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Suramin Therapy for Patients With Symptomatic Hormone-Refractory Prostate Cancer: Results of a Randomized Phase III Trial Comparing Suramin Plus Hydrocortisone to Placebo Plus Hydrocortisone

From the University of California at San Francisco Comprehensive Cancer Center, San Francisco; University of California at Davis Cancer Center, Sacramento; and Cedars-Sinai Cancer Center, Los Angeles, CA; Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co, Ann Arbor, MI; Southeastern Medical Oncology Center, Goldsboro, NC; Hamilton Regional Cancer Center, Hamilton, Ontario, Canada; and Johns Hopkins University, Baltimore, MD.

Address reprint requests to Eric J. Small, MD, University of California at San Francisco, UCSF-Mount Zion Cancer Center, 2356 Sutter St, 5th Floor, San Francisco, CA 94115; email smalle{at}medicine ucsf.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer (HRPC). A prospective randomized clinical trial was designed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant, opioid analgesic–dependent pain.

PATIENTS AND METHODS: A double-blind, placebo-controlled trial randomized patients to receive a 78-day, outpatient regimen of either suramin plus hydrocortisone (HC, 40 mg/d) or placebo plus HC. Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred; placebo patients were allowed to cross-over to open-label suramin plus HC. In addition to pain and opioid analgesic intake, prostate-specific antigen (PSA) response, time to disease progression, quality of life, performance status, and survival were compared.

RESULTS: Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC (rank sum P = .0001). Pain response was achieved in a higher proportion of patients receiving suramin than placebo (43% v 28%; P = .001), and duration of response was longer for suramin responders (median, 240 v 69 days; P = .0027). Time to disease progression was longer (relative risk = 1.5; 95% confidence interval, 1.2 to 1.9) and the proportion of patients with a greater than 50% decline in PSA was higher (33% v 16%; P = .01) in patients who received suramin. Neither quality of life nor performance status was decreased by suramin treatment, and overall survival was similar. Most adverse events were of mild or moderate intensity and were easily managed medically.

CONCLUSION: Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PROSTATE CANCER IS the most prevalent form of cancer and the second leading cause of death due to cancer in North American men.¹ The most common metastatic site is bone, and progressive bone pain that is refractory to analgesics is one of the most frequent and intractable symptoms of metastatic prostate cancer. Metastatic disease is initially treated with androgen deprivation, which achieves stabilization or regression of disease in approximately 80% of patients.² However, despite secondary hormonal manipulations,³ all patients ultimately develop hormone-refractory prostate cancer (HRPC). The median survival for this group of patients is less than 1 year. To date, no agent has been shown to prolong survival in HRPC patients,^4,5 and prospectively validated palliative interventions are few. Novel therapeutic agents for the treatment of HRPC are urgently required.

The lack of acceptable and validated end points in studies of patients with HRPC has long challenged clinical investigators. Although a difference in survival between treatment arms remains the gold standard, this end point is increasingly difficult to evaluate in randomized clinical trials. Patients and investigators often demand a cross-over study design to ensure that all patients have access to potentially beneficial therapy. The lack of bidimensionally measurable disease in more than 70% of patients also precludes using responses in measurable disease as an end point. Reductions of prostate-specific antigen (PSA) have been the subject of multiple reports, yet PSA change as a surrogate marker of response has not been prospectively validated.^6-8 Because the goal of HRPC treatment is frequently palliation, the assessment of pain response and changes in quality-of-life (QOL) measures have become increasingly important trial end points.⁹

