Suramin: A Novel Growth Factor Antagonist With Activity in Hormone-Refractory Metastatic Prostate Cancer By Charles Myers, Michael Cooper, Cy Stein, Renato LaRocca, McClellan M. Walther, Gary Weiss, Peter Choyke, Nancy Dawson, Seth Steinberg, Margaret M. Uhrich, Jane Cassidy, David R. Kohler, Jane Trepel, and W. Marston Linehan Purpose: Suramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy. Patients and Methods: Suramin was administered by continuous infusion at a rate designed to reach a peak of 300 Fg/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m 2 . Results: In 17 patients with measurable soft tissue disease, three had complete disappearance of soft tissue disease for 4, 5, and 11 months, whereas three patients had a t 50% decrease in the sum of the products of the diameters of all measurable disease for > 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and

ONE

OF THE MOST important developments in cancer research has been the identification of the genetic basis for malignant transformation. This identification has been followed by the discovery of some of the biochemical mechanisms through which these genetic changes alter cell behavior. One well-documented mechanism of transformation, originally proposed in 1980, is through autocrine growth stimulation, by which a cell produces its own growth-stimulating factors and renders it independent of normal external growth control.' By 1984, malignant transformation by simian sarcoma virus was shown to be the result of autocrine stimulation by the v-sis gene product, which is highly homologous with the [ chain of platelet-derived growth factor (PDGF).2 In that same year, Williams et a13 demonstrated that suramin was able to reverse malignant transformation by simian sarcoma virus because it was able to bind the v-sis gene product and, thus, prevent the association of this peptide with its cell-surface receptor. Suramin has been shown to inactivate also basic fibroblast growth factor (FGF), transforming growth factor-3, 4 Kaposis(K)FGF,

5

insulin-like growth factor-1,

6

and interleukin-2

7

(IL-2) by binding to each of these growth factors. Keating et a18 demonstrated that the suramin-induced

decrease in PDGF receptor tyrosine phosphorylation was reversed by the addition of orthovanadate, an inhibitor of tyrosine phosphatase activity, and suggested that activation of tyrosine phosphatase by suramin might

normalized in one (6%). The remaining 21 patients had disease limited to bone, and only one of these experienced resolution of more than 50% of all lesions on bone scan. Of these 21 patients, pretreatment PSA decreased by 75% or more in eight (38%) and normalized in five (25%). Median time to progression for all patients was 26.3 weeks, and median survival was 42.3 weeks. Patients with bone involvement alone exhibited a better survival than patients with soft tissue involvement (P2 = .02). Survival was strongly correlated (P2 = .0001) with a decline in the pretreatment PSA of a 75% by the eighth week on therapy, with nearly an 85% survival at 1 year compared with a 20% survival for those whose pretreatment PSA did not decline by that amount. Conclusion: We conclude that suramin is an active agent in hormone-refractory prostate carcinoma. J Clin Oncol 10:881-889. © 1992 by American Society of Clinical Oncology.

play a role in drug action. Suramin has also been shown to inhibit protein kinase C. 9 Both tyrosine phosphorylation and protein kinase C play an important role in signal transduction for the growth factors listed. Thus, in addition to blocking the binding of growth factors to their receptors, suramin may block growth factor action at the level of signal transduction. These observations led us to initiate a program to test this drug in a range of human malignancies. One tumor that we have studied has been prostate carcinoma. This choice has been supported by two observations. First, FGF family members clearly stimulate the growth of normal and malignant prostate cells in vitro, and the prostate is a rich source of FGF.10-13 Male transgenic mice expressing INT-2, an FGF family member, develop From the Clinical Pharmacology Branch, Surgery Branch, and Biostatistics and Data Management Section, COP, DCT, National Cancer Institute, Bethesda, MD; the Departments of Radiology, Nursing, and Pharmacy, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD; and the Division of Hematology-Oncology, Walter Reed Army Medical Center, Washington, DC. Submitted September 30, 1991; acceptedJanuary 28, 1992. Address reprint requests to Charles Myers, MD, Chief Clinical Pharmacology Branch, Clinical Oncology Program,Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Building 10, Room 12C103, Bethesda, MD 20892. @ 1992 by American Society of ClinicalOncology. 0732-183X/92/1006-0003$3.00/0

Journal of Clinical Oncology, Vol 10, No 6 (June), 1992: pp 881-889

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 5, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

881

882

MYERS ET AL

benign prostatic hypertrophy. 14 Second, suramin is active in vitro against the human prostate carcinoma cell 5 lines LNCAP, PC-3, and DU145.1 Our experience with suramin indicates that it is an active agent in the treatment of prostate cancer and can cause objective responses in patients with measurable soft tissue disease, dramatic declines in prostate-specific antigen (PSA) levels, and significant pain relief in a majority of the patients so treated. PATIENTS AND METHODS

