuppression, minimal alopecia, and very little cardiotoxicity.^5-7 Ranson et al demonstrated a 31% overall response rate in women with metastatic breast cancer using PLD at doses of 45 to 60 mg/m² every 3 or 4 weeks.⁷ In a phase II trial of patients with advanced ovarian cancer refractory to both platinum- and taxane-containing regimens, PLD had substantial clinical activity, resulting in durable clinical responses in 26% of patients.⁸ In a phase III trial, PLD demonstrated statistically significant improvement in both progression-free survival (PFS) and overall survival (OS) compared with topotecan in ovarian cancer patients who progressed more than 6 months after first-line platinum-based chemotherapy (usually in combination with paclitaxel).⁶ Together, these studies provide the rationale for studying the efficacy and safety of PLD in women with metastatic breast cancer after taxane failure.

The present phase III trial represents the first randomized, controlled study of PLD in patients with taxane-refractory advanced breast cancer. Due to the lack of a universally accepted single salvage regimen, patients in the control group received either vinorelbine or mitomycin C plus vinblastine, regimens previously shown to have moderate efficacy,^9,10 and considered by the participating physicians to be the usual treatment in this setting, before the onset of the study. PFS, OS, and health-related quality of life (HQL) were assessed to determine whether PLD was superior to the comparator in women with taxane-refractory advanced breast cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
Study Design
This randomized, controlled, open-label, parallel-group, multicenter phase III trial compared the efficacy and safety of PLD (1-hour intravenous [IV] infusion of 50 mg/m² every 4 weeks) with that of commonly used salvage chemotherapy regimens (comparator). The choice of comparator was determined by the investigator at site initiation to be either vinorelbine (6- to 10-minute IV infusion of 30 mg/m² weekly), or mitomycin C (10 mg/m² IV on days 1 and 28) and vinblastine (5 mg/m² IV on days 1, 14, 28, and 42 for two cycles [days 1 to 56]); subsequent cycles were mitomycin C (10 mg/m² IV on day 1) and vinblastine at 5 mg/m² IV on days 1 and 21. Mitomycin C was administered at 6- to 8-week intervals after adequate hematologic recovery.

The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines. Informed consent and protocol were reviewed and approved by the appropriate local ethics or review boards before study initiation.

Inclusion Criteria
Women with taxane-refractory advanced breast cancer were eligible for enrollment. Taxane failure was defined as disease progression during or within 6 months of the last dose of a taxane-containing regimen for advanced disease. However, no more than 2 months could have elapsed between demonstration of taxane failure and study inclusion. Histological proof of breast cancer and radiographic evidence of locally advanced or metastatic breast cancer (stages IIIB and IV)¹¹ were required. At least one measurable or assessable lesion, as well as one, but no more than two prior chemotherapy regimens for advanced disease (excluding adjuvant therapy) were required. The last regimen must have included a taxane.

Patients had to demonstrate a stable Karnofsky performance status of 60%, a left ventricular ejection fraction (LVEF) greater than or equal to the institutional lower limit of normal, baseline HQL questionnaire completion, and written informed consent. Women of childbearing potential had to demonstrate that they were not pregnant and had to practice appropriate birth control throughout the entire study.

Exclusion Criteria
Patients with any abnormalities in hematological parameters, or renal or liver function were excluded. Exposure to any experimental drug within the month before randomization, prior anthracycline therapy with a cumulative doxorubicin-equivalent dose greater than 450 mg/m², or a cumulative epirubicin dose greater than 840 mg/m² were also reasons for exclusion, as were history of cardiac disease, uncontrolled systemic infection, prior therapy with PLD, and radiation to diseased areas within 3 weeks of study.

Method of Random Assignment
Patients were randomly assigned in a 1:1 ratio to receive either PLD or the comparator. To balance the treatment groups, patients were stratified before random assignment with respect to number of previous chemotherapy regimens for metastatic disease (one or two) and presence of bone metastases only (yes or no).

