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Comparison of Gemcitabine Versus the Matrix Metalloproteinase Inhibitor BAY 12-9566 in Patients With Advanced or Metastatic Adenocarcinoma of the Pancreas: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group

M.J. Moore, J. Hamm, J. Dancey, P.D. Eisenberg, M. Dagenais, A. Fields, K. Hagan, B. Greenberg, B. Colwell, B. Zee, D. Tu, J. Ottaway, R. Humphrey, L. Seymour

From the Princess Margaret Hospital, University Health Network, Toronto; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario; Centre Hospitalier de L’Universite Montreal Pavillon Saint-Luc, Montreal, Quebec; Cross Cancer Institute, Edmonton, Alberta; Nova Scotia Cancer Centre, Halifax, Nova Scotia, Canada; Alliant Health System, Louisville, KY; Sutter Health Cancer Research Center, Greenbrae, CA; Hematology and Oncology Associates of Virginia, Richmond, VA; and University of Connecticut Health Center, Farmington, CT.

Address reprint requests to Malcolm J. Moore, MD, Department of Medical Oncology, Princess Margaret Hospital, 5-205, 610 University Ave, Toronto, Ontario M5G 2M9, Canada; e-mail: malcolm.moore{at}uhn.on.ca.

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: To compare the selective matrix metalloproteinase inhibitor BAY 12-9566 with the nucleoside analog gemcitabine in the treatment of advanced pancreatic cancer.

Methods: Patients with advanced pancreatic adenocarcinoma who had not previously received chemotherapy were randomly assigned to receive BAY 12-9566 800 mg orally bid continuously or gemcitabine 1,000 mg/m² administered intravenously on days 1, 8, 15, 22, 29, 36, and 43 for the first 8 weeks, and then days 1, 8, and 15 of each subsequent 28-day cycle. The primary end point was overall survival; secondary end points were progression-free survival, tumor response, quality of life, and clinical benefit. The planned sample size of the study was 350 patients. Two formal interim analyses were planned.

Results: The study was closed to accrual after the second interim analysis on the basis of the recommendation of the National Cancer Institute of Canada Clinical Trials Group Data Safety Monitoring Committee. There were 277 patients enrolled onto the study, 138 in the BAY 12-9566 arm and 139 in the gemcitabine arm. The rates of serious toxicity were low in both arms. The median survival for the BAY 12-9566 arm and the gemcitabine arm was 3.74 months and 6.59 months, respectively (P < .001; stratified log-rank test). The median progression-free survival for the BAY 12-9566 and gemcitabine arms was 1.68 and 3.5 months, respectively (P < .001). Quality-of-life analysis also favored gemcitabine.

Conclusion: Gemcitabine is significantly superior to BAY 12-9566 in advanced pancreatic cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
ADENOCARCINOMA OF the pancreas is the fifth leading cause of cancer mortality in North America. The 5-year survival rate is less than 5%, the worst in the Surveillance, Epidemiology and End Results database. Better systemic therapies are needed. Gemcitabine (difluorodeoxycytidine) is a nucleoside analog with a wide spectrum of activity in murine and human tumor models.¹ In 1996, gemcitabine was approved for the treatment of advanced pancreatic cancer in the United States. The basis of this approval was a randomized study comparing weekly gemcitabine 1,000 mg/m² with weekly fluorouracil (FU) 600 mg/m² conducted in 126 patients with symptomatic advanced disease.² This study demonstrated an improvement in median survival (5.7 v 4.4 months; P < .002), 1-year survival (18% v 2%), and clinical benefit (a composite algorithm of pain relief, weight change, and performance status; 24% v 5%) with the use of gemcitabine.

The matrix metalloproteinases (MMPs) are a family of at least 11 zinc-containing endoproteinases that are capable of degrading collagen and proteoglycan. Degradation of the extracellular matrix is an important component of tumor invasion and metastases, and correlations between the aggressiveness of tumors and MMP secretion, particularly MMP-2 and MMP-9, have been demonstrated in a variety of solid tumors, including pancreatic cancer.^3,4 MMPs are also expressed to a greater degree in pancreatic neoplasms than in normal pancreatic tissue.⁵

BAY 12-9566 is a specific inhibitor of MMP-2, MMP-3, MMP-9, and MMP-13 with Ki of 11, 134, 301, and 1,470 nmol/L, respectively. It also has antiangiogenic properties on the basis of its ability to inhibit degradation and invasion of the extracellular matrix by endothelial cells, a process necessary for tumor neovascularization.⁶ Phase I studies demonstrated that doses up to 1,600 mg/d given continuously were well tolerated and gave serum concentrations greater than 2 to 4 logs higher than the Ki for MMP-2, MMP-3, and MMP-9. Absorption was saturable at the higher doses, and a dose of 800 mg bid was chosen for phase III studies.^7–9 In phase I testing there were patients with prolonged stable disease, with some patients remaining on drug for more than a year.

