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Androgen Deprivation and Four Courses of Fixed-Schedule Suramin Treatment in Patients With Newly Diagnosed Metastatic Prostate Cancer: A Southwest Oncology Group Study

From the Department of Medicine, Division of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI; Southwest Oncology Group Statistical Center, Seattle, WA; Department of Medicine and Irving Center for Clinical Research, Columbia Presbyterian Medical Center, New York, NY; University of Kentucky Medical Center-Urologic Cancer Outreach Program, Lexington, KY; Departments of Medicine and Urology, San Francisco Urologic Cancer Outreach Program, San Francisco, CA; Johns Hopkins Oncology Center, Johns Hopkins Hospital, Baltimore, MD; and Departments of Radiation and Oncology, University of Colorado, Denver, CO.

Address reprint requests to Southwest Oncology Group (SWOG-9343), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.

	ABSTRACT

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PURPOSE: To assess the feasibility of administering a combination of suramin and hydrocortisone in addition to androgen deprivation in a cooperative group setting; to assess the feasibility of treatment with multiple courses of suramin; and to assess progression-free and overall survival in patients with newly diagnosed metastatic prostate cancer who underwent such treatment.

PATIENTS AND METHODS: Patients with newly diagnosed metastatic prostate cancer who had adequate hematologic, hepatic, renal, neurologic, and coagulation parameters were treated by combined androgen deprivation and suramin plus hydrocortisone. Suramin was administered on a 78-day fixed dosing schedule (one cycle), and suramin treatment cycles were repeated every 6 months for a total of four cycles. The statistical design was developed on the basis of the feasibility of administering suramin, as judged by the number of patients who developed neurotoxicity of grade 3 or higher or by treatment interruption of 4 weeks or longer due to any persistent suramin-related toxicity.

RESULTS: Of the 62 patients enrolled onto the study between August 1994 and January 1997, 59 were eligible and assessable for toxicity on the first cycle. Thirty-two (54%) of 59 patients received a second cycle, 13 (22%) of 59 patients received a third cycle, and only five patients (8%) received a fourth cycle. During the first cycle, 27 patients were removed from the study: 17 because of toxicity, five because of disease progression, two who had died, and three because of other reasons. There was one therapy-related death. Grade 4 toxicities were noted in 11 and three patients during first and second courses, respectively. Neurotoxicity of grade 3 or higher was observed in nine and seven patients during the first and second cycles, respectively. Fifteen patients had treatment interruptions of 4 weeks or longer. Overall, only 54% (95% confidence interval, 41% to 67%) of the patients demonstrated acceptable limits of toxicity.

CONCLUSION: Suramin plus hydrocortisone and androgen deprivation has limited applicability in the treatment of patients with newly diagnosed metastatic prostate cancer.

	INTRODUCTION

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OVER THE PAST 50 YEARS, the treatment of metastatic prostate cancer has adhered fairly strictly to the concept of permanent suppression of androgenic stimuli. Despite high subjective and objective response rates, the median progression-free survival (PFS) and overall survival times of 12 to 20 months and 24 to 36 months, respectively, have not been significantly affected.^1-3 The basic problem is the predictable and irreversible progression to androgen independence in virtually all treated patients. Recent studies of the biology of prostate cancer progression have enhanced the understanding of this complex process. A variety of genetic and growth-factor alterations have been associated with progression to the androgen-independent phenotype of prostate cancer.² This, coupled with the clinically documented inability of androgen deprivation to permanently eradicate all clones of metastatic prostate cancer, provided the rational for therapy intensification using agents with nonhormone-mediated mechanisms of action in combination with androgen deprivation.