Clinical Assessments
A complete medical history, physical examination, Karnofsky performance status,¹² hematology profiles, serum chemistries, HQL questionnaire, and adverse event assessment were performed at baseline and repeated every 4 weeks. LVEF, as determined by multigated acquisition (MUGA) scan, was calculated at study entry and repeated at cumulative anthracycline doses of 300 mg/m² and every 100 mg/m² thereafter (PLD only). Objective assessments of tumor measurement were done every 8 weeks. Survival status on all study patients was updated as of October 2001.

Primary Efficacy Assessments
The primary efficacy variable was PFS, which was defined as the date of random assignment to the date of disease progression, death, or last follow-up (censored), whichever occurred first. Secondary efficacy analyses included OS, overall response rate, response duration, event-free survival, tolerability, HQL, and clinical benefit response.

Safety Assessments
Safety was monitored by clinical and laboratory evaluations. The presence of any preexisting signs and symptoms (pretreatment) were noted by the investigator, as were adverse events that occurred during the study treatment and/or during follow-up. Adverse event data included date of onset and resolution, severity, frequency, impact on study treatments, and outcome.

Statistical Methodology
The cutoff date for this analysis was April 1, 1999. Based on the two-sided, log-rank test, with 225 disease progressions or deaths, the study was designed to detect a 50% improvement in median PFS from 3 months to 4.5 months (corresponding to a hazard ratio [HR] of 1.5), with an overall power of 85%, while maintaining a .05 overall level of significance. The analysis was based on the O'Brien-Fleming group sequential procedure and allowed for a maximum of three assessments. All tests were performed on the intent-to-treat population, which included all randomly assigned patients. PFS curves were calculated using the Kaplan-Meier method, and the stratified log-rank test was used to detect any potential differences between the two treatment groups. A Cox regression analysis was performed to assess the potential influence of the following prognostic factors on PFS: age (< 55 years, 55 years), performance status (> 80%, 80%), site of metastases (bone only, not bone only), prior anthracycline exposure (yes, no), primary anthracycline resistance (yes, no), estrogen receptor status (positive, negative, not specified), disease-free interval (< 24 months, 24 months), and number of previous chemotherapy regimens (one, two).

Overall response rate and response duration (time from complete response [CR] or partial response [PR] to progression/death) were compared using descriptive statistics. OS (date of randomization to date of death or last follow-up [censored]) was measured by the Kaplan-Meier method and stratified log-rank test.

Calculation of each European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30, version 2.0) HQL domain scale and checklist module was performed according to scoring guidelines for each HQL measure.¹³ Change from baseline HQL scores was calculated, and longitudinal data analysis was performed to compare HQL between treatment groups.

Clinical benefit response was based on achieving a response in all three of the EORTC QLQ-C30 domains of physical and social functioning and global quality of life. A response in a domain was considered if one of the two following conditions were met: (1) a baseline score at or above 80 and a week-9 to -12 average maintained at or above 80, or (2) a baseline score below 80 and a week-9 to -12 average at or above 50 that had not deteriorated by more than 10 points from baseline. Quality-adjusted survival was calculated using the Quality-Adjusted Time Without Symptoms of Disease and Toxicity of Treatment (Q-TWiST) method.¹⁴

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
A total of 301 women with advanced breast cancer were enrolled at 52 centers (PLD, n = 150; vinorelbine, n = 129; mitomycin C plus vinblastine, n = 22). Baseline patient demographics and disease characteristics were representative of patients with advanced breast cancer and comparable between treatment groups (Table 1). At enrollment, the majority of patients in each group (approximately 65%) had a large tumor burden, as assessed by visceral-dominant disease with multiple metastatic sites. The majority (83%) of patients in each group received prior anthracycline therapy, and 37% had primary anthracycline-resistant breast cancer, defined as disease progression during or within 6 months of the last dose of an anthracycline-containing regimen for metastatic disease (Table 2). Thirty-five patients in the PLD group and 34 patients in the comparator group did not meet one or more of the inclusion/exclusion criteria. The most common deviation in both groups was for number of prior chemotherapy regimens for advanced disease (no prior chemotherapy [15 patients] or more than two prior chemotherapy regimens for advanced disease [16 patients]).

