|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 16 (August 15), 2004: pp. 3357-3365 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.103 Results of a Phase II Upfront Window of Pharmacokinetically Guided Topotecan in High-Risk Medulloblastoma and Supratentorial Primitive Neuroectodermal TumorFrom the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children’s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The Children’s Hospital at Westmead and the University of Sydney, Sydney; and Department of Hematology Oncology, Royal Children’s Hospital and the University of Melbourne, Melbourne, Australia Address reprint requests to Amar Gajjar, MD, Department of Hematology-Oncology (Room 6024), St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: amar.gajjar{at}stjude.org
PURPOSE: To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients. PATIENTS AND METHODS: After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL·h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization. RESULTS: Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range. CONCLUSION: Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.
Medulloblastoma accounts for 20% of all CNS tumors in pediatric patients. Standard treatment for this population consists of maximal surgical resection followed by craniospinal irradiation (CSI), with or without the use of chemotherapy. This treatment results in progression-free survival (PFS) rates of approximately 50% to 60% for high-risk patients and 70% to 80% for standard-risk patients.1-6
During the last two decades, chemotherapy regimens used to treat medulloblastoma patients have included nitrosoureas, cisplatin, carboplatin, cyclophosphamide, etoposide, and vincristine.1,7-12 Historically, high-risk patients treated with radiation therapy alone have had 5-year PFS rates of 25% to 40%. The impact of combined-modality therapy has been most impressive in a series using chloroethyl nitrosourea, cisplatin, and vincristine in a broadly defined high-risk group that included patients with totally resected M0 disease who had brainstem invasion as a high-risk feature. However, the 5-year PFS rate of 86% is reduced to less than 65% when one includes patients with M+ disease and/or During the last two decades, we have conducted upfront window phase II trials to determine the sensitivity of newly diagnosed medulloblastoma to therapy with platinating agents and etoposide.11,12 These studies provide valuable tumor response information that cannot be obtained from trials using postirradiation chemotherapy. The use of neoadjuvant regimens, which delay definitive irradiation, did not adversely affect long-term outcome.13 To improve the outcome for these patients, a need clearly exists for the rational development of new anticancer drugs that show efficacy in preclinical models before testing their efficacy in children with disease. Medulloblastoma cells tend to disseminate throughout the neuraxis; thus, it is critical that tumors are exposed to drugs from both the blood and CSF. Given that CSF drug exposure is clinically relevant for this tumor model, a drug with significant CSF penetration after intravenous (IV) administration theoretically has the potential of killing disseminated tumor cells along the entire neuraxis. The topoisomerase I inhibitor, topotecan, is an excellent candidate drug for several reasons, including extensive antitumor activity against pediatric xenograft models such as medulloblastoma and other CNS tumors14,15 as well as avid CSF penetration in nonhuman primates16 and in children with CNS malignancies.17 Although topotecan has shown antitumor activity against CNS malignancies in xenograft models, the topotecan concentration and length of exposure associated with maximal cytotoxicity currently are unknown. To define the CSF exposure duration threshold (EDT), we compared different topotecan exposures and schedules in cell lines derived from pediatric medulloblastoma. Topotecan was cytotoxic to Daoy and SJ-Med 3 medulloblastoma cells in vitro when the concentration was 1 ng/mL for 8 hours.18 We performed pharmacokinetic simulation studies to determine the topotecan lactone systemic exposure, measured by the area under the plasma concentration-time curve (AUC), required to achieve the CSF EDT (1 ng/mL for 8 hours). Our results showed that at a topotecan lactone AUC of 120 to 160 ng/mL·h, we had a high likelihood of achieving the desired CSF EDT. Then we were faced with how to attain this plasma topotecan AUC since we have observed a high interpatient variability in topotecan clearance (eg, at least a seven- to 10-fold range).19,20 Thus, to account for this interpatient variability in topotecan systemic clearance, we chose to use a pharmacokinetically guided dosing approach in this study.21 With this approach we were able to measure the topotecan clearance in each patient, and then perform a dosage adjustment to attain a topotecan AUC within the desired plasma target range. Thus, our hypothesis was that pharmacokinetically guided topotecan dosing would attain the desired plasma AUC, yielding an appropriate CSF exposure as defined by our preclinical models. Therefore, we planned a phase II study in patients with newly diagnosed high-risk medulloblastoma or supratentorial primitive neuroectodermal tumor (PNET) who have measurable residual disease after surgical resection, to document the response rate to an upfront window of two cycles of topotecan. In addition, we planned to evaluate the plasma and CSF disposition of topotecan in these patients.