Patient Characteristicsand Evaluation Between July 1988 and September 1989, 38 patients with metastatic prostate cancer were entered onto this trial. Their characteristics are listed in Table 1. All patients had undergone unsuccessful medical or surgical castration, and 68% had an unsuccessful second hormonal manipulation. While approximately 85% of metastatic prostate carcinoma patients present with bone involvement as their only site of metastatic involvement, responses in this group of patients can be difficult to assess. On the other hand, soft tissue disease may differ in a biologically significant way from bone-only disease and is relatively uncommon. For this reason, we sought a balance between these two manifestations of prostate cancer. We required that the patients have a Karnofsky performance status of 80% or better, a life expectancy of at least 12 Table 1. Pretreatment Characteristics Total no. of patients Bone only involved Measurable soft tissue Mean age (years) Range Previous treatment Surgical castration Medical castration Second hormonal treatment Previous radiation treatment Previous chemotherapy Extent of disease Minimal* Severe Prostate-specific antigen Median Range Patients > 100 ng/mL Alkaline phosphatase Median Range Patients > 115 Other medical problems (no. of patients) Hypertension History of cardiac arrhythmia Diabetes Angina pectoris Chronic alcoholism Previous myocardial infarct

38 21 17 66 49-80 30 8 26 21 8

4 34 172 ng/mL 3.2-7,465 ng/mL 29 292 15-2,648 35 18 5 3 3 2 2

*Minimal includes involvement of pelvis and spine. tSevere includes involvement extending beyond pelvis and spine.

3 weeks, platelet counts greater than 100,000/mm , and a creatinine clearance greater than 40 mL/min. Chemotherapy, radiation therapy, and all forms of hormonal therapy were discontinued at least 4 weeks before entry onto protocol. Patients were not excluded on the basis of age or other medical conditions as long as they met the other eligibility criteria. As a result, patients on this trial had a range of medical conditions other than prostate cancer common in this age group (Table 1). The extent of disease was evaluated before entering the protocol and while on the protocol by radionuclide bone scan, routine skeletal survey, and abdominal computed tomographic (CT) scan. Additionally, CT scan was used to evaluate any soft tissue involvement. Measurable soft tissue disease was evaluated at the beginning and end of each cycle, and at 2 and 4 weeks after the end of each cycle. PSA levels were also measured at the beginning and end of each cycle, and at 2 and 4 weeks after the end of each cycle. Bone scans were repeated at least once every 3 months while the patient was on therapy. The PSA was determined by the Hybritech method, which has been discussed elsewhere. 161, 7 The top of the normal range for this test is 4.0 ng/mL. The PSA levels were measured at least once a week during suramin administration, and again at 2 weeks and 4 weeks after the end of each infusion. Androgen levels were determined by radioimmunoassay according to methods previously 18 reported in detail. A complete response required the disappearance of all measurable disease and the resolution of all skeletal lesions, both radiographically and by bone scan. A partial response required that the sum of the product of the largest perpendicular diameters decrease by 50% or more for more than 1 month. For patients with only bone disease, 50% or more of the lesions on bone scan must have resolved.

Treatment Protocol Because suramin can cause adrenal insufficiency, all patients on this trial received replacement hydrocortisone for the duration of the protocol. 19,20 The initial starting dose was 25 mg orally in the morning and 15 mg orally in the evening. These doses were then increased if the patient exhibited signs of adrenal insufficiency or was subjected to unusual stress. Surainin was supplied in a 10-mL vial containing 1 g of sodium suramin, United States Pharmacopeia, as a sterile-freeze dried powder. Reconstitution with 10 mL of sterile water for injection yielded a 100 mg/mL solution. Suramin was diluted further in either 500 mL dextrose (5%) in water (D5W) and infused over a 24-hour period, or diluted to a total volume of 90 mL with D5W and delivered by a portable infusion pump over a 24-hour period. The manner in which suramin was administered in this trial differs considerably from the customary practice for most anticancer drugs. The typical course of suramin blood levels is illustrated in Fig 1. The goal of this protocol was to achieve a suramin plasma level of 300 jg/mL at the end of 14 days. However, because of the considerable variation in suramin pharmacokinetics observed in our patient population, some patients reached this level as early as 7 days, whereas other patients took 3 to 4 weeks. Suramin was given by continuous infusion at a rate of 350 mg/m 2 per day for the first week. This dose rate was chosen because, in the average patient, it would have led to the target blood level at the end of 14 days. At the end of that week, suramin blood levels were determined, and if the blood level was > 300 tg/mL, infusion was discontinued. If the target blood level had not been reached, the dose rate was adjusted

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 5, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

883

SURAMIN FOR PROSTATE CARCINOMA

cycles: (1) cycle 1 dose rate in mg/M 2 /day is 684 to 1.55 *(plasma suramin) in Ig/mL; and (2) cycle 2 dose rate in mg/m 2 /day is 572 to 1.40 *(plasma suramin) in ýLgimL. The equation used for cycle 1 resulted in the protocol-specified drug level within 1 week in one patient, and within 2 weeks in 27 patients. The remaining 10 patients took a mean of 23.4 days ± 1.2 days (SE) to reach the target blood level, with the longest time being 29 days. For cycle 2, the equation specified uniformly succeeded in achieving the targeted blood level of 300 I±g/mL by the end of the second week.

