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© 1999 American Society for Clinical Oncology Irinotecan Therapy in Adults With Recurrent or Progressive Malignant GliomaFrom the Departments of Surgery, Medicine, Pediatrics, Radiology, and Pathology, Duke University Medical Center, Durham, NC; Pharmacia & Upjohn, Kalamazoo, MI; Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN; and Department of Medicine, University of California Los Angeles School of Medicine, Los Angeles, CA; email fried003@mc.duke.edu. Address reprint requests to Henry S. Friedman, MD, Duke University Medical Center, Box 3624, Durham, NC 27710.
PURPOSE: To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma. PATIENTS AND METHODS: Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (IV) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients. RESULTS: All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment. CONCLUSION: Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance.
THE PROGNOSIS FOR adults with malignant gliomas remains dismal, with a 2-year progression-free survival rate of 38% to 50% for patients with anaplastic astrocytoma.1,2 Survival is only measured in months for those patients with glioblastoma multiforme.3,4 Supportive care in the management of malignant glioma usually begins soon after the diagnosis of brain tumor and includes use of corticosteroids and anticonvulsants. Corticosteroids, prescribed for treatment of cerebral edema, can improve symptoms, assist in maintaining clinical improvement for extended periods of time,5 and may even decrease the size of some malignant gliomas on computerized axial tomography (CT) scans.6,7 Anticonvulsants are also prescribed for patients with cerebral neoplasms.8 First-line treatment of malignant glioma typically uses multimodal therapy, including surgery, when feasible, and adjuvant radiotherapy. Randomized studies have established a role for adjuvant treatment,9,10 but standard second-line treatment is not well-defined. A number of agents have been tested, with response rates generally in the range of 0% to 20%.11-15 Patients with recurrent malignant gliomas after initial therapy uniformly fail existing second-line chemotherapy and die. Newer active chemotherapeutic agents are needed if outcomes are to be improved. Irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) is a water-soluble chemical derivative of camptothecin, an alkaloid originally extracted from the Chinese tree Camptotheca acuminata.16 Camptothecin and its analogs inhibit topoisomerase I, an enzyme that is essential for DNA transcription, replication, and repair. After intravenous (IV) administration, CPT-11 is metabolized by carboxylesterase enzymes to form SN-38 (Fig 1). SN-38 is approximately 1,000 times more potent than CPT-11 as an inhibitor of topoisomerase I.17-21 The major site of bioactivation of CPT-11 to SN-38 is believed to be human liver; however, extrahepatic metabolism in normal tissues and tumors has also been documented. SN-38 is further conjugated by uridine diphosphate glucuronosyltransferase to form the secondary metabolite, SN-38 glucuronide (SN-38G).22-24 Recently, a new metabolite, denoted aminopentane carboxylic acid (APC), was isolated from human plasma and characterized by mass and nuclear magnetic resonance spectrometry.25 The enzyme isoform responsible for the initial oxidation of CPT-11 to this piperidine ring–opened carboxylic acid metabolite has been identified as CYP3A4.26 SN-38G and APC only demonstrate 1/50th to 1/200th the activity of SN-38 in cytotoxicity assays.25,27 Thus, it does not seem that either SN-38G or APC contributes substantially to the activity and toxicity profile of CPT-11 in vivo.
In laboratory studies devoted to the identification of antineoplastic agents with novel mechanisms of action against glial malignancies, CPT-11 has shown marked activity against a broad panel of CNS xenografts. Tumors included glioblastoma multiforme, ependymoma, and medulloblastoma growing subcutaneously and intracranially in athymic nude mice.28-30 On the basis of these preclinical results, this phase II clinical trial of CPT-11 in the treatment of adults with recurrent malignant glioma was initiated. The objectives of this trial were to determine the antitumor activity of CPT-11, including response, time to tumor progression, and survival time, in the treatment of adults with progressive, persistent, or recurrent malignant glioma and to evaluate the toxicity of CPT-11 in this patient population. The pharmacokinetics and pharmacodynamics of CPT-11 and its active metabolite SN-38 also were to be characterized in these patients.
