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© 2003 American Society for Clinical Oncology Phase II Trial of Thalidomide and Carmustine for Patients With Recurrent High-Grade GliomasFrom the Neuro-Oncology Branch, National Cancer Institute, National Institutes of Neurologic Disorder and Stroke, and Cancer Therapeutics Branch and the Cancer Prevention Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; and Center for Neuro-Oncology, Dana-Farber Cancer Institute, Department of Neurology the Brigham and Women’s Hospital, and the Massachusetts General Hospital, Harvard Medical School, Boston, MA. Address reprint requests to Howard A. Fine, MD, Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, 10 Center Drive, MSC 1911, Building 10, Room 12S245, Bethesda, MD 20892-1911; email: hfine{at}mail.nih.gov.
Purpose: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas. Patients and Methods: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated. Results: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls. Conclusion: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.
PRIMARY BRAIN tumors are an important cause of cancer mortality in the United States, representing the leading cause of cancer deaths in children and the fourth leading cause of cancer deaths in young adults. Progress in the treatment of these tumors has been slow since the demonstration more than 20 years ago that fractionated radiotherapy could significantly extend survival.1–3 Although improved neurosurgical techniques have lessened the morbidity of extensive resections, the impact of such procedures on the overall survival of patients with high-grade gliomas remains modest at best, given the diffuse infiltrative nature of the tumor. Chemotherapy has recently been demonstrated to have some activity in specific subtypes of malignant gliomas such as oligodendrogliomas and anaplastic astrocytomas.4,5 The effectiveness, however, of standard chemotherapy for the most common and most malignant of the gliomas, glioblastoma (GBM), is marginal at best.6,7 Clearly, novel therapeutic approaches and novel drug targets are needed. On the basis of pioneering work done more than two decades ago, it is now generally accepted that solid tumor growth is at least partially dependent on the recruitment of pre-existing vascular networks and the induction of new vascular growth through a process known as angiogenesis.8 A natural correlate to the hypothesis that solid tumor growth is angiogenesis-dependent is that angiogenesis inhibition should perturb normal tumor growth. Abundant preclinical studies seem to support this theory.9–15 High-grade gliomas are highly angiogenic, apparently through the acquisition of a number of genetic alterations that enable them to overexpress inducers of angiogenesis or downregulate natural inhibitors of angiogenesis.16,17 Thus, angiogenesis inhibition may represent an important therapeutic target for high-grade gliomas. Indeed, preclinical data have demonstrated that angiogenesis inhibition can slow the rate of glioma growth in various syngeneic and xenograft rodent models.18–21 Thus, angiogenesis inhibition seems to represent a promising new target for therapeutic intervention for malignant gliomas. Thalidomide is a central nervous system sedative with potent teratogenic properties22 that has been demonstrated to possess antiangiogenic activity in several nontumor models.23 Given the ease of administration and overall favorable toxicity profile, we previously conducted a phase II trial of thalidomide in patients with malignant gliomas.24 This trial demonstrated clear, although not highly potent, antitumor activity. Preclinical data have demonstrated synergistic activity of antiangiogenic agents in combination with cytotoxic agents.25–28 Thus, we subsequently initiated this phase II trial of thalidomide combined with carmustine (BCNU), the traditional cytotoxic agent used in patients with gliomas. We believe the results presented here demonstrate a potential benefit of the drug combination compared with administration of either drug alone, indicating that further studies are warranted.
