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Suramin is a polysulfonated naphthylurea that inhibits the function of growth factors and growth factor receptors implicated in glioma progression, angiogenesis, and radioresistance. The safety and benefits of combining inhibitors of angiogenesis and growth factors with cytotoxic therapies in patients with neoplasms of the central nervous system remain unclear. The objectives of this phase 2 study were to determine the safety of administering suramin with standard cranial radiotherapy (RT) and to estimate survival using this approach in patients with newly diagnosed glioblastoma multiforme (GBM). Fifty-five patients with newly diagnosed GBM (Karnofsky performance status ≥ 60) were enrolled in this multi-center phase 2 study. Patients received suramin by a conventional intermittent fixed-dosing regimen for 1 week prior to and during cranial RT (60 Gy in 30 fractions, weeks 2–7). Patients with stable or responsive disease at week 18 received an additional 4 weeks of suramin (weeks 19–22). The median survival for suramin-treated patients was 11.6 months, with 1-year and 18-month survival rates of 49% (95% confidence interval [CI], 36%–62%) and 18% (95% CI, 8%–28%), respectively. Overall, 55% of the patients (30/55) had greater than grade 2 toxicity at least possibly related to suramin therapy. Two patients died of possibly related neurologic events (i.e., stroke, elevated intracranial pressure). Otherwise, toxicities were generally transient and self-limited. Administration of suramin using an intermittent fixed-dosing regimen during cranial RT was generally well tolerated. However, overall survival is not significantly improved when compared with the New Approaches to Brain Tumor Therapy GBM database or other comparable patient populations.
Suramin is a polysulfonated naphthylurea that was developed in the 1920s as a treatment for African trypanosomiasis and later found useful in the treatment of onchocerciasis. Suramin has received attention recently as a potential antineoplastic agent because of its ability to interfere with the function of a number of peptide growth factors, such as platelet-derived growth factor (Hosang, 1985; Huang and Huang, 1988), basic fibroblast growth factor (Coffey et al., 1987; Moscatelli and Quarto, 1989), vascular endothelial growth factor (Waltenberger et al., 1996), and hepatocyte growth factor (Galvani et al., 1995), thereby antagonizing tumor cell proliferation, tumor cell survival, and tumor angiogenesis. Other second-messenger mechanisms for suramin’s in vivo antiproliferative effects have been proposed (Butler et al., 1988; Hensey et al., 1989). Suramin has modest activity in the treatment of patients with metastatic prostate carcinoma refractory to androgen deprivation (LaRocca et al., 1991; Myers et al., 1992). The New Approaches to Brain Tumor Therapy (NABTT)3 CNS Consortium has previously reported the results of a phase 1 study of suramin in 12 patients with recurrent malignant glioma, which demonstrated that suramin administered intravenously on an intermittent fixed-dosing regimen was safe with potential therapeutic activity in a subset of patients (Grossman et al., 2001; Reyno et al., 1995).
There is increasing in vitro and preclinical in vivo evidence that antigrowth factor and antiangiogenesis strategies including suramin may cooperate or synergize with cytotoxic therapy such as radiation therapy or chemotherapy (Howard et al., 1995; Palayoor et al., 1997; Teicher et al., 1995). While the mechanism for these cooperative antineoplastic actions is not clear, there is evidence that they may result from increased tumor cell sensitivity to chemotherapy- or radiation-induced apoptosis. This suggests that suramin could be particularly suitable for combined-modality therapies (Teicher et al., 1996).
We report the results of a 55-patient safety and efficacy study of suramin administered for 5 consecutive days (week 1) prior to and during cranial radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM). Patients with stable or responsive disease received an additional 4 weeks of suramin (weeks 19– 22). Radiotherapy consisted of a total dose of 60 Gy given in 30 treatments over 6 weeks. The primary objectives of this trial were to estimate the feasibility, toxicity, and survival outcome of this therapy.
Patients were required to have histologically confirmed supratentorial Grade IV astrocytoma (GBM), untreated except for biopsy or other surgery and/or corticosteroids. Other eligibility criteria included age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, absolute neutrophil count ≥ 1500 cells/mm3, hemoglobin ≥ 9.0 g/dl, platelets ≥ 100,000 cells/mm3, creatinine ≤ 1.7 mg/dl, bilirubin ≤ 1.5 mg/dl, and transaminases ≤ 4.0 times the upper limit of normal. Exclusion criteria included disseminated intravascular coagulation, prior intracranial or intratumoral hemorrhage, history of bleeding disorder or other intercurrent illness that might interfere with protocol treatment, or concurrent malignancy unless disease-free ≥ 5 years (except for curatively treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix). Women of child-bearing potential were required to have a negative serum beta human chorionic gonadotrophin pregnancy test, agree not to breast feed, and use a standard contraceptive regimen. This protocol was approved by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program and the institutional review boards of all participating institutions. Informed consent was obtained from all patients prior to their participation in this study.