In 1997, gemcitabine was not commonly used for the treatment of patients with pancreatic cancer in Canada and had not yet been approved for this indication. The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) had previously completed phase I studies of BAY 12-9566 and had noted the prolonged disease stabilization of some trial patients.⁹ We initiated a phase III study comparing gemcitabine with BAY 12-9566 with two planned interim analyses, one after 60 patients had been entered to provide assurance that the study treatment had acceptable activity and a second after half the planned events had occurred.

	METHODS

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This randomized trial conducted in Canada and the United States was coordinated by NCIC-CTG and sponsored by Bayer Corporation (West Haven, CT). The trial compared BAY 12-9566 given orally twice daily until progression with gemcitabine given intravenously in patients with advanced pancreas cancer. Patients were stratified by prior radiation, measurable versus nonmeasurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status (0 to 1 v 2). The primary end point was overall survival, with secondary end points of progression-free survival (PFS), quality of life (QOL), pain intensity, analgesic consumption, performance status changes, weight change, and response rate. All patients entered onto the trial were observed until death.

Treatments
BAY 12-9566. Eight hundred milligrams administered orally twice a day was given continuously. Each 4-week period was considered one cycle. The drug was supplied as 200-mg tablets, and patients were given a 1-month supply at a time in an individual labeled bottle. Dose escalation of BAY 12-9566 was not permitted. Dose modifications for both hematologic and nonhematologic toxicity were as follows: for grade 0 or 1 toxicity, patients were to continue at a dose of 800 mg bid; for grade 2 toxicity, the dose was reduced by 25%; for grade 3 toxicity, treatment was stopped until recovery to grade 1 toxicity (treatment was then restarted at 50% of the initial dose); for grade 4 toxicity, the patient was removed from study. Doses reduced for toxicity could not be re-escalated.

Gemcitabine. A total of 1,000 mg/m² was administered intravenously as a 30-minute infusion on days 1, 8, 15, 22, 29, 36, and 43 for the first 8 weeks and then on days 1, 8, and 15 of each 28-day cycle. Initial gemcitabine doses were based on body-surface area. Doses could be escalated by 25% to 1,250 mg/m² provided that the patient had received two or more consecutive prior doses with grade 1 or less toxicity. Dose modifications on day 1 for nonhematologic toxicity were as follows: for grade 0, 1, or 2 toxicity, treatment was continued at the previous dose; for grade 3 toxicity, treatment was stopped until recovery to grade 2 (treatment was then restarted at 75% of the previous dose); for grade 4 toxicity, the patient was removed from study. Dose modifications on day 1 for hematologic toxicity were as follows: in the case of granulocyte count 1.5 x 10⁹/L or platelet count 100 x 10⁹/L, treatment was stopped until recovery. Within cycles, gemcitabine was given at full dose in the case of granulocyte count 1.0 x 10⁹/L, platelets 100 x 10⁹/L, and nonhematologic toxicity no worse than grade 2. The dose was reduced by 50% in the case of granulocyte count 0.5 to 0.99 x 10⁹/L, platelets 50 to 99 x 10⁹/L, or grade 3 nonhematologic toxicity, and held for granulocytes less than 0.5 x 10⁹/L, platelets less than 50 x 10⁹/L, or grade 4 nonhematologic toxicity. Doses that were held during a cycle were considered missed. Day 1 doses of gemcitabine that were reduced for toxicity could not be re-escalated.

Patients could receive other supportive measures with the exception of colony-stimulating factors, biologic response modifiers, or other investigational agents. Treatments were to continue until evidence of progressive disease, intolerable toxicity, intercurrent illness that prevented continuation, patients’ voluntary withdrawal, or physician decision to stop therapy. Therapy after completion of the study protocol was at the discretion of the investigator. BAY 12-9566 was not available for patients who experienced disease progression while being treated with gemcitabine.