View larger version (15K): [in this window] [in a new window]   Fig 1. Progression-free survival (PFS). PFS was similar for pegylated liposomal doxorubicin (PLD) and comparator (hazard ratio, 1.26; 95% CI, 0.98 to 1.62; P = .11; median PFS, 2.9 months v 2.5 months for PLD and comparator, respectively).

View larger version (33K): [in this window] [in a new window]   Fig 2. Progression-free survival by subgroups. Hazard ratio less than 1 favors comparator; hazard ratio greater than 1 favors pegylated liposomal doxorubicin (PLD). Numbers in parentheses indicate sample size for PLD/sample size for comparator. Recept, receptor; Chemo, chemotherapy.

View larger version (33K): [in this window] [in a new window]   Fig 3. Overall survival by subgroup. Numbers in parentheses indicate sample size for pegylated liposomal doxorubicin/sample size for comparator. Recept, receptor; Chemo, chemotherapy.

A quality-adjusted survival analysis demonstrated that the mean duration of survival and the time without toxicity or progression were comparable for both treatment groups (the PLD group had 0.14 more months without toxicity or progression).

Safety
The safety population included all randomized patients: PLD (n = 150), vinorelbine (n = 129), and mitomycin C plus vinblastine (n = 22). Eighty-three percent of PLD cycles, 56% of vinorelbine cycles, and 83% of mitomycin C plus vinblastine cycles were administered at more than 80% of the dose. The mean cycle length with PLD was 29.8 days, and the mean cycle dose for PLD was 48.6 mg/m². The median treatment durations were 66, 57, and 71 days with PLD, vinorelbine, and mitomycin C plus vinblastine, respectively. In the PLD group, more patients received more than 6 months of treatment compared with the other two groups: 15% with PLD versus 9% with vinorelbine and 9% with mitomycin C plus vinblastine. In the PLD group, the mean anthracycline dose received was 163 mg/m² not including prior anthracyclines, and 374 mg/m² when prior anthracyclines were included.

The most frequently reported adverse events common to all three groups (PLD, vinorelbine, and mitomycin C plus vinblastine, respectively) were nausea (31%, 27%, 23%), vomiting (20%, 17%, 18%), fatigue (20%, 21%, 9%), and asthenia (9%, 15%, 32%; Table 5). Alopecia was low, occurring in approximately 5% of both groups. The most common treatment-related adverse event with PLD was palmar-plantar erythrodysesthesia (PPE) occurring in 37% of patients (grade 3 = 18%, grade 4 = 1 patient). The discontinuation rate due to PPE was 8%. Infusion reactions were more common with PLD than with the control group (11% v 5%). Stomatitis was observed more frequently with PLD (22% all grades) than with vinorelbine (4% all grades).

View this table: [in this window] [in a new window]   Table 5. Adverse Events 5%

Changes in LVEF values were only assessed in patients receiving PLD. Cardiac toxicity was defined as either a decrease of 15 points from baseline or a 5-point decrease from baseline with a level below the lower limit of normal for the institution. Twenty-two patients developed LVEF changes consistent with cardiac toxicity. However, decreases in LVEF did not correlate with cumulative anthracycline dose and none of these patients developed clinical congestive heart failure. The majority (n = 14) discontinued due to progressive disease. There were four patients who discontinued treatment due to cardiac toxicity (LVEF decrease), three patients who discontinued due to noncardiac adverse events, and one patient who discontinued due to noncompliance.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
In this randomized phase III trial comparing PLD with commonly used salvage regimens in women with taxane-refractory advanced breast cancer, PFS and OS were comparable between treatment groups. To our knowledge, this is the only published randomized, phase III trial in taxane-refractory metastatic breast cancer. Vinorelbine, the cytotoxic agent utilized in 85% of the patients in the comparator group, had previously been reported to induce a 25% response rate and result in a median survival duration of 6 months in 40 women with metastatic breast cancer refractory to anthracyclines and taxanes.¹⁰ In a randomized phase III trial, both median PFS and OS were significantly better with vinorelbine compared with melphalan for second- and third-line treatment of anthracycline-resistant metastatic breast cancer (PFS: 12 weeks v 8 weeks, P < .001; OS: 35 weeks v 31 weeks, P = .034).¹⁵ The PFS and OS outcomes for vinorelbine in this prior study were comparable to those for the control in the present study, confirming that the control was an active salvage therapy for metastatic breast cancer refractory to anthracyclines and taxanes.