The activity of suramin as an antineoplastic agent in HRPC patients has been appreciated since the late 1980s. Suramin is a highly charged polysulfonated napthylurea that is capable of binding a number of proteins, including a variety of growth factors such as basic fibroblast growth factor. However, the degree to which the antitumor effects of suramin are mediated by this mechanism is not clear. Other potential mechanisms include its adrenolytic effects as well as a variety of biologic targets, such as protein kinase C, topoisomerase II, and glycosaminoglycan degradation.¹⁰ Although several reports have suggested that suramin possesses clinically significant antitumor activity as reflected by measurable disease responses, swift and durable declines in PSA levels, pain relief, and a relatively long time to disease progression,^11-14 there have been conflicting reports on the efficacy of suramin.^15,16 Furthermore, the adrenal suppressive properties of suramin require the concomitant administration of hydrocortisone (HC), which is itself an agent with some palliative and antitumor properties.¹⁷ In addition, the antiandrogen withdrawal syndrome^18,19 had not been characterized at the time when most of these studies were conducted. Thus some of the observed responses may have been due to antiandrogen withdrawal or the effect of HC. The evaluation of suramin in a large, controlled, multicenter, randomized trial was subsequently made possible by the development of a fixed dose schedule, which simplified the administration of suramin while reducing both the frequency and intensity of adverse events.¹²

A double-blind, placebo-controlled phase III trial was therefore undertaken to evaluate the efficacy of suramin plus HC in patients with symptomatic HRPC. This clinical trial is the largest randomized study of a cytotoxic agent undertaken in HRPC, and it evaluates several end points, including patient-derived measures of palliation, while controlling for confounding variables such as placebo, antiandrogen withdrawal, and corticosteroid effects.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Eligibility Criteria
Eligible patients had histologically confirmed adenocarcinoma of the prostate with painful bone metastases that necessitated a stable chronic regimen of opioid analgesics over the course of a lead-in period of at least 2 weeks, evidence of disease progression (defined by increasing bone pain or conventionally defined objective evidence of tumor growth) despite standard hormonal therapy, serum testosterone level 50 ng/mL, PSA level 10 ng/mL, Karnofsky performance status 60%, and an expected survival duration of at least 3 months. Two consecutive increasing PSA levels were required, with at least one obtained 28 days or more after antiandrogen discontinuation. Required laboratory parameters included serum creatinine 2.0 mg/dL, AST and ALT 2.5 times the upper limit of normal, bilirubin less than 1.5 mg/dL, albumin 3.0 g/dL, hemoglobin 9 g/dL, platelets more than 100,000/µL, absolute neutrophil count 1,500/µL, and normal prothrombin time and partial thromboplastin time. Exclusion criteria included requirements for systemic corticosteroids, any prior nonhormonal systemic therapy, radiation therapy within 28 days, strontium-89 therapy within 90 days, or prior malignancy. All patients provided written informed consent before study enrollment.

Study Design
Patients without prior orchiectomy continued on gonadal suppression with a luteinizing hormone–releasing hormone agonist. On day 1, patients were stratified according to PSA level ( 100 ng/mL or > 100 ng/mL) and presence of soft tissue metastases and were randomized in a double-blind fashion to receive suramin or placebo. Patients who were randomized to suramin received a loading dose of 1,000 mg/m² in 500 mL of 5% dextrose or normal saline infused over 2 hours on day 1. One-hour infusions of 400, 300, 250, and 200 mg/m² (in 500 mL of diluent) were given on days 2, 3, 4, and 5, respectively, followed by 275-mg/m² (also in 500 mL of 5% dextrose or normal saline) infusions twice a week for 2 weeks (days 8, 11, 15, and 19) and once weekly thereafter for weeks 4 through 12 (days 22, 29, 36, 43, 50, 57, 64, 71, and 78; Fig 1). This dosing regimen was designed to achieve a sustained suramin plasma concentration of 100 to 300 µg/mL. Patients who were randomized to placebo received equal volumes of saline or 5% dextrose according to the same schedule. Hydrocortisone 40 mg/d was administered orally to all patients beginning on day 1. The therapy received by each patient was identified (unblinded) only in the event of progressive disease or dose-limiting toxicity (DLT). In such cases, patients who were receiving suramin were withdrawn from the study and followed-up for survival, and patients who were receiving placebo were eligible to cross-over and receive open-label suramin on the same 78-day regimen. PSA levels were measured weekly during treatment and then monthly after treatment ended. Measurable lesions were assessed at baseline, week 13, and then every 3 months. Opioid analgesic dosage was continuously adjusted as clinically indicated. Toxicity was graded according to the Cancer and Leukemia Group B expanded common toxicity criteria. If grade 3 or 4 toxicity occurred, dosing was interrupted until the toxicity resolved to grade 2 or baseline. Patients who experienced any persistent (8 weeks or more) or recurrent grade 3 or 4 toxicity without significant antitumor response were considered to have reached DLT and were removed permanently from study treatment.