300

"E 200 1o

StatisticalMethods

1

2

3

Weeks

Fig 1. Patterns of suramin blood levels of patients. Curve A, a patient who rapidly reached the target blood level and had therapy discontinued at the end of 1 week; curve B, a patient who reached the target blood level at the planned 2-week interval; curve C, a patient who loaded slowly and required 3 weeks of suramin to attain a blood level of 300 pg/mL. according to equation 1 (see Drug Level Monitoring), and therapy continued for an additional week. This process was repeated each week until blood levels reached 300 pRg/mL. At that point, suramin administration was discontinued. After an 8-week rest, suramin therapy was reinitiated. For all subsequent cycles, the drug was infused at a rate of 280 mg/m 2 per day for the first week. At the end of the first week, suramin blood levels were measured, and the dose rate was adjusted according to equation number two. The time between cycles could be delayed as long as 10 weeks, if the patient did not recover from the toxicity of the first cycle or had other medical problems that warranted a delay in treatment. Additionally, if the patient tolerated the drug well and had an inadequate tumor response, the time between cycles could be shortened to 6 weeks.

Drug Level Monitoring Because suramin plasma levels above 350 pg/mL are associated with severe toxicity,2 1,22 this trial was designed to achieve a peak blood level of 300 xg/mL. Our previous studies have also demonstrated a large individual variation in suramin blood level for a given dose.21 For this reason, drug level monitoring was a critical part of this protocol and played an important role in attaining desired therapeutic response and in controlling toxicity. Suramin levels were determined by reverse-phase high-performance liquid chromatography with ion pairing as previously described.23 Collins et a123 proposed that a single-compartment model should be sufficient to account for suramin pharmacokinetics. To provide a scheme for dose adjustment, such a single-compartment model was used along with information available from our previous trials to construct the simple equation listed for cycle 1. This equation was used to adjust the dose rate based on the plasma drug level measured each week. After the first six patients had received their second cycle, it was apparent that suramin blood levels rose much more rapidly during the second cycle than during the first, and a separate equation was constructed for the second and subsequent

Survival times and times to progression were calculated from the date the patient was entered onto the study until progression, the date of death, or last follow-up. The Kaplan-Meier method was used to calculate the probability of survival or progression-free survival as a function of time. 24 The Mantel-Haenszel procedure was used to evaluate the significance of the effect of each prognostic factor, and provided the significance of the difference between a pair of corresponding Kaplan-Meier curves.25 The Cox proportional hazards modeling technique was used to identify which factors, when simultaneously evaluated, may together affect survival in a statistically significant way.26,' All P values are two-sided and denoted by P2.

RESULTS Evidence ofAntitumorActivity

Of the 38 patients on this trial, 17 had measurable tumor masses. Of these 17, three had complete disappearance of all soft tissue disease for 4, 5, and 11 months. The patient who experienced tumor regrowth by 4 months initially had massive generalized adenopathy and a large prostate, with extension into the bladder. At 4 months, his recurrent tumor responded to reinitiation of therapy with an additional response. This was less than complete because it was associated with several small foci of residual tumor in the bladder wall and prostate gland. Despite repeated cycles of suramin, these foci of tumor remained. Finally, after 1 year and 7 months on suramin associated with stable disease, we elected to irradiate this residual disease and discontinue suramin. The patient is currently being observed off all therapy without evidence of disease activity more than 2 years and 7 months after entering the protocol. The patient who experienced a 5-month response had five biopsy-documented, PSA-positive skin lesions on the face, which rapidly disappeared during his first cycle of suramin. The third patient had a large mass in his perineum, which disappeared with the first cycle of therapy. This patient also experienced severe renal impairment and received no further therapy. He finally progressed after 11 months. An additional three patients had a greater than 50% reduction of the sum of the products of the perpendicular diameters of all

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 5, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

884

MYERS ET AL

measurable disease for more than 1 month. In one of these patients, the soft tissue site was a large mass that arose from a pelvic bony metastasis and was growing rapidly. The other two patients had lymph node metastasis. In every case, soft tissue responses had reached their maximum before the initiation of the second cycle. In none of the 17 patients did bone lesions resolve. According to the criteria used in this study, six of 17 had objective PRs. Of the 21 patients with bone-only involvement, only one patient experienced resolution of more than 50% of all lesions on bone scan. This single bone response was observed after 5 months of treatment. No patient experienced radiologic resolution of bone lesions. PSA values reflect the total volume of prostate tissue, both normal and malignant. 28 The speed and degree of decline in PSA has been found to have prognostic value after surgery 16 ,28,29 or radiation therapy 30 for local dis-

ease, and hormonal therapy for metastatic prostate cancer. 31,32 Therefore, we observed the PSA serially in our patients. Of all patients on this trial, 21 (55%) experienced a 2 50% decline in their PSA. The decline in the PSA was complete before the second cycle with only two exceptions. Substantial, but less than complete (70% to 90%), declines in PSA have been correlated with enhanced survival in patients undergoing hormonal therapy for metastatic prostate cancer. Table 2 lists the specific PSA changes observed in those patients on our trial whose PSA declined by 75% or more by 8 weeks after suramin was started. One patient had a pretreatment PSA within the normal range (2.2 ng/mL) that became unmeasurable by week 8. Two additional patients had marginally elevated PSAs of 5.2 and 6.1, one of which decreased to the unmeasurable range at 8 weeks. All other patients had PSAs above 23 ng/mL. In our patient population, five of the patients with soft