The majority of patients in this study had been previously exposed to anthracyclines: 83% of the patients had received prior anthracycline therapy, and 37% of the patient population entered the study with primary anthracycline-resistant breast cancer, defined as having progressed on anthracycline before study entry. Thus, the enrolled patients represented a particularly poor prognosis population; that is, they were less likely to respond to re-treatment with an anthracycline. Despite this exposure, PLD demonstrated activity in the subgroup of women with anthracycline- and taxane-refractory metastatic breast cancer, suggesting that PLD is not completely cross-resistant with anthracyclines and taxanes.

There were many factors that might have had an impact on the study outcome, including the overall clinical status of patients enrolled. Thirty-three percent of PLD patients, and 41% of the control patients progressed within 8 weeks of entry. Similarly, 21% to 24% of the patients in each group died within 4 months of study initiation. The fact that median PFS for both groups was lower than the predefined statistical assumption of 3 months in the protocol indicates that this patient population had a much poorer prognosis than anticipated. This potentially could have compromised the ability to show a difference between the two groups and could explain the low response rate seen in this study. Nevertheless, the duration of response was 6.7 months with PLD and 6.0 months with the comparator, indicating that for those patients who did achieve a response, it was durable. These outcomes are similar to those seen in a single-arm, nonrandomized phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer patients where median time to progression was 93 days, and median OS was 12.8 months.¹⁶

The safety profile seen here is consistent with the safety profile of PLD seen in previous solid tumor studies using the same dosage regimen of 50 mg/m² every 4 weeks. The most frequently reported adverse events common to all three groups (PLD, vinorelbine, and mitomycin C + vinblastine, respectively) were nausea, vomiting, and fatigue/asthenia. Skin toxicity (PPE), a reversible non–life-threatening event, occurred in 37% of patients (18% grade 3, one patient with grade 4). Last, the incidence of alopecia was low in both the PLD and vinorelbine groups. In this study, PLD had a better safety profile than the control group with regard to myelosuppression. Most notably, grade 3/4 decreases in leukocytes were more common with the control group than with PLD: 54% with vinorelbine and 30% with mitomycin C + vinblastine, compared with 20% with PLD.

In conclusion, the efficacy of PLD was comparable to commonly used salvage regimens used in the treatment of women with taxane-refractory metastatic breast cancer. PLD-mediated efficacy after taxane failure could be achieved in the absence of significant myelosuppression and neuropathy using a convenient monthly infusion. Thus, PLD is a useful palliative treatment for women with heavily pretreated, taxane-refractory, advanced breast cancer.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix REFERENCES