Patients and Treatment Patients 18 years of age and older with recurrent high-grade gliomas and a Karnofsky performance status (KPS) ≥ 60 were eligible for the trial. Patients were required to have a diagnosis of high-grade glioma (anaplastic astrocytoma, anaplastic mixed glioma, or GBM) and to have been previously treated with at least standard fractionated external beam radiation. Patients may have had a maximum of two prior chemotherapy regimens, including a nitrosourea. Patients previously treated with stereotactic radiosurgery were eligible for the study if they had radiographic signs of tumor progression that were clearly outside of the radiation volume, and/or had histologic verification of recurrent tumor rather than radiation necrosis. Patients had to receive a stable dose of glucocorticoids for at least 2 weeks before initiation of therapy and the baseline magnetic resonance imaging (MRI) scan. Therapy consisted of 800 mg/d of thalidomide (supplied by Celgene Pharmaceuticals, Warren, NJ) for the first 2 weeks, which was escalated by 200 mg every 2 weeks until a final dose of 1,200 mg/d was reached, or until the patient experienced dose-limiting toxicity defined as grade 3 somnolence or neurotoxicity (National Cancer Institute common toxicity criteria). BCNU was administered as an intravenous infusion for 1 hour at a dose of 200 mg/m2 every 6 weeks. Dose modifications in BCNU and thalidomide were made for grade 3 hematologic and nonhematologic toxicities. Cycles were defined as every 6 weeks. Patient assessment consisted of weekly complete blood counts; a complete history; a physical and neurological examination every 3 weeks; and serum electrolytes, liver, and renal function tests every 6 weeks. MRI scans were repeated at 6-week intervals or earlier if clinically indicated. All patients with measurable tumors were evaluated by objective criteria as previously described.29 When the MRI scan demonstrated changes of unclear significance, patients underwent metabolic imaging such as technetium-thallium dual-isotope single-photon emission computed tomography scanning, magnetic resonance spectroscopy, dynamic MRI, and/or positron emission tomography scanning. If these studies failed to clarify the nature of the radiographic changes and if the patient was neurologically stable or improved, treatment was continued for another cycle. In such cases, the patient was removed from study if the next 6-week MRI scan showed any progression, at which point the date of tumor progression was calculated to be the date of the first MRI scan that demonstrated a question of tumor progression. Biopsies for indeterminate scans were performed when medically indicated and appropriate. All patients were placed on an aggressive prophylactic bowel regimen because thalidomide can cause severe constipation. Patients were allowed to maintain their normal regimen of antiseizure medications, although no benzodiazepines or sedative neuroleptics were permitted because of the sedative effects of thalidomide. This study protocol was approved by and the trial was conducted in accordance with the rules of conduct for clinical trials as determined by the Institutional Review Board of the Dana-Farber Cancer Institute, Harvard Medical School (Boston, MA).
Study Design and Statistical Methods The data were collected and analyzed using Simon’s two-stage design for small phase II clinical trials.31 A positive response consists of remaining progression free for more than three cycles, or 126 days. All P values for the associated analyses were exact and one-sided. Mean and median time to progression and survival times after the start of treatment, plus 95% confidence intervals (CIs), were estimated using the Kaplan-Meier method by the S-Plus 2000 package (MathSoft, Inc, Data Analysis Products Division, Seattle, WA).
Immunoassays and Pharmacokinetic Analyses
Forty patients with recurrent high-grade gliomas were enrolled onto this trial, 38 of whom had a diagnosis of GBMs. The demographics of this patient population are outlined in Table 1  .
Therapy was generally well tolerated (Table 2 ). Thrombocytopenia was the most common hematologic side effect, with one episode of grade 4 thrombocytopenia but no episodes of clinically significant bleeding. Neutropenia occurred in three patients but was accompanied by fever or evidence of infection in only one patient. Thromboembolic events occurred in 12 patients, including eight deep venous thromboses and seven pulmonary emboli. This high incidence of thromboembolic events is consistent with both the reported frequency of such complications in patients with advanced glial neoplasms and our high vigilance in screening for this complication.33 Nevertheless, it is impossible to know for certain whether treatment with BCNU and thalidomide increased the underlying risk of thromboembolism. Although no clinically apparent pulmonary toxicity was observed (ie, pneumonitis or pulmonary fibrosis), minor to moderate (up to 35%) decreases in the pulmonary diffusion capacity, as assessed by pulmonary function testing, were observed in some patients after two or more cycles of BCNU. The type and number of adverse events attributable to thalidomide were consistent with those seen in other studies.24 In particular, although most patients experience sedation when starting thalidomide therapy, the severity of the sedation significantly diminished after the first 2 weeks of treatment. There were five episodes of grade 3 neurocognitive toxicity attributable to tumor progression, although at least one patient experienced agitation that seemed to be directly related to the thalidomide. A thalidomide-induced, moderately severe maculopapular rash was seen in two patients that necessitated termination of the thalidomide therapy. A number of other patients developed less severe, nonsymptomatic erythrodermas during the course of their therapy that were not clearly related to thalidomide. We continued thalidomide treatment in these patients with either stabilization or spontaneous resolution of the erythroderma. Because all of our patients received prophylactic stool softeners and were maintained on high-fiber diets, constipation was generally not a significant problem. There were no patients with clinically apparent peripheral neuropathy.