tissue disease and eight of those with bone involvement only experienced such a decline in PSA. On the other hand, five of the patients with bone-only disease normalized their PSAs compared with only one of those with soft tissue tumor deposits. Thus, while major declines in PSA are observed in nearly one third of patients with either soft tissue disease and bone involvement alone, these groups differ in the degree with which normalization of the PSA occurs. Bone pain can present a major management problem in patients with prostate cancer. Of the patients on this trial, 21 had pain of sufficient severity to require chronic use of opiates. Of these, 15 (71%) experienced sufficient pain relief to stop or reduce their use of opiate analgesics by one half. This usually occurred rapidly and as early as the fourth day of treatment. It is important to note that all of these patients were placed on replacement doses of hydrocortisone, which is often effective in relieving pain. Thus, it is not possible to determine the extent to which the pain relief was the result of suramin administration or other means. Time to Progressionand Survival The median time to progression for all patients on this trial was 26.3 weeks and the median survival was 42.3 weeks. The survival of patients with bone-only disease was significantly better than that of patients with soft tissue involvement (P2 = .02) (Fig 2A and B). We examined the correlation of pretreatment and posttreatment PSA and survival. One important bias in many comparisons of survival between responders and nonresponders is that patients who have aggressive disease and die early do not have the opportunity to respond. Thus, the responders may be biased toward those with slower-growing tumors or less extensive tumor, patients who would have had a better survival

Table 2. PSA Levels (ng/mL) Before Treatment and 8 Weeks After the Initiation of Therapy Decrease of

Ž

75%

Decrease of < 75%

Increase

No.

Pretreatment

8 Weeks

No.

Pretreatment

8 Weeks

No.

Pretreatment

8 Weeks

1 2 3 4 5 6 7 8 9 10 11 12 13

58.7 79 23 41 219.2 87 200 644.9 110 219 260 6.1 2.2

17.1 13.9 3.6 6.2 32 4.9 7.4 12.4 2.0 1.2 -

1 2 3 4 5 6 7 8 9 10 11

469 314 5.2 1,334 137.6 339.6 7,465 291.6 172.9 206.1 140.0

447.1 284.3 4 836.8 84.3 187.5 4,010 142.8 69.5 76.0 47.0

1 2 3 4 5 6 7 8 9 10

48.5 85.6 429.8 223.6 113.3 154.0 149.0 115.7 2,424.0 172.0

101.3 119.0 388.0 303.6 151.5 186.1 176.9 127.0 2,631.3 173.6

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 5, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

885

SURAMIN FOR PROSTATE CARCINOMA

w w

U-

-J

co cc:

zEr

I--

I-

LU a

0

z•o w

z L.) w

uJ

nw

10

A Fig 2.

20

30

40

50

60

70

80

90

100

PROGRESSION-FREE INTERVAL IN WEEKS

B

SURVIVAL TIME IN WEEKS

Time to progression (A) and survival (B) of patients with measurable soft tissue disease (0) compared with bone involvement alone (*).

even without any therapeutic intervention. The druginduced decline in the PSA was complete in all but two patients by 8 weeks after therapy was initiated. At 8 weeks, only one patient on the trial had died; therefore, we believe that the bias is minimal in this instance. Figure 3 shows the survival of patients whose PSA at 8 weeks had declined by 0% to 25%, 25% to 50%, 50% to 75%, or more than 75%. It is clear that only patients whose PSA quickly declined by 75% had an improved survival, with a nearly 85% survival probability at 1 year compared with a 20% probability of survival at 1 year for all other patients; these differences are highly significant (P2 = .0001). The correlation between a PSA decline of 75% or more and survival was equally significant for patients with bone-only and soft tissue disease (P2 = .016 and .0184, respectively). We have also examined whether the actual value of the PSA before and after treatment correlated with outcome. The pretreatment PSA above (28 patients) or below 100 ng/mL (10 patients) was

correlated with survival (P2 = .01). As expected, a PSA above or below 100 ng/mL at 8 weeks showed an even better correlation with survival (P2 = .0005). It is apparent in Table 2, that a majority of the patients who experienced a 75% decline in the PSA level had initial PSA levels of 100 ng/mL or less. Of the patients with pretreatment PSA values above 100 ng/mL, six experienced a decline of 2 75% in PSA. In contrast, of the 10 patients with pretreatment PSA values below 100 ng/mL, seven experienced a > 75% decline in the pretreatment PSA. Toxicity Toxicities were graded using the National Cancer Institute Cancer Therapy Evaluation Program (CTEP) Common Toxicity Criteria. 33 The most severe toxicities experienced by the patients were CTEP grade 1 or 2 for 16%, grade 3 for 63%, and grade 4 for 16%. There were two patients (5%) who died of drug-related toxicity. One 1(

-'J

-J

I.-

I-

z

zW 0

LU UJ a.

w

a-

1U

A

e

ouU U

IU IU

SURVIVAL TIME IN WEEKS

10

IW W

B

20

30

40

50

60

70

80

90

100

SURVIVAL TIME IN WEEKS

Fig 3. The association between the percent decline in pretreatment PSA by 8 weeks on therapy and survival is shown. Values were available for 34 of the 38 patients treated. A, survival of patients whose PSA decreased by a 75% (*), 50%to 75% (0), 25% to 50% (*), and less than 25% (f); B, survival of patients whose PSA decreased by ? 75% (*) compared with less than 75% (0).