Eligibility Criteria For entry onto the study, patients were required to have a histologically confirmed diagnosis of a recurrent primary malignant glioma (glioblastoma multiforme [GBM], anaplastic astrocytoma [AA], or anaplastic oligodendroglioma [AO]), be at least 18 years of age, exhibit evidence of recurrent or progressive primary CNS neoplasm on contrast-enhanced magnetic resonance imaging (MRI) obtained within 2 weeks before study initiation, and have a Karnofsky performance status  60%. It also was stipulated that an interval of at least 3 weeks between prior surgical resection, or 6 weeks between prior radiotherapy or chemotherapy, and enrollment onto the clinical trial must have elapsed unless unequivocal evidence of tumor progression after surgery, radiotherapy, or chemotherapy was detected. Additional enrollment criteria included adequate pretreatment bone marrow, renal, and hepatic function (hematocrit concentration > 29%, absolute neutrophil count > 1,500 cells/µL, platelet count > 125,000 cells/µL, serum creatinine level < 1.5 mg/dL, blood urea nitrogen level < 25 mg/dL, serum AST and bilirubin levels < 1.5 times the upper limit of normal). For patients on corticosteroids, a stable dose for 2 weeks before entry was required. Women of reproductive potential were required to take contraceptive measures for the duration of therapy with CPT-11. All patients were informed of the investigational nature of the study and were required to provide signed informed consent as approved by the institutional review board. Patients were excluded from the study if they were pregnant, lactating, or taking immunosuppressive agents other than prescribed corticosteroids. Patients who had received more than one prior chemotherapy regimen also were excluded.
Drug Administration and Dose Modifications CPT-11 dose modifications were based on the worst preceding toxicity observed in each patient. Changes in doses consisted of adjustment on treatment days during a course and adjustment at the beginning of a new course of therapy, based on laboratory results obtained on the scheduled treatment days and on maximum toxicity experienced in the previous course as detailed in the CPT-11 package insert. Toxicities were graded according to the NCI Common Toxicity Criteria. If no toxicity was experienced during a course of therapy, the dose of CPT-11 could be increased by 25 mg/m2 (up to a maximum dose of 150 mg/m2) at the start of a subsequent course of therapy.
A new course of treatment could begin when the granulocyte count was Patients were to be treated until there was evidence of progressive or recurrent disease as documented by MRI after the completion of at least one course of therapy, until unacceptable toxicity was noted in spite of dose modification and/or supportive care, until initiation of external-beam radiotherapy, or until the patient withdrew from the study.
Supportive Care
Evaluation During Therapy
Response determination was based on both comparison of the baseline contrast-enhanced MRI scan with those performed before every 6-week course of therapy and changes in physical findings upon neurologic examination. A complete response was defined as the complete disappearance of all enhancing tumor from baseline on consecutive scans at least 4 weeks apart combined with discontinuation of corticosteroids and neurologic stability or improvement. A partial response was defined as
Pharmacokinetic Methods Human plasma specimens were assayed for total concentrations of CPT-11 and SN-38 using validated, sensitive, and specific isocratic high-performance liquid chromatography (HPLC) methods with fluorescence detection. Briefly, each plasma specimen was mixed with an internal standard (IS; camptothecin) in acidified acetonitrile to precipitate plasma proteins and incubated for 15 minutes at 40°C to convert the analytes to their respective lactone forms. After addition of triethylamine (TEA) buffer (pH 4.2), the sample was centrifuged, and the supernatant was transferred to an amber vial for injection (40 µL) onto the HPLC system. Chromatographic separation was achieved using a Zorbax-C8 column (MAC-MOD Ananlytical, Inc, Chadds Ford, PA) and a mobile phase consisting of 28:72 (vol/vol) acetonitrile 0.025 TEA buffer (pH 4.2). The fluorescence detector was operated at an excitation wavelength of 372 nm; CPT-11 and IS were monitored at an emission wavelength of 425 nm, whereas SN-38 was monitored at 535 nm. To determine the concentrations of SN-38G, a separate portion of each plasma sample was hydrolyzed via the addition of a J-glucuronidase solution. The conversion reaction was terminated by precipitating the proteins using an acidified acetonitrile solution of the IS, and the remainder of the procedure was repeated. Plasma concentrations of SN-38G were estimated as the increase in SN-38 concentration after incubation of plasma with J-glucuronidase.