Suramin was supplied by the NCI Division of Cancer Treatment and Diagnosis (Bethesda, Md.). Suramin in 600-mg vials was reconstituted with 6 ml of Sterile Water for Injection (United States Pharmacopeia, Rockville, Md.) to yield a 10% (100-mg/ml) solution of suramin sodium. The reconstituted suramin was stored at ambient temperature and used within 24 h of reconstitution since the drug did not contain preservatives.
Suramin was administered by intravenous infusion over a 1-h period (except for first dose, infused over 2 h) beginning 1 week prior to initiation of radiation therapy using the intermittent fixed-dosage regimen designed to maintain plasma concentrations in the 150- to 250-μ g/ml range (Grossman et al., 2001). The first dose (day 1) was 1100 mg/m2, the second (day 2) was 400 mg/m2, the third (day 3) was 300 mg/m2, the fourth (day 4) was 250 mg/m2, and the fifth (day 5) was 200 mg/m2. All subsequent doses administered during weeks 2 through 7 (on days 8, 11, 15, 19, 22, 29, 36, 43) during radiation therapy were 275 mg/m2. Patients with no undue toxicity and stable or responsive disease as determined by contrast-enhanced MRI scans received an additional 4 weeks of twice-weekly intravenous infusions of 275 mg/m2 beginning 12 weeks after completion of radiation therapy.
Standard cranial radiation therapy to a dose of 60 Gy in 2.0-Gy fractions for 30 fractions over 6 weeks was given. The initial field was treated to 46.0 Gy delivered to the tumor plus edema with a 2-cm margin as determined by MRI or a 3-cm margin as determined by CT scan. The conedown consisted of an additional 14.0 Gy to gross tumor or tumor bed with a 2.0-cm margin if determined by MRI and a 3.0-cm margin if determined by CT scan. If a 3-dimensional treatment planning system was used, the dosimetric margin for the 100% iso-dose line was 1 cm if volumes were determined by MRI and 2 cm if determined by CT scan.
Patients were assessed for adverse events and toxicity weekly during cycle 1 and the maintenance cycle, monthly during the 12 weeks following completion of radiation therapy, and every 2 months following the maintenance cycle and when off study. The NCI Common Toxicity Criteria version 2.0 (NCI, 1999) was used to record toxicities. Dose-limiting toxicity was defined as any grade 3 or 4 toxicity (except for grade 3 neurotoxicity responding to corticosteroids, diuresis, or anticonvulsants) thought to be possibly, probably, or definitely related to suramin. Electrolytes, complete blood count, prothrombin time or partial thromboplastin time (PT/PTT), and anticonvulsant levels were determined before treatment and through the first cycle of suramin therapy. Electrolytes, complete blood count, and PT/PTT were determined weekly during the maintenance cycle of suramin.
The primary end points of this study were survival and toxicity. The primary efficacy analysis included all accrued patients, and analyses were intention-to-treat. Overall survival time was calculated as time from histological diagnosis until death from any cause. Event times were censored if patient was alive at time of last follow-up (September 2002). The failure rate was calculated as the number of deaths divided by the total exposure (follow-up time). Survival distributions were estimated by the product limit method (Kaplan and Meier, 1958) and compared by using the log-rank test (Kalbfleisch and Prentice, 1980).
Patients treated on this trial were compared to patients treated on similar trials of therapies administered concurrently with RT for newly diagnosed GBM by the NABTT CNS Consortium. To control for the effects of prognostic factors on survival, adjusted risk ratios were calculated by using the proportional hazards regression model (Cox, 1972). These prognostic factors included age, KPS, and extent of surgical resection coded as craniotomy or biopsy.
The sample size of 55 was chosen to provide sufficient events over 2 years of study to have 78% power to find a 30% reduction in the hazard rate compared to the NABTT historical database to be statistically significant with a one-sided 0.10 α -level test. No interim analyses were planned or conducted.