Suramin, a polysulfonated napthylurea, is a novel agent with broad-spectrum biologic effects, including the ability to inhibit the binding of growth factors to their receptors, glycosaminoglycan degradation, membrane-associated ion pumps, protein kinase C, glycolysis, and cell motility.^4-8 The observation that suramin has inhibitory effects on several growth factors believed to be operational in prostate cancer growth and progression and the experimental data from suramin-treated prostate cancer cell lines led to its investigation in hormone-refractory prostate cancer, with interesting early results. The capacity of suramin to cause adrenal suppression necessitates the use of hydrocortisone. When the combination of suramin and hydrocortisone was used, partial responses of 9% to 50% in measurable disease sites were observed in several clinical trials, with approximately half of the patients demonstrating a greater than 50% decline in prostate-specific antigen (PSA).^9-13 These responses were viewed positively because virtually all the prior chemotherapy experience (which was primarily derived before PSA was regularly monitored) was disappointing, with less than 10% objective responses.¹⁴ Since the original trials, the suramin dosing schedule has been significantly simplified, with the development of a 78-day fixed dosing schedule that did not require pharmacokinetic monitoring,¹⁵ thereby facilitating larger-scale testing of this agent in prostate cancer.¹⁶

In 1993, a Southwest Oncology Group trial was designed to test the feasibility of chemohormonal therapy using suramin for patients with newly diagnosed metastatic prostate cancer. This study was designed with the following specific objectives: (1) assessing the feasibility of administering suramin and hydrocortisone in combination with androgen deprivation in an unlimited institutional setting, (2) assessing the feasibility of multiple courses of suramin therapy, and (3) assessing progression-free and overall survival times using this treatment.

	PATIENTS AND METHODS

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Eligibility Criteria
All patients had to have a histologic or cytologic diagnosis of newly diagnosed metastatic prostate cancer (stage D2) with no prior hormonal therapy for the treatment of metastatic disease. Although at the time of initial activation, there were no restrictions on the basis of the extent of metastatic sites, the study was later amended to include only patients who had seven or more bony metastases, as determined by bone scan, or visceral organ involvement so that the patients’ eligibility criteria did not overlap with those of the intergroup trial (INT-0162). This criterion for this study was also intended to select relatively high-risk patients for more intense therapy. Prior finasteride or neoadjuvant hormonal therapy was allowed, provided that the former was given for 9 months or less and the latter for 4 months or less. Treatment with both therapies must have been completed more than 1 year from the time of entry onto this study. Patients had to have an absolute granulocyte count of 1,500 cell/mm³ or higher, platelet count the institutional lower limit of normal, and prothrombin time (PT) and partial thromboplastin time (PTT) grade 1 elevation. Patients had to have an AST level twice the institutional upper limit of normal (IULN) and a bilirubin level the IULN, unless this elevation was unequivocally proved by a liver biopsy to be secondary to metastatic disease or if the elevation is due to a known benign condition. A serum creatinine concentration the IULN and a calculated creatinine clearance rate of 50 mL/min or more were required. Patients had to have a Southwest Oncology Group performance status of 0 to 2; no significant active concurrent medical illness precluding protocol therapy or survival; no clinical evidence of neurosensory abnormality, bleeding disorder, or coagulopathy; and must have recovered from major infections and/or surgical procedures. All patients had to be informed of the investigational nature of the study and sign an informed consent as approved by the institutional review board.

Evaluation and Follow-Up
All patients had to provide a complete medical history and undergo a physical examination. Laboratory tests must have been performed 14 days before registration and must have included a complete blood cell, differential, and platelet count; determination of serum creatinine concentration and creatinine clearance rate (calculated or measured); determination of AST, bilirubin, alkaline phosphatase, calcium, phosphorous, and PSA levels; and measurement of PT and PTT. Laboratory tests, as described in the prestudy evaluation, were repeated before each suramin dose treatment, starting on day 8.

Baseline diagnostic imaging included a bone scan, chest radiograph, and computed tomography of the abdomen and pelvis. X-rays and scans used for disease assessment were performed every 6 months and otherwise as clinically indicated.