Calibration standard responses were linear over the range from 1.28 to 3,840 ng/mL for CPT-11 (r2
CPT-11 concentrations were expressed in free base units for pharmacokinetic analyses. The actual times of the initiation of drug infusion and of blood sampling were recorded, and the time interval relative to the start of drug infusion was used for calculating area under the concentration-time curves. CPT-11, SN-38, and SN-38G plasma concentration data were analyzed by noncompartmental methods using the computer program WinNonlin (Version 1.1; Scientific Consulting, Inc, Cary, NC). The apparent terminal elimination rate constants (
Peak plasma concentrations (Cmax) and the time at which they occurred were determined from individual patient CPT-11, SN-38, and SN-38G concentration-time curves. Area under the plasma concentration-time curves from time zero until 24 hours after the end of the infusion (AUC0-24) were calculated using the linear trapezoidal rule from time zero to the last sampling at which quantifiable drug concentrations were detected (Clast). Area under the CPT-11 plasma concentration-time curves through infinite time (AUC0-
Statistical Considerations A display of pharmacokinetic parameters from this study and from prior studies in patients with colorectal cancer was prepared to place the current results in context relative to past findings. Ninety-five percent confidence limits on the parameters for each study were computed. Whenever the confidence limits for a given parameter were widely separated from each other between studies, it was inferred that true differences were likely to exist. In addition, a comparison of differences in mean pharmacokinetic parameters between the glioma and colorectal cancer patient populations was performed using an unpaired two-sample t test.
Baseline Patient Characteristics As outlined in Table 1, 60 patients with recurrent brain tumors consented to participate in the study and were enrolled between October 1996 and August 1997. All patients had a Karnofsky performance status 60%. The median age was 46 years, and there was a slight male predominance. Consistent with the epidemiology of CNS neoplasms in adults, the majority of patients had glioblastoma multiforme. Most patients were heavily pretreated, with a majority having undergone prior radiotherapy (88%) and/or chemotherapy (68%). None of the 41 patients with previous chemotherapy, hormonal therapy, or immunotherapy had experienced an objective response to prior treatment. The steroid and anticonvulsant medications used are listed in Table 2.
Treatment Delivery Dose escalations to 150 mg/m2 were permitted by the protocol in patients who had absolutely no adverse events; however, vigorous attempts were not made to increase doses, and only one patient (1.7%) was treated at the 150-mg/m2 dose level.
Efficacy
Time-to-tumor progression data were available for all patients. The median time to tumor progression was 12 weeks (range, 6 to 68 weeks; Table 4). Twenty-six (43%) of the 60 patients who enrolled onto the study were alive as of the data cutoff date, and three (5%) remained on therapy with CPT-11. The median estimated survival for all 60 patients was 43 weeks (range, 6 to 73 weeks), and the 1-year survival estimate was 33%. Final median survival estimates are likely to be higher because of the distribution of the 26 censored survival times. GBM patients (n = 48) had a median survival of 42 weeks. Median survival for AA patients (n = 10) cannot yet be estimated because eight of these patients were still alive as of the data cutoff point; however, current data indicate that it will be at least 40 weeks. In a Cox multivariate analysis, no baseline demographic data (age, sex, tumor histology) or prior therapies (surgery, surgery + radiotherapy, or surgery + radiotherapy + chemo/immuno/hormonal therapy) were predictive for longer time to tumor progression or survival. As might be expected, patients with responding tumors had longer survival times than those with overtly progressive disease. This was confirmed when response to CPT-11 therapy was added to the multiple regression model; in such an analysis, tumor response became the only significant positive predictor of longer survival (P = .026).