Patient Population
The study population consisted of patients with histologically confirmed, unresectable, locally advanced or metastatic pancreatic adenocarcinoma. Measurable disease was not an eligibility criterion. Patients taking analgesia were required to have stable analgesic usage (not > 10% change in daily dose for the 5 days before randomization). Prior radiation therapy for the localized disease was allowed providing that disease progression after radiation was documented and it was completed at least 6 weeks before randomization. No prior chemotherapy was allowed, with the exception of FU given concurrently with radiation as a radiosensitizer. At baseline, patients were required to have a performance status (ECOG) of 2 or less, absolute granulocyte count of 1.5 x 10⁹/L, platelet count of 100 x 10⁹/L, serum bilirubin less than 1.5 x the upper limit of normal (ULN), AST and ALT less than 4 x ULN, and serum creatinine less than 1.5 x ULN.

Exclusion criteria were CNS metastases, prior MMP inhibitor therapy, and prior investigational therapy within 30 days of study entry. Pregnant and breast-feeding women were also not eligible for study. Patients with any active infections that might expose them to undue risk were also excluded. Patients with other malignancies (other than nonmelanoma skin cancer or in situ cancers), those who were unable to swallow oral medications, those who had malabsorption, or who had had a major vascular event within 3 months of study entry were excluded.

All patients had to be able and willing to give written consent according to local institutional and university human experimentation committee requirements before randomization. Protocol treatment was started within 5 days of randomization.

Evaluation
Medical history and physical examination were performed at baseline and then at least every 4 weeks. Independent assessment of performance status (by a person other than the treating physician) was performed at the same intervals. Routine biochemical testing and urinalysis were performed at baseline and every 4 weeks thereafter. Hematologic parameters were assessed every 4 weeks in patients receiving BAY 12-9566 and weekly in patients receiving gemcitabine. A baseline toxicity evaluation was performed, and toxicities were collected at each treatment visit and graded according to the NCIC-CTG Expanded Common Toxicity Criteria.¹⁰

Evaluation of disease, including a chest x-ray and abdominal computed tomography scanning, were required at baseline and at subsequent 8-week intervals. If a patient met the criteria for complete or partial response or for equivocal progression (see Response to Therapy), then a repeat evaluation was performed 4 weeks later. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30,¹¹ Functional Assessment of Cancer Therapy Fatigue subscale,¹² and a trial-specific pain checklist were to be completed at baseline and every 4 weeks thereafter while patients were on study. Patients collected analgesic consumption data daily and recorded pain intensity on a 100-mm linear analog scale once a week.

Response Assessment
Patients must have received at least 8 weeks of therapy to be considered assessable for response, unless disease progression or death from cancer occurred. A complete response was defined as disappearance of all evidence of tumor on two observations at least 4 weeks apart. A partial response required a 50% or greater decrease in the overall sum of the product of the longest diameter and its perpendicular of measurable lesions on two observations at least 4 weeks apart, with no new lesions or increase in any pre-existing lesion. Response duration was measured from the time of first meeting the measurement criteria until the time of tumor progression. Progressive disease was defined as an unequivocal increase of 25% in the overall sum of measurable lesions, a 50% increase in a single lesion that was smaller than 2 cm², appearance of new lesions, or clinical progression (a significant deterioration in pain, analgesic use, performance status maintained for at least 2 weeks and felt to be related to disease). As disease within the pancreatic bed is difficult to assess, the protocol allowed for patients with an increase of up to 50% in their pancreatic tumor with no new lesions or clinical progression to continue on therapy with a repeated computed tomography scan in 4 weeks. Stable disease was defined as an absence of partial response or progressive disease maintained for at least 6 weeks with no new lesions detected.