We performed separate outcome analyses on the entire group of patients (intent-to-treat cohort, 40 patients) and for the patients with GBMs (38 of 40 patients; Fig 1 ). The Kaplan-Meier estimated curves for the interval of 175 to 184 days was used to approximate the APFS6. For our entire study group, the Kaplan-Meier estimates of the mean proportion APFS6 with Greenwood SE and an asymmetric 95% CI was 27.5% ± 7.06% (asymmetric 95% CI, 16.66 to 45.50). For the GBM-only group, the mean APFS6 was 27.03% ± 7.30% (asymmetric 95% CI, 15.90 to 45.90). In contrast, Wong et al reported a mean proportion APFS6 of 15% with a 95% CI of 10 to 19 for GBM patients. From these results, we can obtain a crude estimate of the SE from the study by Wong et al30 of ([0.19 to 0.10]/2 x 1.96) = 0.023. In turn, we can use a normal approximation formula to compare the proportions between the two studies. The comparison between our total group of patients compared with the Wong cohort demonstrates a difference at the 5% significance level in favor of the BCNU-thalidomide–treated patients (z score, 1.68; two-sided P = .092; one-sided P = .046). In contrast, the evidence was weaker that the APFS6 was significantly better for the BCNU-thalidomide–treated GBM-only patients (z score, 1.57; two-sided P = .116; one-sided P = .058).
We next addressed the question of whether there was a difference in the overall median PFS of the BCNU-thalidomide–treated patients compared with the median PFS of 63 days (95% CI, 56 to 70) for patients with GBM reported by Wong et al.30 The median PFS for our entire study group was 100 days (mean ±SE, 154 ± 24.9 days; 95% CI, 58 to 172). Similarly, the median PFS of our GBM-only group was 104 days (mean ±SE 157 ± 26.4 days; 95% CI, 58 to 172). By comparing the median PFS between groups,34 we demonstrate that the increased median PFS seen in the BCNU-thalidomide–treated patients group compared with the patients with GBMs in the Wong cohort was statistically significant (z score, 2.66; asymmetric 95% CI of the ratio, 1.13 to 2.23; two-sided P = .008; one-sided P = .004). Similarly, there was a highly significant statistical difference in the prolonged median PFS in the GBM-only patients treated with BCNU-thalidomide compared with the GBM patients in the Wong series (z score, 2.79; asymmetric 95% CI of the ratio, 1.16 to 2.35; two-sided P = .005; one-sided P = .003).
In addition to PFS, we also evaluated objective radiographic tumor responses. Thirty-eight of the 40 patients were assessable for radiographic response. Of the two patients who were not assessable for radiographic response, one patient never received therapy and one patient never had a follow-up MRI scan after enrollment because of rapid disease progression and patient refusal. Of 38 assessable patients, there was one complete response (CR, 3%), eight partial responses (PR, 21%), and nine patients with stable disease (SD, 24%; Fig 2
Although older age was a significant negative prognostic factor for overall survival from time of initial diagnosis (P = .02), it did not affect PFS or overall survival from time of enrollment. Similarly, KPS had no apparent effect on PFS or overall survival. A prior history of chemotherapy did not seem to be an independent factor for PFS (P > .1, log-rank test), nor did it predict for longer survival (P = .1, log-rank test). Patients, however, were more likely to have a radiographic response to BCNU and thalidomide (including SD) if they had never received prior chemotherapy (60% v 30%), although there was no real difference in the overall objective radiographic response rate (CR, PR) between patients who had or had not received prior chemotherapy (30% v 20%, respectively). Unlike in our first study, we found no correlation between peak serum levels of bFGF and radiographic response to therapy, PFS, or overall survival (data not shown).24 There were too many inconsistencies in the sample collection to make any definitive statements about the trend in bFGF levels during the course of therapy in individual patients. The pharmacokinetic profile of thalidomide seen in this trial was consistent with that already reported in other patients with gliomas.24 Although peak thalidomide concentrations varied among patients, they tended to be lower in patients who responded to therapy than those who did not respond (median concentrations 6,009 ng/mL [SE = 992 ng/mL] v 8,265 ng/mL [SE = 1,969 ng/mL], respectively). Regression analysis demonstrated a small but significant relationship between lower peak thalidomide concentrations and PFS, although the correlation with overall survival did not reach significant levels (R2 = 0.19, F = 4.73, P = .04; R2 = 0.158, F = 3.74, P = .06; respectively). Levels of the 5'OH thalidomide metabolite were often below the levels of detection, making pharmacokinetic profiling impossible.