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 5, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

886

MYERS ET AL

patient died of an intracranial bleed associated with anticoagulation and thrombocytopenia. Before protocol entry, this patient had extensive bone marrow involvement. Additionally, he had a tumor-induced diseminated intravascular coagulation (DIC) that rapidly worsened shortly after the initiation of suramin therapy, and was associated with a rapid decrease in his PSA. The relative role of suramin compared with the release of prostate tumor products known to fuel DIC remains unresolved in this case. The other patient died of renal failure associated with sepsis, the use of aminoglycoside antibiotics, and suramin. During this trial, hematologic toxicities were the most common problems faced (Table 3). Anemia, thrombocytopenia, and, to a lesser extent, neutropenia were most frequently observed in patients with extensive marrow replacement by tumor or with a previous history of extensive radiation or chemotherapy. Lymphocytopenia was also a common event, but was not related to the extent of tumor or to previous therapy. Infectious complications were common in this trial; 16 of 38 patients experienced culture-documented bacterial infections. Although lymphocytopenia was much more severe than neutropenia, all but three of the infections observed were bacterial in origin. Another unusual aspect of the hematologic side effects was that all CTEP grade 3 or 4 episodes of thrombocytopenia, anemia, and neutroTable 3. Percent of Toxicities Toxicity

Hematologic Lymphocytopenia Anemia Neutropenia Thrombocytopenia Prothrombin time Partial thromboplastin time Infection Renal Blood urea nitrogen Creatinine Proteinurea Hypomagnesemia Hepatic Bilirubin Transaminase elevation Neurologic Sensory Motor Hyperglycemia Skin rash Fatigue Fever Nausea

Grade 1-2

Grade 3-4

5 53 32 47 79 45 32

37 37 11 5 8 13 11

52 37 8 16

3 16 0 0

32 68

5 3

79 16 73 39 39 32 32

11 11 13 11 5 0 0

penia occurred with the first cycle of suramin, and were much more moderate with subsequent cycles. Additionally, 66% of the infectious episodes occurred during the first cycle or in the time interval between the first and second cycle. An additional 16% of the episodes occurred with the second cycle of therapy. The remaining episodes occurred at a frequency of no more than two per cycle in any of the subsequent cycles. One possible explanation for this phenomenon would be that a less intense therapy was administered on the subsequent cycles; however, the mean percent of the protocolspecified suramin level attained was 111%, 114%, and 118% on the first, second, and third cycle, respectively. Another way that toxicity might be moderated is to delay therapy after cycle 1 for a significant number of patients to allow for recovery from toxicity. However, in 8% of patients, the time between cycles 1 and 2 was shortened from 8 to 6 weeks, and in 8% it was lengthened from 8 to 10 weeks. Between cycles 2 and 3, 33% of patients had therapy shortened from 8 to 6 weeks, and 25% had it lengthened from 8 to 10 weeks. Thus, the time between cycles was shortened as often as it was lengthened. These findings suggest that the impairment of host defenses by suramin was at its maximum during the first cycle of therapy. In earlier trials, suramin administration was associated with a series of toxicities including life-threatening sensory-motor polyneuropathy, anticoagulation, and adrenal insufficiency, the frequency and severity of which were diminished on the current trial. 19,2 1,22 ,34 Early in

this trial, before we had implemented a separate dose modification scheme for cycle 2 and beyond, six patients developed drug levels considerably in excess of 300 ptg/mL during their second cycle. These patients developed grade 3 or 4 peripheral sensory and motor toxicity, from which they recovered only gradually over a matter of months. After implementation of the full, dosing scheme outlined in the Patients and Methods section, the neurologic toxicity in this trial was limited to grade 1 or 2 peripheral sensory neuropathy. Because of the careful monitoring of drug levels, prothrombin time and partial thromboplastin time, clinically significant anticoagulation was also less of a problem. Slightly more than 10% of the patients had serious anticoagulation (CTEP grade 3 or 4), and only two individuals had significant hemorrhagic sequelae (CTEP grade 3 or more). One of these patients died and was previously discussed. Also, in earlier trials with this drug, adrenal insufficiency was a problem. 19,21,35 In this trial, we made the assumption that every patient was at risk for this complication; therefore, we administered replacement

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 5, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