Differences in patient characteristics between groups were tested for statistical significance by using chi-squared and t tests. Confidence intervals were calculated by standard methods. SAS software version 8.2 (SAS Institute, Cary, N.C.) was used to perform analyses. All P-values reported are two-sided.
Fifty-five patients with histologically confirmed newly diagnosed GBM were accrued to this trial at 8 NABTT institutions between November 1999 and February 2001. Baseline demographic and clinical characteristics of the study patients are reported in Table 1. Thirty-five of the 55 patients (64%) completed the first cycle of suramin with radiation as planned. Twenty of the 35 patients who completed the first cycle ultimately completed the second cycle of suramin.
Three patients developed a deep vein thrombosis (DVT) while on study and in accordance with the original protocol were removed from treatment. Because of the known high incidence of DVT in patients with glioblastoma, the protocol was subsequently amended to allow patients who develop a DVT or require heparin for <7 days to remain on study. Fifty-five percent of patients (30/55) experienced grade 3 or greater toxicity considered to be at least possibly related to suramin therapy. The most common of these events included fatigue, rash, electrolyte imbalance, pancreatitis or elevated serum amylase/lipase, pulmonary symptoms including 1 patient with acute respiratory distress syndrome, neuropathy, leukopenia, and thrombocytopenia (Table 2). Four patients experienced infectious events unassociated with neutropenia. One patient died of CNS ischemia and another of progressive cerebral edema during radiation, both possibly related to suramin. One patient developed transient renal failure related to suramin requiring removal from study.
Fifty-three of the 55 patients accrued to this study have died. The total follow-up time of all patients in this trial was 52.2 years, and the minimum follow-up time for surviving patients was greater than 20 months. The 12-month survival rate was 49% (95% CI, 36%–62%), and at 18 months it was 18% (95% CI, 8%–28%). Median survival was 11.6 months (95% CI, 9.6–14.2).
The historical NABTT reference group consisted of 164 patients enrolled in 4 other NABTT trials of therapies concurrent with RT for patients with newly diagnosed GBM with or without measurable disease. The trials included in the reference group were a dose-finding trial of a synthetic allosteric modifier of hemoglobin (RSR13, n = 19), a safety and efficacy trial of RSR13 (n = 50), a safety and efficacy trial of penicillamine (n = 40), and a safety and efficacy trial of carboxy-amido triazole (n = 55). Patients were accrued to these trials between February 1997 and November 2000. The trials in the reference group had similar eligibility criteria and were accrued at NABTT CNS Consortium institutions. Comparative baseline demographic and clinical characteristics are presented in Table 1.
In this reference group, 153 of the 164 patients have died. Follow-up time for the 11 surviving patients ranged from 21.1 to 61.8 months. The total follow-up time for the reference group was 188.4 years. The failure rates for the suramin patients and the reference group are in Table 3. Kaplan-Meier survival curves for the patients in this study and the NABTT reference group are depicted in Fig. 1. The survival estimates were not significantly different (log-rank test; P = 0.08). A proportional hazards regression model adjusting for the prognostic factors age, KPS, and extent of surgical resection yielded a hazard ratio of 1.32 (P = 0.08) for this trial compared to the historical NABTT reference (Table 4).
The overall rationale for this study combining suramin with RT was multifold. Radiation therapy has proven, but limited efficacy when used as a single modality in the therapy of GBM. Suramin is an investigational agent with preclinical efficacy in a number of tumor types, including glioma, with the mechanism of action related to interference with growth factor function and tumor-associated angiogenesis (Bernsen et al., 1999; Coomber, 1995; Olson et al., 1994; Takano et al., 1994). Preclinical data strongly support the concept that antigrowth factor modalities including antiangiogenesis can cooperate with conventional cytotoxic modalities, including radiation, in solid tumor therapy (Teicher et al., 1996). Clinical trials show that suramin has modest therapeutic activity in hormone refractory prostate cancer (Eisenberger et al., 1993; Myers et al., 1992; Small et al., 2000). In a previous study of 12 patients with recurrent glioblastoma, the NABTT CNS Consortium demonstrated that suramin could be administered safely on an intermittent-infusion, fixed-dosing regimen, and results suggested potential but marginal efficacy in brain tumor patients (Grossman et al., 2001). The design of the present study incorporated and extended these observations by administering suramin concurrent with standard RT. Importantly, while there is evidence that suramin crosses the blood-brain barrier in animal brain tumor models (Olson et al., 1994), the ability of radiation therapy to increase blood-brain barrier permeability would be expected to enhance suramin delivery to brain tumors. Despite this rationale and the previous data, we found that adding suramin to radiation therapy failed to improve survival in this patient population when compared to NABTT historical controls. This study was powered to determine if the overall survival was significantly different than this control group. These results suggest that further study of this agent in patients with newly diagnosed GBM is not likely to be productive.