View larger version (16K): [in this window] [in a new window]   Fig 1. Treatment regimen.

Pain scores and opioid analgesic doses were averaged weekly and analyzed in two different ways. The first set of analyses compared average change from baseline by treatment group for pain scores and/or analgesic doses at two predetermined time points: 6 weeks and end of treatment (EOT). Nonparametric and parametric testing of the changes from baseline were carried out (see Statistical Considerations). The second analysis of pain and analgesic use was a Pain Responder Analysis. Pain response was achieved when, for a minimum of 3 weeks, (1) pain decreased three points from baseline while opioid analgesic use either decreased or remained stable (< 15% increase), and/or (2) opioid analgesic use decreased 33% from baseline while pain either decreased or remained stable (< two-point increase). For patients with baseline pain scores of 2 but less than 3, a reduction to 0 was required to achieve response. Similarly, for patients with baseline daily opioid analgesic use 5 mg but less than 15 mg (morphine equivalents), a decrease by 5 mg was required to achieve pain response. By definition, pain response could not be achieved on the basis of pain reduction for patients with baseline pain scores of less than 2 or on the basis of opioid analgesic use reduction in patients with baseline daily intake of less than 5 mg (morphine equivalents). These definitions of pain response were prospectively defined before unblinding or analysis. Although these definitions are arbitrary, they were selected in an effort to identify clinically meaningful improvements in pain (decline in more than three points on an 11-point scale or a decrease in opioid analgesics by one third). Thus if categories of pain severity are arbitrarily defined by partition of the 11-point scale into three ranges (mild pain, 0 to four points; moderate pain, four to seven points; severe pain, seven to 10 points), then the mandated decline of three points or more would mean that nearly all responding patients would decrease their pain by an amount that would place them into the next lower category of pain severity.

Secondary end points included PSA decline (measured as 50% decline in PSA maintained for at least 28 days), measurable disease response, time to progression, survival, and QOL changes, as evaluated by a patient-rated assessment, the Functional Assessment of Cancer Therapy-General (FACT-G) scale.²¹ The FACT-G consists of five domains rated by the patient: physical well-being, functional well-being, social well-being, emotional well-being, and relationship with physician. The FACT-G questionnaire was completed at baseline (before therapy) and then weekly throughout the course of treatment during each patient’s clinic appointment. The questionnaire was also completed at the end of treatment (week 13) and every 3 months thereafter on the day of scheduled follow-up visits. Performance status was measured weekly with the validated Revised Rand Functional Limitations Scale (RRFLS),²² which captured each patient’s self-assessment of everyday activities, such as self-care and mobility, ranging from a score of 8 (least functional impairment) to 40 (most functional impairment).

Objective disease progression was defined as an increase in the size of measurable lesions, development of new osseous lesions, new urinary outflow obstruction secondary to tumor that required intervention, new malignant pleural effusion, or new spinal cord compression. In all patients, regardless of their pain response status, demonstration of objective disease progression was considered evidence of treatment failure and resulted in unblinding of treatment. Pain (subjective) progression was prospectively defined as a two-point increase in the weekly average of the daily worst pain score or a more than 15% increase in the weekly average of the total daily opioid analgesic intake, each with deterioration from baseline in RRFLS performance status by eight points. An accompanying decline in the RRFLS score was mandated to make disease progression defined by pain and/or opioid requirements more rigorous and, therefore, more likely to be clinically significant. Treatment assignment was unblinded when either disease progression or DLT occurred, and patients found to be on placebo were then offered open-label suramin. A minimum of 6 weeks on study was required before treatment could be unblinded. Removal from treatment for disease progression before 6 weeks required approval by the study chair.