887

SURAMIN FOR PROSTATE CARCINOMA doses of hydrocortisone, which effectively prevented us from accurately determining the frequency of adrenal gland damage caused by suramin. Hyperglycemia was quite common; however, severe hyperglycemia was observed in only five patients, three of whom were diagnosed as diabetic before the initiation of suramin therapy. Hyperglycemia was easily controlled with an increase in the insulin dose. Similarly, although elevation of the hepatic transaminases was common, severe elevations in these enzymes, as well as hyperbilirubinemia, were limited to patients with chronic alcoholism or other hepatic pathology that predated suramin administration, but that rapidly worsened on suramin administration. Although modest elevations in the blood urea nitrogen and serum creatinine were common, severe renal functional impairment was associated with severe infections, the coadministration of nephrotoxic antibiotics, and/or severe hypotension. Skin rash was common and occurred in 50% of the patients; it consisted of an erythematous macular/papular eruption that began on the chest and back and spread outward. In only one case was drug administration suspended until recovery occurred. In no case on this trial did the rash reappear during the second or subsequent cycles. Although hypophosphatemia occurred in 12 patients, there are no standard CTEP criteria for this complication; therefore, it is not included in Table 3. In these 12 patients, the median serum phosphate level was 1.8 mg/dL, with a range of 1.3 to 2.2 mg/dL. In patients on suramin for more than three cycles, we noted a syndrome of cumulative toxicity characterized by fatigue and weight loss. In five patients, this syndrome, not progressive tumor, led us to lengthen the time between cycles to 3 to 4 months. In three of these five patients, suramin therapy was suspended after five to eight cycles. DISCUSSION The results of this trial indicate that suramin is an active agent in the treatment of patients with prostate carcinoma who have failed hormonal therapy, and that the drug is tolerated by an elderly patient population, with a range of chronic medical illnesses. The evidence that suramin is an active agent in hormone-refractory prostate cancer rests on three observations: (1) the drug-induced shrinkage of measurable soft tissue masses; (2) it caused dramatic decreases in the PSA with considerable frequency; and (3) it caused pain relief in a high percentage of patients. Of the three, pain relief is the least dependable index of suramin's

antitumor activity. All of these patients are on replacement hydrocortisone, which can, by itself, cause significant pain relief in patients with prostate cancer. Additionally, there is undoubtedly a strong placebo effect. In this trial, patients with measurable soft tissue disease did less well than patients with bone-only disease, as judged by the frequency with which the PSA normalized and by survival. This result is difficult to reconcile with the relative paucity of objective bone responses as judged by the resolution of bone scan abnormalities or the healing of osteoblastic lesions, even though 71% of patients with significant bone pain had pronounced resolution of those symptoms. Because this discrepancy became apparent early in the trial, we have had time to study the impact of suramin on bone physiology in work submitted elsewhere. Prostate cancer, which spreads to the bone in the vast majority of patients who develop metastatic disease, has been shown to induce both an osteolytic and an osteoblastic effect on bone. We previously have shown that prostate carcinoma produces a systemically acting factor with parathyroid hormone (PTH)-like activity that can induce hypercalcemia, as well as hypophosphatemia in tumor-bearing animals.3 6,3 7 In a

study performed to evaluate the effect of suramin on bone, we have demonstrated that suramin effectively blocks the ability of erythrocyte glutathione reductase, tumor necrosis factor, parathyroid hormone, and parathyroid hormone-related peptide to mobilize calcium from bone, while it enhances the ability of calcitonin to deposit calcium in bone. 38 Thus, suramin exposure blocks a wide range of signals for bone resorption, while apparently enhancing a major signal for bone deposition. These phenomena may well explain the infrequency with which patients on this trial resolve osteoblastic metastases either by a bone scan or a radiologic method despite the other indications of response, such as a decline in PSA or pronounced relief of bone pain. It is already well established that PSA values correlate with the total bulk of normal and malignant prostate tissue. One of the more dramatic findings in this trial was the correlation between an early decrease of 75% in the PSA and ultimate survival, which was highly significant in spite of the relatively small number of patients involved. A similar association has been noted for radical prostatectomy, radiation therapy, and hormonal therapy of prostate carcinoma. 28-32 This association has led to the suggestion that such alterations in the PSA might be used as an indicator for tumor response, while under the assumptions that the decrease in PSA value mirrored a parallel change in tumor mass and that this

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 5, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

888

MYERS ET AL

alteration in tumor mass was responsible for the correlation between PSA decrease and survival. It is clear that the PSA would offer a number of advantages over the current indicators of response in patients with bone-only prostate carcinoma. Remodeling of the bone in elderly men can be slow; therefore, resolution of bone lesions often takes 6 months or longer. Additionally, biopsy results of blastic lesions remaining after significant and prolonged response to hormonal therapy have shown that these lesions may persist even though they are free of tumor cells. 39 One classic problem in comparing survival rates in responders with nonresponders is that patients with aggressive disease may die too rapidly to be candidates for response. Because the median survival of patients with hormone-refractory prostate carcinoma is approximately 6 to 10 months,40 all responders compared with nonresponders in whom bone healing is used, are subject to this bias. For this reason, there is a distinct advantage in the ability of the PSA, with its half-life of 2 days, to reflect rapidly changes in tumor volume. Thus, for the bone-only patient, the PSA offers the possibility of a more quantitative, more rapid, and more sensitive assay of tumor response than the traditional measures of response in patients with bone-only disease. Interestingly, approximately one third of the patients on this trial would be judged to be responders, regardless of whether the criteria of measurable tumor shrinkage or a 75% decrease in PSA were used. The toxicity of suramin warrants discussion. Because of the wide range of growth factors inhibited by suramin and other biologic actions attributed to the compound, there were ample reasons to suspect that the drug might be too toxic for clinical use. We have found that drug level monitoring makes aggressive administration of this drug to a generally elderly population of patients with prostate cancer possible. After we implemented therapeutic drug monitoring to reduce the risk of neurologic toxicity, we noted an associated decrease in certain other toxicities. In this trial, the frequency and severity of anticoagulation, proteinurea, and clinical symptoms