Safety
Pharmacokinetics
The Cmax of CPT-11 was comparable to that observed in prior trials. However, CPT-11 clearance was approximately two-fold higher than that reported in prior studies, resulting in a mean AUC that was only 40% of the CPT-11 AUC previously observed (95% CI, 3,959 to 4,901 ng · h/mL and 10,320 to 12,030 ng · h/mL, respectively). SN-38 and SN-38G Cmax values were only 47% and 71%, respectively, of those seen in past experience. AUCs for SN-38 and SN-38G were both approximately 25% of those previously observed (95% CI for SN-38, 58.4 to 94.9 ng · h/mL and 315 to 380 ng · h/mL, respectively; 95% CI for SN-38G, 369 to 510 ng · h/mL and 1,442 to 1946 ng · h/mL, respectively). Differences in mean CPT-11, SN-38, and SN-38G Cmax and AUC values between the two populations were all statistically significant (P < .0001). The low ratio of SN-38 to SN-38G AUC suggests that glucuronidation of SN-38 might have been somewhat greater in patients on this trial than in those receiving CPT-11 for non-CNS cancers (95% CI, 0.1423 to 0.2147 ng · h/mL and 0.2422 to 0.3151 ng · h/mL, respectively). Twenty-nine (91%) of the 32 patients with pharmacokinetic data in this trial were receiving enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, and phenobarbital), and all 32 patients were receiving chronic dexamethasone. None of the patients with colorectal cancer in the prior studies had been receiving such supportive care. It is possible that the use of these concomitant therapies may have resulted in the observed pharmacokinetic differences between the two populations. The nearly universal use of these antiepileptic agents precluded comparative evaluation in this trial of the pharmacokinetic parameters between patients who were receiving enzyme-inducing antiepileptics and those who were not.
The majority of patients with malignant glioma experience failure of current therapy. Unfortunately, no treatment strategy identified to date is likely to change this outcome.32,33 Despite an extensive series of both small and large clinical trials evaluating adjuvant use of single agents such as carmustine or lomustine, or combinations of lomustine, procarbazine, and vincristine, only a modest increase in progression-free survival has been noted.4,14,34-39 Newer approaches, such as tumor vaccines or gene therapy, have not yet been proven to show substantial activity against malignant glioma but remain intriguing possibilities. Advances in chemotherapy are needed, along with exploration of these newer approaches, if the dismal prognosis for patients with these tumors is going to be improved. CPT-11 currently is approved for therapy in patients with recurrent colon carcinoma and also is being investigated against a broad spectrum of other tumors.40 When CPT-11 was evaluated against human glioblastoma multiforme, medulloblastoma, and ependymoma xenografts growing in athymic nude mice, impressive activity was observed against all tumors tested.28,41 These encouraging preclinical results were the rationale for conducting this phase II study of CPT-11 in gliomas. Because this was the first assessment of CPT-11 in this disease, only patients with recurrent cancers were enrolled. Patients who participated had been heavily pretreated; the majority had undergone attempts at resection, irradiation, and chemotherapy. None of the patients had responded to prior chemotherapy. CPT-11 showed clear antitumor activity with an overall, confirmed intent-to-treat response rate of 15% (95% CI, 6% to 24%). Activity was observed both in glioblastoma multiforme and anaplastic astrocytoma, as indicated by radiographic evidence of tumor regression in nine of 60 patients treated. Because only two patients with AO were enrolled, activity could not be assessed adequately in this group. Median overall survival in the study was 43 weeks and 1-year survival was 33%; overt differences in survival were not apparent based on tumor histology. Other baseline patient characteristics also were not significantly predictive of survival in multiple regression modeling. However, when confirmed response to CPT-11 chemotherapy was added to this model, it became the most significant positive predictor of longer survival (P = .026). Although such an analysis must be interpreted cautiously in a single-arm study, it is reasonable to conclude that chemotherapy response may have either a therapeutic or prognostic value for better outcome. The most prominent toxicities of single-agent CPT-11 in previous clinical trials using the weekly schedule of administration have been diarrhea and neutropenia.40,42-45 In pivotal trials of CPT-11 in patients with colorectal cancer, grade 3/4 diarrhea occurred in 33.7% (65 of 193) of patients at the 125-mg/m2 starting dose, and