Statistical Considerations
All patients who received any treatment were included in efficacy and safety analyses. Sample size calculations were based on the ability to achieve at least an 80% power to detect differences between treatment groups, consisting of (1) a two-point difference in the mean change from baseline in the daily worst pain score (using a two-sided t test with a 5% level of significance), (2) a difference of 20% in the proportion of patients experiencing pain symptom improvement, and (3) a difference of 15% in the proportion of patients experiencing a 50% decline in PSA. A sample size of 186 assessable patients per treatment group was required. Assuming a 20% rate of unassessability, enrollment of 233 patients per treatment group (466 total) was planned.

Using a formal step-down procedure, changes from baseline in pain and opioid analgesic use were analyzed at week 6 and EOT with a rank-sum²³ test combining pain and opioid analgesic use as a first step. This analysis was followed by univariate rank tests for pain and opioid analgesic use separately as the second step. Analysis of covariance (ANCOVA) was used to estimate the size of treatment effects at both time points, and the Last Observation Carried Forward (LOCF) technique was used for data handling in all fixed time-point analyses. Pain response rates and the proportion of patients with PSA decline between treatment groups were compared with the Pearson ² test and the Cochran-Mantel-Haenszel (CMH) method²⁴ stratified by baseline measurable disease and PSA level. Time to progression, duration of pain response, and survival time were estimated with the Kaplan-Meier method.²⁵ Risk ratios based on proportional hazard models were also provided. Treatment group differences in mean change from baseline of RRFLS and FACT-G at week 6 and EOT were analyzed with ANCOVA. Additionally, the mean change from baseline to EOT for the FACT-G subscales was analyzed by treatment group (suramin plus HC v placebo plus HC) and also by pain response (responders v nonresponders) without regard to treatment.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Characteristics
From February 1994 to December 1996, 460 patients were entered onto the study, 229 in the suramin plus HC group and 231 in the placebo plus HC group. All patients enrolled were included in an intent-to-treat analysis, with the exception of two patients (one in each arm) who were randomized but were found to be ineligible and did not receive treatment. The two groups of patients were balanced regarding age, race, baseline pain score, baseline daily narcotic requirements, RRFLS performance status, Karnofsky performance status, site of disease (bone only v bone plus soft tissue), PSA level, hemoglobin level, and prior hormonal therapy (Table 1).

View larger version (17K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of duration of pain response for the two treatment arms. Abbreviation: CI, confidence interval.

View larger version (34K): [in this window] [in a new window]   Fig 3. Distribution of morphine equivalent requirements and pain scores in responders and nonresponders. * Morphine equivalents (mg).

View larger version (16K): [in this window] [in a new window]   Fig 4. Kaplan-Meier plot of time to disease progression based on intent-to-treat analysis of initial double-blind treatment phase.

View larger version (14K): [in this window] [in a new window]   Fig 5. Mean change (± 95% confidence interval) from baseline to EOT for the FACT-G subscales. Mean changes were analyzed according to (A) treatment group (, suramin, n = 215; , placebo, n = 221) and (B) pain responders (, n = 157) versus nonresponders (, n = 271) for both groups combined.

Survival
Kaplan-Meier estimates of survival indicated no statistically significant difference between the two treatment groups. The median survival duration was 286 days for patients in the suramin arm and 279 days for patients in the placebo arm. However, 71.3% of the patients who were initially assigned to the placebo arm subsequently received suramin therapy on cross-over and were included in this survival analysis. Overall, 331 (72.3%) of 458 of patients had died by the time of this analysis.