of vortex keratopathy38 were all moderated. Patients who are most likely to have problems with this drug in general fall into four easily identifiable groups: those with compromised marrow reserve, diabetes, ongoing liver disease, or kidney disease. Additionally, recent research suggests some of these toxicities may be preventable. For example, the immunosuppression caused by suramin may result from inactivation of interleukin-2 (IL-2), a phenomenon reversible in vitro by the addition of exogenous IL-2. 7 It may well be that the other hematologic toxicities of this drug may be moderated by other interleukins or colony-stimulating factors. The method of drug administration used in this study resulted in a duration of individual cycles that ranged from 1 to 4 weeks. However, most patients reached the target suramin level within 14 days. In this trial, we noted no association between the time it took a patient to reach the target blood level and either toxicity or response. Since the design and execution of this trial, there have been several advances in the use of suramin. First, two groups have shown that Bayesian pharmacokinetics provide much more accurate control of plasma blood 41 levels than the nomogram used in the current trial. -43 Second, both groups have found that it is possible to preserve the antitumor activity of suramin while lessening its toxicity. In both trials, this was accomplished by prolonging drug administration to 8 or more weeks, which is associated with lower target drug plasma levels, 215 Rg/mL for continuous infusion or restraining peaks, and by drug concentrations of 150 to 250 Vg/mL for bolus administration. We would recommend either one of these schedules as superior to the one used in the current trial. The major disadvantage of this approach is that the current software available for Bayesian pharmacokinetics remains complex and cumbersome, and this is likely to be a barrier to its widespread use. For this reason, major emphasis should be placed on the development of simplified methods for the safe and effective administration of this drug.

REFERENCES 1. Sporn MB, Todaro GJ: Autocrine secretion and malignant transformation of cells. N Engl J Med 303:878-880, 1980 2. Garrett JS, Coughlin SR, Niman HL, et al: Blockade of autocrine stimulation in simian sarcoma virus-transformed cells reverses down-regulation of platelet-derived growth factor receptors. Proc Natl Acad Sci U S A 81:7466-7470, 1984 3. Williams LT, Tremble PM, Lavin MF, et al: Platelet-derived growth factor receptors form a high affinity state in membrane preparations. Kinetics and affinity cross-linking studies. J Biol Chem 259:5287-5294, 1984

4. Coffey RJ, Leof EB, Shipley GD, et al: Suramin inhibition of growth factor receptor binding and mitogenicity in AKR-2B cells. J Cell Physiol 132:143-148, 1987 5. Moscatelli D, Quarto N: Transformation of NIH 3T3 cells with basic fibroblast growth factor or 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 6. Pollak M, Richard M: Suramin blockade of insulinlike growth factor I-stimulated proliferation of human osteosarcoma cells

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 5, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