Treatment Plan
All patients were treated with androgen deprivation (the patient could choose either treatment with monthly depo luteinizing hormone– releasing hormone agonist [either leuprolide or goserelin] or bilateral orchiectomy) plus oral flutamide 250 mg three times per day plus oral hydrocortisone 25 mg every morning and 15 mg every evening plus suramin. Table 1 lists the suramin dose and schedule for cycle one and subsequent cycles. Suramin was administered as a 2-hour infusion on day 1 of the first cycle and as a 1-hour infusion for all other courses. This suramin dose schedule was modeled to maintain plasma concentrations between a trough of 150 µg/mL and a peak of 250 µg/mL.¹⁵

To prospectively validate the dosing schedule chosen for this study, and to evaluate the effects of multiple cycles of suramin on plasma levels, blood samples were taken during the first course before infusion (trough) on days 8, 15, and 78 and 30 minutes after infusion (peak) on day 8. For all subsequent cycles, blood samples were taken before treatment on day 8. Suramin levels were measured by use of high-performance liquid chromatography, using the methods described by Tong et al.¹⁷

Toxicity Evaluation and Dose Modifications
Toxicity was graded according to the Southwest Oncology Group Toxicity criteria. Patients who experienced persistent suramin-related grade 3 or greater toxicity for 4 weeks or longer were taken off suramin therapy permanently and considered to have reached dose-limiting toxicity. Patients who restarted suramin therapy after a delay for transient toxicity (toxicity lasting for less than 4 weeks), with reduction in the grade of the toxicity to the specified level for that toxicity, received the dose that was missed and continued treatment as otherwise planned. In general, suramin therapy was withheld for neurotoxicity or nephrotoxicity of grade 2 or higher and rash, malaise/fatigue, coagulopathy, or nausea and vomiting of grade 3 or higher. For liver function abnormality of grade 2 or higher during suramin and flutamide therapy, suramin treatment was discontinued, then standard evaluations for other causes of hepatitis were performed. If there was no improvement after 1 week, flutamide was then withheld. Patients were removed from protocol therapy for unacceptable toxicity; disease progression; intercurrent illness that would, in the judgment of the investigator, require protocol therapy discontinuation; patient’s request; physician’s discretion; or the administration of other treatment for metastatic prostate cancer. Removal from the study (because of patient’s request or at the discretion of the managing physician) because of any toxicity, irrespective of grade, was coded as "off protocol due to toxicity."

Statistical Design and Methods
This study was designed as a single-stage phase II feasibility trial with a primary end point of examining toxicities. The use of suramin in patients with newly diagnosed metastatic prostate cancer would be deemed feasible if it could be demonstrated that the toxicity resulting from suramin treatment was within acceptable limits. A patient was defined as a toxicity failure if he developed a grade 3 or higher neurologic toxicity or if treatment had to be interrupted for 4 weeks or longer because of any toxicity. The toxicity criterion for the study was defined as 90% of patients or more not being classified as toxicity failures. The null hypothesis was that P = .75 versus the alternative hypothesis that P = .9, where P was the proportion of patients who were not classified as toxicity failures. If the null hypothesis was rejected in favor of the alternative hypothesis, then suramin would have met the toxicity criterion. A type I error level of 0.05 and power of 90% were specified. On the basis of these assumptions, it was computed that a sample size of 54 patients was required.

Criteria for Evaluation
Progression was defined as a 50% increase or an increase of 10 cm² in the sum of the products of measurable disease, the reappearance of any lesion that had disappeared, clear worsening of any assessable disease, appearance of a new lesion or disease site, or failure to return for evaluation because of deteriorating condition (unless clearly not due to disease progression). In case of discrepancy between the scan reports and the decision of the treating physician, it was the treating physician’s responsibility to document all reasons to justify the decision. Worsening of existing nonassessable disease did not constitute progression, including an isolated rise in PSA level. Time to progression was measured from the treatment start date until the date of first evidence of progression.