Angiogenesis inhibition represents a promising therapeutic strategy for a wide variety of tumors, including high-grade gliomas. Enthusiasm for this approach, however, has been tempered by preclinical data indicating that angiogenesis inhibition, as a single therapy, slows tumor growth but is not generally cytotoxic. In contrast, results from animal studies demonstrate that combinations of antiangiogenic agents and cytotoxic therapies may be significantly more potent than either treatment approach alone.25–28 Thus, we chose to evaluate the clinical effectiveness of combining BCNU, the most commonly used cytotoxic drug for gliomas, with thalidomide, the most highly studied antiangiogenic agent in malignant gliomas. This single-institution phase II trial demonstrates that the combination of BCNU and thalidomide is generally well tolerated and has activity in patients with recurrent high-grade gliomas. Assessing brain tumor responses to therapy can be difficult because of variability among different scanning techniques (ie, amount and timing of contrast administration), MRI scans with different magnet strengths, differentiation between tissue necrosis and tumor, and the difficulty in quantifying tumor sizes given that gliomas grow in irregular three-dimensional shapes. The problem of assessing brain tumor responses is further complicated by the uncertainties of how to assess the activity of cytostatic agents rather than cytotoxic agents. Thus, we chose to use PFS in addition to objective radiographic response as primary end points. Although originally designed as a phase II trial for recurrent high-grade gliomas of all types, review of the final pathologic diagnoses demonstrated that 38 of 40 patients had GBM. Thus, for purposes of assessing the activity of this drug combination, we used a similarly treated group of patients with GBM as our historical comparison. Data were analyzed both on an intention-to-treat basis (thereby including the two patients with anaplastic astrocytomas) using a separate analyses for the cohort of 38 patients who only had GBMs. Patients in this study treated with BCNU and thalidomide seemed to have improved median PFS when compared with a published database of a group of similar patients treated in eight different phase II studies conducted at two major brain tumor institutions (104 v 63 days, P = .003).30 Similarly, the objective radiographic response rate of 24% for the thalidomide-BCNU–treated group as a whole, or the 22% response rate of the patients with GBM, compared favorably to the 6% objective response rate reported by Wong et al30 in their historical database. It is important to note that the PFS and time to tumor progression estimates in our trial were not falsely inflated (which sometimes occurs in similar trials) because of prolonged scanning intervals because patients were required to undergo MRI scans every 42 days. Thus, the mean (154 days) and the median (100 days) time to progression encompass more than three and two scanning intervals, respectively. Finally, the APFS6 and objective response rate (27.5% and 22%, respectively) for our GBM patients treated with thalidomide and BCNU also compares favorably with a similar group of patients treated in a randomized phase II trial with either temozolomide (APFS6, 21%; objective response, 5%) or procarbazine (APFS6, 9%; objective response, 5%).35 Nevertheless, such a comparison needs to be interpreted with caution given the propensity for greater patient selection bias in single-institution trials compared with multi-institutional trials. We were unable to identify significant prognostic factors in our patient population. In particular, previously reported predictive factors such as age and KPS had no impact on the likelihood of response, PFS, or overall survival. Similarly, a prior history of chemotherapy did not prove to be a significant predictive factor for PFS or overall survival, although patients who had prior chemotherapy demonstrated a lower radiographic response rate. Whether the effects of therapy negated the influence of age and KPS on PFS and overall survival, or whether the number of patients in this trial was too small to discern reliably the effects of these factors is not known. Data from this trial indicate that the combination of thalidomide and BCNU has activity against GBMs. Whether this drug combination is more active than either of the drugs used alone cannot be determined with certainty without performance of a randomized trial. Nevertheless, our