Statistical Methods
The planned sample size was 350 patients in order to have 80% chance of detecting, with a two-sided 5% level test, a 40% increase in median survival from the expected 6-month survival with gemcitabine and 84% power to detect the same risk ratio of 1.4 for PFS. The efficacy analyses were based on intent-to-treat principles. Overall survival was defined as the time from randomization to the time of death from any cause. Patients alive at the time of analysis were censored, and their survival time was measured as the time from randomization until last contact. The Kaplan-Meier method was used to analyze the time-to-event end point. A stratified log-rank test was used to compare survival difference between the two arms. A Cox proportional hazards model was used to assess prognostic factors, and the treatment effect was also tested after controlling for important prognostic variables. PFS was compared between treatment arms using a Kaplan-Meier estimate. The full QOL and clinical benefit analysis will be reported in more detail separately. Here we only present some results of the EORTC Quality of Life Questionnaire C30. The Likert-type responses of patients were scored into different domains or as a single item according to the standard manual of the EORTC. For each scale or measure, a linear transformation was applied to standardize the raw score to a range between 0 and 100. The resulting scores range from 0 to 100, with 100 representing the best possible response for functional domains (physical, role, emotional, cognitive, and social) and global QOL and the worst for symptom domains (fatigue, nausea and vomiting, pain) and single items (dyspnea, insomnia, constipation, diarrhea, financial difficulty). Because few patients were available after 8 weeks, the means and standard deviations of the change scores (from the baseline) at 4 and 8 weeks were calculated and compared using the Wilcoxon rank sum test.

Two interim analyses were planned to allow early termination if the study treatment was ineffective or extremely positive. The first interim analysis used a 2-month progression-free rate as the end point with a phase II stopping rule by Fleming.¹³ We considered a 10% progression-free rate at 2 months as an early indication of inactivity. The first interim analysis was carried out after there were 30 patients in each of the two arms with a null hypothesis that the proportion of patients free of progression is 10% versus an alternative hypothesis of a proportion of 30%. We would have stopped the study if there were six patients or fewer of 30 receiving BAY 12–9566 who were free of progression at 2 months. This stopping rule provided us with 84.0% power at a significance level of 2.6%. A similar assessment was made in the gemcitabine arm. The primary objective of this interim analysis was to provide preliminary evidence that the study treatment had acceptable antitumor activity.

The second interim analysis was based on overall survival and PFS when there were a total of 140 deaths in the study. The early stopping rule was based on a two-sided significance level of .0056 in the overall survival comparison. This significance level is based on the type I error spending function as proposed by Lan and DeMets¹⁴ with O’Brien and Fleming¹⁵ type boundary such that the final significance level is maintained at .048 level. The stopping rule called for termination of the study if either the overall survival or PFS of one arm compared with the other was significantly inferior at the .0056 level. The data from the two planned interim analyses was provided to the Data Safety Monitoring Committee (DSMC) of the NCIC-CTG.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The study was activated on December 15, 1997. The first interim analysis was performed in the fall of 1998, at which time the recommendation of the DSMC was to continue. The study was closed to accrual July 1999 after the second interim analysis based on the recommendation of the DSMC. At this time, patients receiving BAY12-9566 were advised to discontinue treatment and start gemcitabine. The data set for the final analysis of the study was frozen on May 3, 2000.

There were 277 patients assigned, 138 to BAY 12-9566 and 139 to gemcitabine. Two patients were deemed ineligible (one had no evidence of progression after radiation and one had biochemistry outside the permissible range). All patients are included in the analysis. The baseline patient characteristics are listed in Table 1. Most patients had ECOG performance status] of 1 with 22% having ECOG 0 and 19% having ECOG 2. A minority of patients had received prior therapy to the primary tumor. More than 90% of patients had either the local tumor present or a recurrence in the pancreatic bed, and 63% had metastatic disease. The most common sites of metastases were the liver (56%) and lung (12%).

The rates of serious toxicity were low in both arms. The incidence of grade 1 and 2 lethargy, nausea, and diarrhea and hematologic toxicity was greater with gemcitabine (Table 2). There were no incidences of febrile neutropenia. These analyses may underestimate the hematologic toxicity of BAY 12-9566, as this was only assessed every 4 weeks as compared with weekly for patients on gemcitabine. There were more patients with elevations of serum bilirubin in the BAY 12-9566 arm and slightly more patients with elevations of transaminases in the gemcitabine arm (Table 2).

View larger version (12K): [in this window] [in a new window]   Fig 1. Overall survival by study arm. (——), Bay 12-9566; (- - -), gemcitabine.