	RESULTS

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Between August 1994 and January 1997, 62 patients were enrolled onto the study. Of these 62 patients, two patients were not eligible for study: one lacked a histologic diagnosis of prostate cancer and the other did not have metastatic disease. Another patient never received the suramin and thus was not analyzable for toxicity. There were no other major protocol deviations. Table 2 lists patients’ characteristics and Table 3 lists the treatment summary. Fifty-nine eligible patients were assessable for toxicity for the first treatment cycle; of those 59 patients, 32 patients (54%) continued into a second cycle. Thirteen (22%) of the 59 patients received a third cycle of treatment and only five patients (8%) underwent a fourth cycle. Of the latter five patients, only two completed the treatment as planned, and three were removed because of toxicities. During the first cycle, 17 patients were removed because of toxicity, five because of disease progression, two had died, and three were removed for other reasons. Over all cycles, 33 patients were removed because of variable-grade toxicities. These included patients who were removed because they had achieved a dose-limiting toxicity, as defined in Statistical Design and Methods, and patients who were removed at their request or at their physician’s discretion because of any toxicity. Of the 33 patients removed, nine were removed because of neurotoxicity, five because of cardiac toxicity, four because of weakness and fatigue, three because of hepatic toxicity, two because they had requested removal because of treatment-related poor quality-of-life issues, two because of dyspnea (one was associated with Pneumocystis carinii pneumonia), two because of unknown specific toxicity, and six patients because of severe peripheral edema, hypotension, renal failure, severe diarrhea, and mesenteric thrombosis (one patient each).

There were no grade 4 or greater toxicities in the 13 patients who received a third cycle of suramin. Significant grade 3 toxicities were minimal and included one episode each of dyspnea and paresthesia. No grade 4 or 5 toxicity was encountered during the fourth cycle; however, one patient developed grade 3 neuropathy. Grade 3 or higher neurotoxicity was observed in nine patients during the first cycle and in seven patients during the second. Table 6 lists the total number of patients with the maximum grade of any toxicity during cycles 1 and 2. When all cycles were considered, 27 patients had treatment interruptions of 4 weeks or longer at some point during therapy, secondary to toxicities, and/or neurotoxicity of grade 3 or higher (11 patients had only treatment interruption, 12 had only neurotoxicity of grade 3 or higher, and four had both). On the basis of the extent of the neurotoxicity and treatment interruptions over all cycles, only 54% (32 of 59; 95% confidence interval, 41% to 67%) of the patients demonstrated acceptable limits of toxicity, as defined in Statistical Design and Methods. This was significantly below the toxicity threshold of 90% tolerability that was specified in the protocol.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The recognition of the limited effects of hormonal therapy in altering survival in patients with metastatic prostate cancer has prompted the investigation of alternative therapeutic strategies, including chemohormonal therapy. This approach is attractive because it is intended to attack androgen-dependent and -independent clones, hence the relevance of this trial. Suramin was the logical choice because of its unique mechanism of action and the encouraging clinical data supporting its use (discussed earlier). Simplification of the suramin treatment schedule has further facilitated its testing in cases of hormone-naïve (current study) and hormone-refractory metastatic prostate cancer in a multi-institutional setting.¹⁶

This trial represents the first cooperative group investigation of chemohormonal therapy using suramin in patients with newly diagnosed metastatic prostate cancer. It also evaluated the feasibility of the repeat administration of the 78-day fixed schedule. The threshold of feasibility was set at 90% or more of the patients not experiencing unacceptable toxicity. Significant broad-spectrum toxicity was observed throughout the study, which led to therapy termination in 33 (56%) of the 59 patients studied. The fact that only half (32 of 59) of the patients were able to receive a second course and only 22% (13 of 59) were able to receive a third course suggests the limited applicability of multiple courses in this setting. The exact cause for the higher than expected incidence of cardiovascular and respiratory toxicities is unclear. Several factors, either singly or in combination, could have been involved, including confounding comorbidities, unexpected negative interactions with flutamide, and the specific suramin schedule used.