previous data using thalidomide alone (which demonstrated a 4% AFPS6, a 6% objective radiographic response rate, and a median time to tumor progression of 70 days) indicate significantly less antitumor activity with the single agent compared with the combination of drugs seen in this current trial. The significant improvement in the outcome of the patients with GBMs treated with the combination of BCNU and thalidomide in this current trial is perhaps even more compelling when one considers that 35% of the study population in the thalidomide-only trial had anaplastic gliomas and thus would be predicted to have a better overall outcome than patients with GBMs. Whether thalidomide combined with BCNU is more active than BCNU alone is less clear given the paucity of reliable, objective clinical data regarding the true activity of BCNU as a single agent in recurrent gliomas. Most of the data that exist concerning the use of BCNU as a single agent for recurrent gliomas come from the era before MRIs and computed tomography scans were available, making the interpretation of those data nearly impossible. Nevertheless, response rates in gliomas to other alkylating agents such as procarbazine and carboplatin are significantly lower than those seen in this trial, indicating that thalidomide may be adding to the antitumor activity of BCNU.35,36 One could also argue that thalidomide must be adding to the antitumor effect seen with the combination secondary to the inverse relationship between peak thalidomide serum concentrations and median PFS. This inverse relationship could be interpreted to mean that patients who more efficiently metabolized thalidomide to its active metabolites derived more benefit from the drug. It is also possible, however, that more efficient thalidomide metabolism merely represented a surrogate marker for patients who were destined to have improved outcomes for reasons unrelated to thalidomide (ie, healthier patients metabolized drugs more efficiently or patients with higher metabolism generated more active BCNU metabolites, thus accounting for their improved outcomes). Thus, although the response rate seen in this trial is probably higher than what most practicing neuro-oncologists would likely expect to see with single-agent BCNU, a definitive answer awaits a randomized trial. In conclusion, this trial demonstrates that the combination of thalidomide and BCNU has activity against recurrent GBMs that compares favorably with other agents or combinations reported in the literature. These results need to be confirmed in a larger phase II trial, preferably in a multi-institutional setting to eliminate the patient-selection bias inherent in single-institutional trials. If the results of this trial are replicated in a larger phase II trial, a phase III trial of the combination could be considered. Because many clinicians believe that the optimal time to use an antiangiogenic agent is at the time of minimal residual tumor burden, the combination of thalidomide and BNCU may be best used in the immediate postoperative or postradiation period. To this end, a recently completed Radiation Therapy Oncology Group phase II trial of newly diagnosed patients with GBM demonstrated that the use of thalidomide in the pre- and postradiation period resulted in survivals that were equivalent to, but no better than, a historical group of similar patients treated with BCNU.37 Thus, a randomized trial of thalidomide in combination with BCNU compared to BCNU alone in the immediate postradiation period should answer many of the questions raised by this current study.
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33. Levin J, Schiff D, Loeffler JS, et al: Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology 43:1111–1114, 1993 34. Friedman LM, Furberg CD, DeMets D: Fundamentals of Clinical Trials (3rd ed). St. Louis, MO, Mosby, 1998 35. Yung WK, Albright RE, Olson J, et al: A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588–593, 2000[CrossRef][Medline] 36. Prados MD, Warnick RE, Mack EE, et al: Intravenous carboplatin for recurrent gliomas: A dose-escalating phase II trial. Am J Clin Oncol 19:609–612, 1996[CrossRef][Medline] 37. Seiferheld W, Mehta M, Del Rowe J, et al: Five years of glioblastoma multiforme (GBM) phase II trials at the Radiation Therapy Oncology Group (RTOG). Presented at Am Soc Clin Oncol Meeting, Orlando, FL, May 18–21, 2002, pp 71a Submitted August 5, 2002; accepted March 21, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