View larger version (12K): [in this window] [in a new window]   Fig 2. Progression-free survival by treatment arm. (——), Bay 12-9566; (- - -), gemcitabine.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
There are few therapies with proven benefit against pancreatic cancer. Gemcitabine was approved for pancreatic cancer on the basis of a randomized study comparing weekly gemcitabine with weekly FU that demonstrated an improvement in median survival, 1-year survival, and clinical benefit. When this study was initially designed, there were reservations as to the real clinical utility of the clinical benefit response, concern that the control arm of FU was not delivered optimally, and a questioning of the clinical significance of the differences seen.

There have now been three randomized trials, including the current report, that have compared single-agent gemcitabine with an alternative in pancreatic cancer.^2,16 In all three, gemcitabine demonstrated a significant improvement in survival and progression rates over the alternative (Table 6). There have been at least four randomized trials in which gemcitabine has been compared with a gemcitabine-based combination (gemcitabine plus FU, gemcitabine plus cisplatin, gemcitabine plus marimastat, and gemcitabine plus tipifarnib), none of which have shown any incremental benefit in terms of survival or QOL.^17–20

This trial is the first to have incorporated a systematic evaluation of QOL in patients with advanced pancreatic carcinoma receiving treatment. Despite a high dropout rate owing to progression, which may influence the results of the analyses, changes in domain and symptom scores favor gemcitabine. These differences were seen despite less toxicity noted among patients receiving BAY 12-9566 and likely reflect poorer control of disease with BAY 12-9566.

The first interim analysis was designed to detect inferiority of the study treatment early and thus prevent further study of an inactive compound. Whether the final results of this study may be considered evidence of failure of this rule could be debated. The ultimate 2-month PFS rate for BAY 12-9566 was 30%. There were only 30 patients on each arm at the time of the first interim analysis, and the confidence limits of the observed outcomes overlapped that of what would be expected with gemcitabine. Thus the decision to continue at that time was statistically appropriate given that the information was relatively early, a time when strong evidence is needed to terminate a study. The fact that the study was eventually stopped early at the second interim analysis shows that the use of several stopping rules in the design of the study was of value.

At present, single-agent gemcitabine remains the standard of care in advanced pancreatic cancer, and our trial can be viewed as further confirmation of its benefit. There has been a substantive increase in clinical investigation of both chemotherapy combinations as well as combinations of gemcitabine with molecularly targeted agents. These studies need to be designed to show improved outcomes rather than equivalency, and it is difficult to justify not including gemcitabine in all arms of any future study. The increased efforts in both basic and clinical research into pancreatic cancer will eventually lead to a better outcome for patients. The present trial demonstrates that the MMP inhibitor BAY 12-9566 is not a useful therapy in advanced pancreatic cancer.