Our findings contrast somewhat with those in the report by Dawson et al,¹⁸ in which 50 patients with new D2 or poor-prognosis D1 prostate cancer were treated with pharmacokinetically derived suramin dosing and hormonal therapy. A high response rate was reported, but more impressive was the fact that the median survival time had not yet been reached after a median follow-up time of 44 months and with a 3-year estimated survival rate of 63%. Although grade 3 and 4 toxicities were noted in 38% of patients, these were predominantly reversible hematologic side effects. This is in contrast to the broad multisystem toxicities observed in our trial. In our trial, hematologic side effects were considered to be acceptable, but a concern must be raised regarding the extent of lymphopenia present. This is likely related to the use of corticosteroids, which is required with suramin. The clinical significance of this finding relates to its possible contribution to a Pneumocystis carinii pneumonia reported in one patient. Dawson et al alluded to increased toxicity with repeated cycles, which is similar to our experience.

The two reports share a comparable distribution of performance status and disease extent, but the patients in the Dawson et al report were approximately 5 years younger (median age, 63 years v 58.5 years, respectively). Although the median survival time in the Dawson et al trial seemed to be favorable, it is important to note that PFS in their study was 12 months, which is somewhat shorter than that expected,^1-3 and 2 months less than that observed in our trial. It must be emphasized that comparisons between these two phase II trials are limited by the small numbers of patients in each; however, the findings may suggest that inherent differences in the patient populations may have contributed to the differences in survival between the two trials.

In developing new therapies, a certain extent of toxicity may be acceptable if it can be demonstrated that there were significant therapeutic gains to the patients. In our study, there were no obvious indications that outcome of therapy was better than expected. This observation is somewhat speculative because the majority of patients (74% of whom had extensive disease) did not receive the planned treatment; therefore, limited conclusions can be made regarding the efficacy of suramin in our patient population. The median PFS time of 14 months and median survival time of 24 months noted in this trial is relatively short, compared with the experience in prior intergroup trials in this patient population. In the trial that compared leuprolide plus placebo to leuprolide plus flutamide therapy, median PFS and survival times of 16.5 and 35.6 months, respectively, were observed in the combined-therapy arm.¹ In the most recent intergroup trial of orchiectomy plus placebo versus orchiectomy plus flutamide therapy, the median PFS and survival times reported for the combined-therapy arm were 20.4 months and 33.5 months, respectively.³ In both of these trials, the proportion of extensive- or severe-disease patients was high, at 86% and 80%, respectively, compared with 74% in this trial. The difference between the study presented here and the two intergroup trials may be a function of differences in the patient population, despite the apparent similarities among patients in disease extent and performance status. Although speculative, the lack of apparent improvement in outcome may reflect the lack of a clinically substantial suramin-related antitumor effect in this setting.

The pharmacokinetic analysis in this trial is limited by the available number of samples; however, it speaks to the validity of the fixed-bolus schedule in achieving and maintaining target suramin levels for the first course. Although it was predictive for the first cycle, the model efficiency could not be assessed in the second cycle because the number of samples was too small for definitive conclusions. Earlier reports have suggested an association between neurologic toxicity and sustained suramin plasma concentrations greater than 300 ig/mL.^9,12,15 In the trial presented here, there was no significant association between suramin peak and trough concentrations and neurotoxicity. The statistical power of this analysis was limited by small numbers (Table 7). The lack of any significant association between suramin levels and neurotoxicity was noted by Kobayashi et al¹² using a fixed suramin dosage but a different schedule. The recently completed Cancer and Leukemia Group B trial that evaluated three dose levels of suramin should clarify this issue.

On the basis of the extent and nature of the toxicities noted in this trial, we conclude that suramin therapy in the dose and schedule tested has limited applicability in the treatment of newly diagnosed metastatic prostate cancer patients. This conclusion must be viewed in light of the relatively nontoxic palliation achieved with standard hormonal therapy in this group of patients.

	ACKNOWLEDGMENTS

 
Supported in part by Cooperative Agreement grants no. CA38926, CA32102, CA46136, CA 37981, CA46441, CA35178, CA27057, CA12213, CA20319, CA46368, CA58416, CA12644, CA76123, CA58861, CA35192, CA35431, CA13612, CA76447, CA76448, CA96429, CA35261, CA46282, CA16385, CA46113, CA22433, CA63850, CA58882, CA14028, and CA42777 from the Public Health Service, National Cancer Institute, Department of Health and Human Services, Bethesda, MD, and grant no. NIHRR00645 to J.O.