grade 3/4 neutropenia was seen in 28.0% (54 of 193) of patients.42 However, toxicity was neither common nor severe in this trial, despite use of the same CPT-11 starting dose. The lower frequencies of grade 3/4 toxicities observed in this trial (diarrhea only, 1.7%; and neutropenia only, 1.7%) are likely related to the concurrent use of chronic dexamethasone and/or anticonvulsants in almost all of these patients. The two-fold higher CPT-11 clearance and lower systemic levels of CPT-11, SN-38, and SN-38G provide pharmacologic evidence of a significant drug-drug interaction between CPT-11 and these supportive care agents. These findings are similar to those reported in pharmacokinetic trials of paclitaxel, 9-aminocamptothecin, and topotecan in patients with CNS cancers.46-50 Although the specific reasons for altered CPT-11 metabolism in these patients remains to be elucidated, several possibilities must be considered based on current knowledge of the drug's disposition. Lower CPT-11 concentrations could be the consequence of enhanced carboxylesterase activity; however, the decreased SN-38 and SN-38G AUCs observed in these patients is not consistent with induction of carboxylesterase-mediated metabolism of CPT-11 activity. Antiepileptic agents and dexamethasone can induce glucuronyl transferase enzymes.51-53 Pretreatment of rats with phenobarbital, a potent inducer of glucuronyl transferase activity, has been shown to cause a 72% enhancement in the AUC of SN-38G.54 Concurrently, there was a 31% and a 59% reduction in the AUCs of SN-38 and CPT-11, respectively. Although enhanced glucuronidation of SN-38 alone would not cause the diminished concentrations of CPT-11, SN-38, and SN-38G observed in the current trial, it may explain the lower SN-38/SN-38G AUC ratio compared with patients with colorectal cancers. Anticonvulsant medications, such as phenytoin, carbamazepine, and phenobarbital, are also potent inducers of hepatic cytochrome P450 enzymes, including CYP3A4.55,56 In addition, dexamethasone has been shown to be an inducer of this isozyme.55 Enhanced CPT-11 clearance and reduced concentrations of SN-38 and SN-38G seen in these study patients are consistent with increased CYP3A4 activity leading to increased conversion of CPT-11 to APC. A bioanalytical method to determine APC from clinical samples is currently being developed and should be used to directly evaluate this hypothesis by measuring concentrations of this metabolite in specimens collected from patients in future studies. Concurrent therapy with anticonvulsants and/or dexamethasone could also enhance biliary excretion of CPT-11 and its metabolites, potentially explaining the lower concentrations observed in our patients. Dexamethasone and phenobarbital treatment have resulted in P-glycoprotein (PgP) expression in primary rat hepatocyte and human colon adenocarcinoma cell lines.55,56 Although multiple transporters are responsible for biliary excretion of CPT-11 and its metabolites, the principle transporter is the canalicular multispecific organic anion transporter, not PgP.57-60 The effects of antiepileptics and dexamethasone on non-PgP transporters, such as the canalicular multispecific organic anion transporter, have not been characterized. The results of this study with CPT-11, as well as studies with topotecan, 9-aminocamptothecin, and paclitaxel, suggest that higher-than-normal doses of many chemotherapeutic agents may be needed in glioma patients receiving concomitant enzyme-inducing antiepileptics and/or dexamethasone. As a result of the low plasma concentrations of CPT-11 and SN-38 that were achieved in this study, it is of significant concern that some patients may have been able to tolerate substantially higher doses. The observed activity thus may actually represent an underassessment of the value of CPT-11 in the treatment of patients with malignant glioma. Further investigation of changes in CPT-11 metabolism and/or excretion resulting from concomitant use of anticonvulsants and chronic corticosteroids is needed in the context of new pharmacokinetic, dose-finding studies. Such trials evaluating both the weekly and every-3-weeks schedules of CPT-11 administration are planned. Clinical application of CPT-11 in combination with other agents that are active in malignant glioma also should be explored.
We thank Janet Lawing for her expert assistance in the preparation of the manuscript.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
z) were estimated by linear least-squares regression of plasma-concentration time points, which were determined to lie in the terminal log-linear region of the plasma concentration-time profiles. The apparent elimination half-life was calculated as 0.693/
) were calculated by adding Clast/