	APPENDIX

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
In addition to the authors, the following investigators participated in this trial: S. Akhtar, Allan Blair Cancer Centre, Regina, SA; Y. Alam, Windsor Regional Cancer Centre, Windsor, ON; T. Al-Tweiger, Saskatoon Cancer Centre, Saskatoon, SA; S. Berry, Toronto Sunnybrook Health Centre, Toronto, ON; N. Bhoopalam, Edward Hines Jr. VA Hospital, Hines, IL; G. Bjarnason, Toronto Sunnybrook Health Centre, Toronto, ON; D. Brooks, Arizona Clinical Research Center, Tucson, AZ; M. Burnell, Saint John Regional Hospital, Saint John, NB; M. Cassidy, Sutter Health Cancer Research Center, Greenbrae, CA; G. Cecchi, Sutter Health Cancer Research Center, Greenbrae, CA; C. Cripps, Ottawa Regional Cancer Centre, Ottawa, ON; P. Czaykowski, Fraser Valley Cancer Centre, Surrey, BC; M. Davis, Nova Scotia Cancer Centre, Halifax, NS; M. Deleo, Berkshire Physicians and Surgeons, Pittsfield, MA; R. Doby, Southwest Regional Cancer Center, Austin, TX; J. Evers, Hematology and Oncology Associates of Virginia, Richmond, VA; J., Southwest Regional Cancer Center, Austin, TX; C., Vancouver Island Cancer Centre, Victoria, BC; J. Gapski, Trillium Heath Centre, Mississauga, ON; J. Giesbrecht, Hotel Dieu, St Catherines, ON; D. Ginsburg, Kingston Regional Cancer Centre, Kingston, ON; R. Goel, Ottawa Regional Cancer Centre, Ottawa, ON; M. Goodyear, Nova Scotia Cancer Centre, Halifax, NS; J. Gurlter, East Jefferson General Hospital, Metairie, LA; R. Haq, St Michael’s Hospital, Toronto, ON; P. Hughes, Hotel Dieu, St Catherines, ON; L. Irwin, Sutter Health Cancer Research Center, Greenbrae, CA; M. Jahanzeb, Comprehensive Cancer Center at JFK Medical Center, Atlantis, FL; R. Kerr, Southwest Regional Cancer Center, Austin, TX; K. Khoo, Southern Interior Cancer Centre, Kelowna, BC; M. King, Trillium Heath Centre, Mississauga, ON; D. Klassen, Vancouver Cancer Centre, Vancouver, BC; W. Kocha, London Regional Cancer Centre, London, ON; A. Koletsky, Comprehensive Cancer Center at JFK Medical Center, Atlantis, FL; M. Kuperminc, Hematology and Oncology Associates of Virginia, Richmond, VA; W. Kwant, Humber River Regional Hospital, Toronto, ON; S. Lebel, Hopital Laval-Ste-Foy, Quebec City, QE; H. Lenz, University of Southern California Norris/Comprehensive Cancer Center, Los Angeles, CA; B. Lesperance, Centre Hospitalier de L’Universite Montreal Pavillon Hotel Dieu, Montreal, QE; W. Lofters, Kingston Regional Cancer Centre, Kingston, ON; S. Malamud, Beth Israel Medical Center, New York, NY; J. Maroun, Ottawa Regional Cancer Centre, Ottawa, ON; R. Marsh, University of Florida, Gainesville, FL; J. Marshall, Lombardi Health Cancer Center, Washington, DC; B. Melosky, Vancouver Cancer Centre, Vancouver, BC; M. Modinao, Arizona Clinical Research Center, Tucson, AZ; M. Moore, Princess Margaret Hospital, Toronto, ON; NOBEL J. Nobel, St Joseph’s Health Centre, Toronto, ON; B. Norris, Fraser Valley Cancer Centre, Surrey, BC; A. Oza, Princess Margaret Hospital, Toronto, ON; B. Pressnail, Royal Victoria Hospital, Barrie, ON; L. Provencher, Centre Hospitalier de L’University Quebec, Hopital du Sacrement, Quebec City, QE; J. Polikoff, San Diego Oncology Research, San Diego, CA; P. Radice, Comprehensive Cancer Center at JFK Medical Center, Atlantis, FL; J. Ragaz, Vancouver Cancer Centre, Vancouver, BC; H. Rayner, Vancouver Island Cancer Centre, Victoria, BC; L. Rudinskas, Humber River Regional Hospital, Toronto, ON; D. Saltman, Pentiction Hospital, Okanagan, BC; R. Sawhnwy, Fraser Valley Cancer Centre, Surrey, BC; M. Schwarz, Hematology and Oncology Associates of Virginia, Richmond, VA; N. Sirott, Sutter Health Cancer Research Center, Greenbrae, CA; L. Siu, Princess Margaret Hospital, Toronto, ON; J. Skillings, Nova Scotia Cancer Centre, Halifax, NS; J. Sporn, University of Connecticut Health Center, Farmington, CT; M. Taylor, London Regional Cancer Centre, London, ON; A. Tomiak, London Regional Cancer Centre, London, ON; D. Trent, Hematology and Oncology Associates of Virginia, Richmond, VA; R. Tria Tirona, Allan Blair Cancer Centre, Regina, SA; H. Tucker, Hematology and Oncology Associates of Virginia, Richmond, VA; M. Vincent, London Regional Cancer Centre, London, ON; B. Weinerman, Vancouver Island Cancer Centre, Victoria, BC; J. Wilson, Humber River Regional Hospital, Toronto, ON; A. Wong, Tom Baker Cancer Centre, Calgary, AB; R. Wong, Dr H. Bliss Murphy Cancer Centre, St Johns, NFLD; L. Wood, Cross Cancer Institute, Edmonton, AB; I. Yaqoob, Allan Blair Cancer Centre, Regina, SA; L. Zibdawi, South Lake Regional Health Centre, Newmarket, ON.

	NOTES

 
Supported by Bayer Corporation, West Haven, CT.

Presented in part at the 36th Annual Meeting of the American Society of Clinical Oncology, May 20–23, 2000, New Orleans, LA.

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Submitted February 20, 2003; accepted June 3, 2003.

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