Safety
Most adverse events were mild or moderate in intensity and were easily managed medically. With the exception of rash, which is a well-known side effect of suramin,²⁶ patients in either treatment arm had a similar profile of common adverse events (Table 4). Rash, asthenia, edema, and nausea/vomiting were the most common adverse events in the 228 patients in the suramin group. Similarly, asthenia, nausea/vomiting, and edema were commonly observed in the 230 patients in the placebo group. Severe (grade 3 and 4) toxicities were infrequent and similar for patients in either treatment arm, with edema, asthenia, and anemia occurring most frequently (Table 5). Twenty-four (11%) of 228 patients receiving suramin and six (3%) of 230 patients receiving placebo discontinued treatment due to an adverse event. Significant neurologic, renal, hepatic, and coagulation toxicities were rare.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

Because the majority of HRPC patients lack measurable disease and responses in osseous disease are difficult to quantify, other clinically relevant end points, such as pain control and analgesic use, have become more widely used.^27,28 However, such patient-derived palliative end points, probably more so than objective end points, are subject to significant bias introduced by a placebo effect. The use of a placebo in the control arm of this double-blind trial reduced this potential bias; this had never been previously undertaken in HRPC trials of antineoplastic agents with palliative end points.^27,28 Although blinding was important for study design, effective blinding was not achieved in all patients, because 57% of patients receiving suramin experienced rash as compared with 13% of placebo-treated patients. A cross-over design addressed the potential ethical concerns raised by denying patients with symptomatic disease access to (possibly) improved palliative therapy. This design ensured that all patients enrolled on the study ultimately had the option of receiving suramin. However, it also confounds the comparison of the effects of suramin versus placebo on overall survival.

An assessment of patient-derived pain scores requires the simultaneous rigorous evaluation of concurrent analgesic use. To be eligible for this trial, patients were required to have painful bone metastases that necessitated chronic opioid analgesics, which were calculated as daily morphine equivalents. A requirement for nonopioid analgesics was not sufficient for trial entry. This eliminated the problem, encountered in prior palliative HRPC trials,²⁷ of calculating nonequipotent analgesic units and insured that a more uniform group of patients with clinically significant pain was treated. It is recognized that the use of nonopioid analgesics may have resulted in some reductions in pain scores. However, because patients had already failed nonopioid pain management at study entry, it seems unlikely that such maneuvers had been previously overlooked. In addition, such events were presumably equally distributed among both treatment arms by the randomization process.

A reduction in PSA levels as well as palliative clinical responses are observed in some HRPC patients after the discontinuation of antiandrogen therapy.^18,19 In addition, the incidence of adrenal insufficiency that is associated with suramin mandates the use of concomitant hydrocortisone, which is itself an agent with some activity in HRPC.^15,17 This is the first phase III study to prospectively control for the confounding effects of both antiandrogen withdrawal and concomitant corticosteroid use.

Although the correlation between PSA changes and clinically significant end points continues to be debated,^6-8 the two-fold increase in the proportion of patients with a 50% decline in PSA in the suramin arm compared with placebo mirrored other markers of response that favored suramin, including pain response (1.5-fold improvement), risk of progression (1.9-fold advantage), and durability of pain response (3.5-fold improvement). These clinical correlations between PSA response and other efficacy outcomes are inconsistent with a previous report based on in vitro data suggesting that suramin-induced PSA decrease is unrelated to reduction in tumor growth.²⁹ Further analyses are being undertaken to determine the association of PSA decline with clinical measures of response, including pain and opioid analgesic use, QOL scores, progression-free survival, and overall survival. Similarly, a retrospective evaluation of PSA-defined disease progression using the PSA Working Group Consensus Criteria³⁰ is being undertaken to correlate PSA increases with other markers of disease progression.