	NOTES

 
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.

	REFERENCES

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1. Crawford ED, Eisenberger MA, McLeod DG, et al: A controlled trial of leuprolide with and without flutamide in prostate cancer. Med 321:419-424, 1989[Abstract]

2. Hussain M, Crawford ED: Androgen deprivation strategies for metastatic prostate cancer, in Raghavan D, Scher HI, Leibel SA, et al (eds): Principles and Practice of Genitourinary Oncology. Philadelphia, PA,Lippincott-Raven, 1997, pp 591-598

3. Eisenberger MA, Blumenstein BA, Crawford ED, et al: Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. Engl J Med 339:1936-1042, 1998

4. Moscatelli D, Quarto N: Transformation of NIH-3T3 cells with basic fibroblast growth factor of the hst/K-fgf oncogene causes downregulation of the fibroblast growth factor receptor: Reversal of morphological transformation and restoration of receptor number by suramin. J Cell Biol 109:2519-2527, 1989[Abstract/Free Full Text]

5. Betsholtz C, Johnsson A, Heldin C, et al: Efficient reversion of simian sarcoma virus-transformation and inhibition of growth-factor-induced mitogenesis by suramin. Proc Natl Acad Sci U S A 83:6440-6444, 1986[Abstract/Free Full Text]

6. Coffey R, Leof E, Shipley G, et al: Suramin inhibition of growth factor receptor binding and mitogenicity in AKR-2B cells. J Cell Physiol 132:143-148, 1987[Medline]

7. Horne MKI, Stein CA, LaRocca RV, et al: Circulating glycosaminoglycan anticoagulants associated with suramin treatment. Blood 71:273-279, 1988[Abstract/Free Full Text]

8. Hensey C, Boscoboinik D, Azzi A: Suramin, an anti-cancer drug, inhibits protein kinase C and induces differentiation in neuroblastoma cell clone NB2A. FEBS Lett 258:156-158, 1989[Medline]

9. Myers CE, Cooper MR, LaRocca RV, et al: Suramin: A novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer. J Clin Oncol 10:881-889, 1992[Abstract]

10. Kelly WK, Scher HI, Mazumdar M, et al: Suramin and hydrocortisone: Determining drug efficacy in androgen-independent prostate cancer. J Clin Oncol 13:2214-2222, 1995[Abstract/Free Full Text]

11. Eisenberger MA, Sinibaldi VJ, Reyno LM, et al: Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone refractory prostate cancer. J Clin Oncol 13:2174-2186, 1995[Abstract/Free Full Text]

12. Kobayashi K, Vokes EE, Vogelzang NJ, et al: Phase I study of suramin given by intermittent infusion without adaptive control in patients with advanced cancer. J Clin Oncol 13:2196-2207, 1995[Abstract/Free Full Text]

13. Dawson NA, Cooper MR, Figg WD, et al: Antitumor activity of suramin in hormone refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables. Cancer 76:453-462, 1995[Medline]

14. Yagoda A, Petrylak D: Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. Cancer 371:1098-1109, 1993

15. Reyno LM, Egorin MJ, Eisenberger MA, et al: Development and validation of a pharmacokinetically based fixed dosing scheme for suramin. J Clin Oncol 13:2187-2195, 1995[Abstract/Free Full Text]

16. Small EJ, Marshall ME, Reyno L, et al: Superiority of suramin + hydrocortisone over placebo and hydrocortisone: Results of a multi-center double blind phase III study in patients with hormone refractory prostate cancer. Proc Am Soc Clin Oncol 17:308a, 1998 (abstr 1187)

17. Tong WP, Scher HI, Petrylak DP, et al: A rapid assay of suramin in plasma. J Liquid Chromatog 13:2269-2284, 1990

18. Dawson NA, Figg WD, Cooper MR, et al: Phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer. J Clin Oncol 15:1470-1477, 1997 [Abstract]

Submitted June 15, 1999; accepted October 29, 1999.

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