 
Participating institutions and investigators include the following.
Ivor Royston, MD and John Gutheil, MD San Diego, CA; ACRC/Arizona Clinical Research Center, Inc., Tucson, AZ (Manuel R. Modiano, MD); Interlakes Oncology & Hematology, P.C./Upstate NY Cancer Research & Education Foundation, Canandaigua, NY (Alex YC Chang, MD and Jonathan Rubins, MD); Rocky Mountain Cancer Centers, Denver, CO (Ioana Hinshaw, MD); UCSF/Mount Zion Cancer Center, San Francisco, CA (Debasish Tripathy, MD); Israel Wiznitzer, MD, Highland Park, IL; Metro-MN CCOP, St. Louis Park, MN (Patrick J. Flynn, MD); Cancer Consultants, Las Vegas, NV (John A. Ellerton, MD); Mark S. Rubin, MD, Fort Myers, FL; Memorial Regional Cancer, Hollywood, FL (James M. Cohen, MD); Hospital Dipreca, Santiago, Chile (Francisco J. Orlandi); Hospital Lainz, Vienna, Austria (Gerhard Baumgartner, MD); Gynecology Univ. Clinic, Vienna, Austria (Ernst Kubista, MD); Wilhelminenspital d. Stadt Wien, Vienna, Austria (Heinz Ludwig, MD); Oncology Center AZ VUB, Brussels, Belgium (J. DeGreve, MD); Cross Cancer Institute, Edmonton, Alberta, Canada (Michael Smylie, MD); Hotel-Dieu de Montreal, Montreal, Quebec (Jacques Jolivet, MD and Jean Latreille, MD); Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario (David G. Warr, MD); Syopatautien klinikka, Kuopio, Finland (Vesa Kataja, MD); Danderyd Hospital, Danderyd, Sweden (Sam Rotstein, MD); Service Oncologie Medicale, Lyon, France (Jean Paul Guastalla, MD and Dr. Bachelot, MD); Centre Francois Baclesse, Caen, France (Dr. Delozier, MD); Centre Rene Huguenin, Saint-Cloud, France (Francois Turpin, MD, Dr. Soulie, MD, and Dr. Brain, MD); Hopital Hotel Dieu, Paris, France (Claude Boiron, MD and Dr. Oudard, MD); Frauenklinik d. med. Hochschule, Hannover, Germany (Hans-Joachim Luck, MD); Frauenklinik und Poliklinik Universitats-Krankenhaus Eppendorf, Hamburg, Germany (Christoph Thomssen, MD); Zentrum F. Frauenheilkunde, Frankfurt, Germany (Manfred Kaufmann, MD); Klinik u. Poliklinik f. Frauenheilk, Klinikum Grosshadern, Munchen, Germany (Michael Untch, MD); Klinikum d. Hansestadt Stralsund Frauenklinik, Stralsund, Germany (Jurgen Heinrich, MD); Oncologia Medica, Genova, Italy (Ricardo Rosso, MD and Lazzaro Repetto, MD); Divisione di Oncologia Medica-IEO, Milano, Italy (Franco Nole, MD and Aaron Goldhirsch, MD); Istituto Oncologico, Bari, Italy (Mario DeLena, MD and Angelo Paradiso, MD); Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy (Emilio Bajetta, MD); St. Elisabeth Hospital, Tilburg, the Netherlands (C. van der Heul, MD, PhD); Hospital Apeldoorn, Apeldoorn, the Netherlands (D. W. van Toorn, MD, PhD); Instituto Valenciano Oncologia, Valencia, Spain (Vincente Guillen, MD); Hospital 12 de Octubre, Madrid, Spain (Hernan Cortes-Funes, MD); Hospital Clinico Universitario, Zaragoza, Spain (Alejandro Tres Sanchez, MD); University Hospital, Linkoping, Sweden (Annika Malmstrom, MD); Karolinska Hospital, Stockholm, Sweden (Johan Hansson, MD); Kantonsspital St. Gallen, St. Gallen, Switzerland (Beat Thurlimann, MD); Guy's Hospital, London, UK (David Miles, MD); Western General Hospital, Edinburgh, UK (R. Leonard, MD); Universita' Cattolica, Roma, Italy (Salvatore Mancuso, MD); Centre Antoine Lacassagne, Nice, France (Jean Marc Fererro, MD and Moise Namer, MD); Centre Rene Gauducheau, Saint-Herblain, France (Pierre Fumoleau, MD).

Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Charles L. Vogel, OrthoBiotech, GlaxoSmithKline. Performed contract work within the last 2 years: Jean-Marc Nabholtz, Schering-Plough Research Institute; Charles L. Vogel, OrthoBiotech, GlaxoSmithKline; I. Craig Henderson, Schering-Plough Research Institute. Received more than $2,000 a year from a company for either of the last 2 years: Gunther von Minckwitz, Schering-Plough Research Institute; Lillian Mellars, Schering-Plough Research Institute; Leila Alland, Schering-Plough Research Institute; Craig Tendler, Schering-Plough Research Institute.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted August 23, 2002; accepted February 11, 2004.

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