This trial has confirmed prior reports that used a simplified suramin dosing schema and demonstrated manageable toxicity.^11,12 This trial was safely conducted on an outpatient basis at 76 centers in the United States and Canada, suggesting that administration of suramin is feasible in a wide variety of settings, including community settings. Although the incidence of adverse events was, as expected, somewhat higher with suramin plus HC than with placebo plus HC, the patterns of adverse events in the two arms were similar. The incidence of adverse events reported in the control group (placebo plus HC) was higher than has been reported in prednisone or hydrocortisone treatment groups in other trials.^27,28 This may reflect a contribution from any or all of the following: (1) a truly higher incidence of corticosteroid-related effects in this study population with more advanced cancer, (2) reduction of bias in the reporting of toxicity in this blinded trial relative to earlier unblinded and potentially biased reports, or (3) a higher level of vigilance in the detection or reporting of adverse events in this trial relative to others. The higher than expected incidence of edema in the control group may reflect the volume (500 mL) of each infusion. Toxicities that occurred more frequently with suramin plus HC (rash, chills/fever, and taste perversion) were mostly mild to moderate in intensity and were largely clinically inconsequential. As opposed to earlier studies using different suramin dosing regimens,^14,31 neurologic, renal, hepatic, and coagulation toxicities were rare.

When the primary end points of this trial (pain and opioid analgesic use) are evaluated, it can be concluded that this is a positive trial: suramin plus HC is superior to placebo plus HC. However, standards for assessing the clinical significance of such findings, either in the context of a therapeutic trial or in the context of routine clinical care, are lacking. Furthermore, any benefits that may have been apparent with suramin in terms of pain and opioid analgesic use were not carried over to an improvement in measured QOL. This lack of association between pain improvement and improvement in QOL may in part result from the use of a general QOL instrument (FACT-G) that does not emphasize pain in the physical domain.

We have reported on a group of patients with far advanced and clinically symptomatic disease that required opioid analgesics for pain control for whom the median overall survival was less than 10 months. It is certainly possible that greater antitumor efficacy could be seen in patients with less advanced disease, especially given the wide range of noncytotoxic mechanisms of action that are attributed to suramin.^11-14 Although suramin was well tolerated in this study, issues of toxicity in a less symptomatic group of patients at baseline need to be addressed. In this regard, a phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer patients demonstrated a high response proportion and longer than anticipated survival, with an acceptable safety profile.³² Alternatively, the combination of suramin with other antineoplastic agents with nonoverlapping toxicities may provide fruitful ground for further investigation. To this end, combinations of suramin with doxorubicin have been undertaken.³³