889

SURAMIN FOR PROSTATE CARCINOMA (published erratum appears in J Natl Cancer Inst 82[18]:1510, 1990). J Natl Cancer Inst 82:1349-1352, 1990 7. Mills GB, Zhang N, May C, et al: Suramin prevents binding of interleukin 2 to its cell surface receptor: A possible mechanism for immunosuppression. Cancer Res 50:3036-3042, 1990 8. Keating MT, Escobedo JA, Williams LT: Ligand activation causes a phosphorylation-dependent change in platelet-derived growth factor receptor conformation. J Biol Chem 263:1280512808, 1988 9. Mahoney CW, Azzi A, Huang KP: Effects of suramin, an anti-human immunodeficiency virus reverse transcriptase agent, on protein kinase C. Differential activation and inhibition of protein kinase C isozymes. J Biol Chem 265:5424-5428, 1990 10. Mydlo JH, Michaeli J, Heston WD, et al: Expression of basic fibroblast growth factor mRNA in benign prostatic hyperplasia and prostatic carcinoma. Prostate 13:241-247, 1988 11. Mori H, Maki M, Oishi K, et al: Increased expression of genes for basic fibroblast growth factor and transforming growth factor type beta 2 in human benign prostatic hyperplasia. Prostate 16:71-80, 1990 12. Shain SA, Koger JD: Differences in responsiveness of clonally derived AXC/SSh rat prostate cancer cells to secreted or prototypic mitogens. Cancer Res 49:3898-3903, 1989 13. Story MT, Livingston B, Baeten L, et al: Cultured human prostate-derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor. Prostate 15:355-365, 1989 14. Muller WJ, Lee FS, Dickson C, et al: The int-2 gene product acts as an epithelial growth factor in transgenic mice. Embo J 9:907-913, 1990 15. LaRocca RV, Danesi R, Cooper MR, et al: Effect of Suramin on Human Prostate Cancer Cells in Vitro. J Urol 145:393-398, 1991 16. Chan D, Bruzek DJ, Oesterling JE, et al: Prostate specific antigen as a marker for prostatic cancer: A monoclonal and a polyclonal immunoassay compared. Clin Chem 33:1916-1920, 1987 17. Hortin G, Bahnson RR, Daft M, et al: Differences in values obtained with 2 assays of prostate specific antigen. J Urol 139:762765, 1988 18. Schiebinger RJ, Chrousos GP, Cutler GB, et al: The effect of serum prolactin on plasma adrenal androgens and the production and metabolic clearance rate of dehydroepiandrosterone sulfate in normal and hyperprolactinemic subjects. J Clin Endocrin Metabol 62:202-209, 1986 19. Stein CA, Saville W, Yarchoan R, et al: Suramin and function of the adrenal cortex. Ann Intern Med 104:286-287, 1986 (letter) 20. Feuillan P, Raffeld M, Stein CA, et al: Effects of suramin on the function and structure of the adrenal cortex in the cynomolgus monkey. J Clin Endocrinol Metab 65:153-158, 1987 21. Stein CA, LaRocca RV, Thomas R, et al: Suramin: An anticancer drug with a unique mechanism of action. J Clin Oncol 7:499-508, 1989 22. LaRocca R, Meer J, Gilliatt RW, et al: Suramin-induced polyneuropathy. Neurology 40:954-960, 1990 23. Collins JM, Klecker RJ, Yarchoan R, et at: Clinical pharmacokinetics of suramin in patients with HTLV-III/LAV infection. J Clin Pharmacol 26:22-26, 1986 24. Kaplan E, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

25. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem Rep 50:163-170, 1966 26. Cox D: Regression models and lifetables. J R Stat Soc 34:187-202, 1972 27. Matthews DE, Farewell VT: Using and Understanding Medical Statistics. Basel, Switzerland, Karger, 1985, pp 148-158 28. Stamey TA, Yang N, Hay AR, et al: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 317:909-916, 1987 29. Stamey TA, Kabalin JN, McNeal JE, et al: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate II. Radical prostatectomy treated patients. J Urol 141:10761081, 1989 30. Chodak GW, Neumann J, Blix G, et al: Effect of external beam radiation therapy on serum prostate-specific antigen. Urology 35:288-294, 1990 31. Arai Y, Yoshiki T, Yoshida O: Prognostic significance of prostate specific antigen in endocrine treatment for prostatic cancer. J Urol 144:1415-1419, 1990 32. Mecz Y, Barak M, Lurie A, et al: Prognostic importance of the rate of decrease in prostate specific antigen levels after treatment of patients with carcinoma of prostate. J Tumor Marker Oncol 4:323-328, 1989 33. Wittes RE: Manual of Oncologic Therapeutics, ed 19891990. Philadelphia, PA, Lippincott, 1989, pp 628-631 34. Horne MD, Stein CA, LaRocca RV, et al: Circulating glycosaminoglycan anticoagulants associated with suramin treatment. Blood 71:273-279, 1988 35. LaRocca R, Stein CA, Danesi R, et at: Suramin in adrenal cancer: Modulation of steroid hormone production, cytotoxicity in vitro, and clinical antitumor effect. J Clin Endocrinol Metab 71:497-504, 1990 36. Linehan WM, Kish ML, Chen SL, et al: Human prostate carcinoma causes hypercalcemia in athymic nude mice and produces a factor which parathyroid hormone-like bioactivity. J Urol 135:616-620, 1986 37. Walther MM, Trahan E, Venzon D, et al: Effect of suramin on egf-, tgf-, pth-, and pthrb-induced bone reabsorption Cancer Res 1991 38. Holland EJ, Stein CA, Palestine AG, et al: Suramin keratopathy. Am J Ophthalmol 106:216-220, 1988 39. Scher HI, Yagoda A: Bone metastases: Pathogenesis, treatment, and rationale for use of resorption inhibitors. Am J Med 82:6-28, 1987 40. Eisenberger MA: Chemotherapy for prostate carcinoma. NCI Monogr 7:151-163, 1988 41. Liberman R, Katzper M, Cooper M, et al: Nonmem population pharmacokinetic analysis and Bayesian forecasting during suramin therapy in prostatic cancer: One versus two compartment pharmacokinetic analysis. Proc Am Soc Clin Oncol 9:262, 1990 (abstr) 42. Jodrell D, Zukowski E, Egorin M, et al: Intermittent bolus dosing with suramin: The use of adaptive control with feedback (ACF). Proc Am Assoc Cancer Res 10:237, 1991 (abstr) 43. Eisenberger M, Jodrell D, Sinibaldi V, et al: Preliminary evidence of antitumor activity against prostate cancer observed in a phase 1 trial with suramin. Proc Am Assoc Cancer Res 10:537, 1991 (abstr)

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 5, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.