The survival figures for other cooperative group protocols in patients with newly diagnosed GBM are similar. The results of several phase 2 multi-institutional Radiation Therapy Oncology Group (RTOG) experimental trials, accruing patients from 1994 through 1997, were published in 2000–2001 and are also available for comparison. These Radiation Therapy Oncology Group trial results included median survival 9.7 months with concurrent paclitaxel and RT (Langer et al., 2001), 9.1 months with BCNU and 64 Gy hyperfractionated RT (Coughlin et al., 2000), 11.0 months with 70.4 Gy hyperfractionated RT and BCNU (Coughlin et al., 2000), and 10.8 months and 9.5 months for patients treated with RT and 2 separate dosing levels of tirapazamine (Del Rowe et al., 2000). The preliminary results have been reported for an Eastern Cooperative Oncology Group randomized trial that accrued patients from 1996 to 1999 (Grossman et al., 2003). Median survival was 11.2 months for concurrent BCNU and RT and was 11.0 months for neoadjuvant cisplatin and BCNU followed by delayed RT.
The previous NABTT CNS Consortium study demonstrated that suramin could be administered safely to patients with recurrent glioblastoma. The present study shows that administering suramin by an identical dosing regimen with radiation therapy is also relatively well tolerated. Two patients died from events possibly but not definitely related to suramin therapy. One experienced fatal progressive tumor-associated edema with elevated intracranial pressure early after starting radiation therapy. Suramin may have enhanced this radiation-induced edema response. Another patient died following an ischemic stroke. Overall, toxicity was generally transient and self-limited.
The NABTT CNS Consortium has designed a class of protocols to evaluate the efficacy of agents that are not cytotoxic (Grossman et al., 1998). As these agents are not necessarily expected to produce reductions in tumor size, they are best studied by using survival as the primary outcome measure. NABTT’s Class B Protocols combine these novel agents with radiation therapy in patients with GBM where the overall survival curve is very predictable. Studying approximately 55 patients in this manner provides sufficient information to decide if further investigation of a novel agent is likely to be productive. There are several advantages to this approach. First, it minimizes the chance of studying inactive agents in large, expensive, and time-consuming phase 3 studies. Second, most cytostatic agents will require trials designed to evaluate therapy provided over a relatively long duration. The treatment of newly diagnosed patients in combination with radiation therapy makes it much more likely that treatment of sufficient duration will occur to adequately assess cytostatic activity. This is in marked contrast to studying these agents in therapy-resistant, rapidly recurring GBM. Finally, most data with this class of agents suggest that they are most likely to succeed when combined with another cytotoxic therapy, such as radiation. The study reported in this manuscript provided suramin with every opportunity to demonstrate efficacy. An earlier study in patients with primary brain tumors demonstrated that the pharmacology of this agent was not affected by P450-inducing anticonvulsants and that it was given at the proper dose (Grossman et al., 2001). Suramin was administered to patients who had received no prior antineoplastic therapy, in combination with a cytotoxic agent, in a setting where long-term exposure was expected, and where survival rather than response was the primary end point. The present study demonstrated that the administration of suramin by an intermittent, intravenous infusion, fixed-dosing regimen prior to, concurrent with, and following cranial RT is tolerable and feasible but does not significantly influence survival in patients with newly diagnosed GBM. The absence of a surrogate biomarker for effective growth factor/angiogenesis inhibition in this study prevents a mechanistic interpretation of this apparent absence of efficacy. The development and testing of therapeutic strategies designed to target cytoprotective and angiogenic pathways in glioblastoma should remain a high priority.
The authors acknowledge the data management skills of Regina Priet and Penny Powers, R.N., as well as the leadership of Joy Fisher.
1This study was supported in part by the Cancer Therapy Evaluation Program of the National Cancer Institute through grant CA62475.
3The abbreviations used are as follows: CI, confidence interval; DVT, deep vein thrombosis; GBM, glioblastoma multiforme; KPS, Karnofsky performance status; NABTT, New Approaches to Brain Tumor Therapy; NCI, National Cancer Institute; RT, radiotherapy.