In summary, this trial is the first randomized, placebo-controlled, double-blind study of an antineoplastic agent for the treatment of HRPC. Importantly, this study prospectively controlled for a placebo effect as well as for the effects of hydrocortisone and antiandrogen withdrawal. The results demonstrate that suramin administered by the dose schedule described is well tolerated and easily administered, and such treatment seems to offer moderate palliative benefits for patients with symptomatic HRPC.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Members of the Suramin Investigators Group are as follows: E.J. Small, University of California at San Francisco, San Francisco, CA; M.E. Marshall, Southeastern Medical Oncology Group, Goldsboro, NC; L.M. Reyno, Hamilton Regional Cancer Center, Hamilton, Ontario, Canada; F.J. Meyers, University of California at Davis, Sacramento; R. Natale, Cedars-Sinai Cancer Center, Los Angeles, CA; M. Eisenberger, Johns Hopkins University, Baltimore, MD; D.M. Waterhouse, Oncology Consultants Inc, Cincinatti, OH; R. Dreicer, University of Iowa Hospitals and Clinics, Iowa City, IA; P.W. Kantoff, Dana-Farber Cancer Institute, Boston, MA; B. Murphy, The Vanderbilt Clinic, Nashville, TN; B.S. Kasimis, East Orange VA Medical Center, East Orange, NJ; T. Kuzel, Northwestern University Medical School, Chicago, IL; R.V. Larocca, Kentuckiana Medical Oncology Associates, Louisville, KY; P. Benedetto, Sylvester Cancer Center, Miami, FL; D. Shevrin, Evanston Hospital, Evanston, IL; A. Hussain, University of Maryland Cancer Center, Baltimore, MD; W.J. John, University of Kentucky, Lexington, KY; G. Spitzer, Clinical Trials Office, Salt Lake City, UT; F.R. Ahmann, Arizona Cancer Center, Tucson, AZ; D. Stewart and D.S. Ernst, Tom Baker Cancer Centre, Calgary, Alberta, Canada; J.L. Ascensao, Nevada Medical Group, Reno, NV; O. Sartor, Louisiana State University Medical School, Shreveport, LA; M.S. Ernstoff, Dartmouth-Hitchcock Medical Center, Lebanon, NH; D. Trump, Pittsburgh Cancer Institute, Pittsburgh, PA; G.L. Miller, Eastern Oklahoma Hematology/Oncology, Tulsa, OK; G. Wilding, University of Wisconsin, Madison, WI; A. Belldegrun, University of California at Los Angeles School of Medicine, Los Angeles, CA; P. Venner, Cross Cancer Institute, Edmonton, Alberta, Canada; D. Peereboom, The Cleveland Clinic, Cleveland, IL; R. Weissman, Virginia Mason Clinic, Seattle, WA; R. Berger, North Shore Hematology/Oncology Associates, Port Jefferson Station, NY; E. Orihuela, University of Texas Medical Branch at Galveston, Galveston, TX; M. Kosty, Scripps Clinic & Research Foundation, La Jolla, CA; R. Chao, Cleveland Clinic Florida, Ft. Lauderdale, FL; D. Petrylak, Columbia Presbyterian Medical Center, New York, NY; P. Burch, Mayo Clinic, Rochester, MN; M. Moore, Ontario Cancer Institute, Toronto, Ontario, Canada; A.B. Einstein, H. Lee Moffitt Cancer Center, Tampa; N. Abramson, Baptist Regional Cancer Center, Jacksonville, FL; L. Hutchins, University of Arkansas, Little Rock, AR; T.W. Ratliff, 81st Medical Group, Keesler Air Force Base, MS; E.R. Gaynor, Loyola University, Maywood, IL; W. Kreis, North Shore University Hospital, Manhasset, NY; J.L. Smith, University of Rochester Cancer Center, Rochester, NY; P.D. Eisenberg, Marin Oncology Associates, Greenbrae, CA; M.J. Hawkins, Lombardi Cancer Research Center, Washington, DC; A. Anagnostou, East Carolina University, Greenville, NC; A. Lipton, Hershey Medical Center/Penn State University, Hershey, PA; T.E. Keane, The Emory Clinic, Atlanta; K. Brown, Eisenhower Army Medical Center, Ft. Gordon, GA; J. Hu, Madigan Army Medical Center, Tacoma, WA; J.P. Kushner, University of Utah, Salt Lake City, UT; T. Dobbs, E. Tennessee Baptist Regional Cancer Center, Knoxville; R. Rago, University of Tennessee, Memphis, TN; M. Schwarz, Virginia Cancer Institute, Mechanicsville, VA; L.J. Bricker, Henry Ford Hospital, Detroit, MI; R. Sadasivan, University of Kansas Medical Center, Kansas City, KS; N. Dawson, Walter Reed Army Medical Center, Washington, DC; and J. Cadiz, William Beaumont Army Medical Center, El Paso, TX.

	NOTES

 
Sponsored by Parke-Davis Pharmaceutical Research.

E.J.S., L.M.R., R.B.N., and M.E. have served on a suramin advisory board for Parke-Davis Pharmaceutical Research, the manufacturer of suramin and sponsor of this trial. F.J.M., P.F.L., and L.C. are employees of Parke-Davis Pharmaceutical Research.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted February 26, 1999; accepted December 7, 1999.

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