Eligibility Eligible patients were between the ages of 3 and 21 years at diagnosis and had not received previous chemotherapy or irradiation. Patients were required to begin the protocol within 28 days of definitive surgery. Additional requirements included normal renal function (serum creatinine  1.2 mg/dL), normal liver function (ALT < 1.5x the normal value, bilirubin < 1.5 mg/dL), normal bone marrow function (hemoglobin > 10 g/dL, WBC count  3,000/µL, absolute neutrophil count > 1,500/µL, platelets > 100,000/µL), and an Eastern Cooperative Oncology Group22 performance score of 0 to 3, except in cases of posterior fossa syndrome. The study was a collaborative effort of St Jude Children’s Research Hospital, Memphis, TN (n = 24); Baylor College of Medicine, Houston, TX (n = 6); The Children’s Hospital at Westmead, Sydney, Australia (n = 4); and Royal Children’s Hospital, Melbourne, Australia (n = 3). The institutional review boards of each participating institution approved the protocol, and informed consent was obtained from patients, parents, or legal guardians as appropriate. Disease was staged as high risk using a modification of the Chang staging system.23 High-risk disease was defined as presence of metastatic disease within the neuraxis as determined by imaging studies or lumbar CSF cytology, or the presence of more than 1.5 cm2 residual disease at the primary site after surgery.
Patient Evaluation
Drug Formulation and Administration After the first 10 patients received topotecan as a 30-minute infusion (initial dosage 2 mg/m2/d), we amended the study to increase the topotecan infusion to 4 hours (initial dosage 5.5 mg/m2/d). This change was made to increase the likelihood that the EDT would be attained in the lumbar CSF as well as the ventricular CSF.24 As described previously, we used a pharmacokinetically guided dosing approach21 to individualize the topotecan dosage in patients to attain the target plasma AUC of 120 to 160 ng/mL·h, which was associated with the CSF EDT.18 Figure 1 illustrates the pharmacokinetically guided dosing approach used. After the first topotecan dose in courses 1 and 2, plasma samples were obtained, processed immediately, and analyzed. If the topotecan plasma AUC was within the target range after this dose, then no dosage adjustment was required. If not, the topotecan dosage was adjusted linearly, on the basis of the topotecan clearance for that patient, to attain the target AUC on day 2, and repeat pharmacokinetic studies were performed. The results of pharmacokinetic analysis of samples obtained on day 5 of course 1 were used to determine the starting dosage for the second course of therapy. During the second course, plasma samples were collected on days 1 and 3, with dosage adjustments made as described for course 1. No samples were routinely obtained on day 5 of course 2.
Filgrastim (5 µg/kg IV or subcutaneous) was started 24 hours after completion of the last topotecan infusion on all patients. For patients who were eligible for peripheral-blood stem cell mobilization, the filgrastim dosage was 10 µg/kg.25
Pharmacokinetic Sampling Strategy In selected patients with existing Ommaya reservoirs we obtained ventricular CSF samples at 1, 3, and 6 hours after the end of the infusion. For each time point, 300 µL of CSF was collected from the Ommaya reservoir, centrifuged in a microfuge for 2 minutes at 7,000 x g, and then processed for topotecan analysis. Calibration curves for CSF samples were constructed using pooled human CSF, and the lower limit of quantitation for topotecan lactone in the CSF was 0.25 ng/mL.
Pharmacokinetic Analysis For those patients enrolled at The Children’s Hospital at Westmead or Royal Children’s Hospital, topotecan plasma samples were obtained, processed, and assayed for topotecan plasma concentrations in Australia. The topotecan high-performance liquid chromatography method used to measure these samples was cross-validated versus the previously described method. The plasma topotecan concentration-time data were sent via e-mail to St Jude Children’s Research Hospital, where the pharmacokinetic analysis was performed and dosage recommendations were made within 24 hours. CSF topotecan disposition was assessed in those patients with indwelling ventricular shunts. Ventricular CSF samples were obtained after the first and third topotecan doses immediately before the infusion, immediately before the end of the infusion, and 1 and 4 hours after the end of the infusion. To assess the CSF topotecan disposition, a three-compartment model (Fig 2) was fit to the topotecan plasma and CSF data using maximum likelihood (ADAPT II). In selected patients who had lumbar taps performed for diagnostic or other clinical purposes, we obtained lumbar CSF fluid and measured topotecan lactone concentrations in these samples. We used a model that added another compartment and two rate constants (K34 and K41) to the model depicted in Figure 2. To perform this analysis we used maximum a posteriori Bayesian with population priors determined in our study for plasma and ventricular CSF pharmacokinetic parameters.
Additional Therapy After assessment of response to the topotecan window, all patients received CSI encompassing the entire subarachnoid volume. The CSI dose was dependent on the M stage of the patient. The primary tumor site received additional radiation therapy delivered by three-dimensional conformal technique. After completion of radiation therapy, patients also received high-dose chemotherapy with peripheral-blood stem cell support.29
Statistical Methods The pharmacokinetic parameters were analyzed through a mixed-effects model in SAS software (Version 8.2; SAS Institute, Cary, NC) using the robust-variance estimator starting with a working covariance structure of compound symmetry. This model takes into account the possible intrapatient correlation due to multiple courses and repeated pharmacokinetic determinations at each course. This model is also used to estimate inter- and intrapatient variability.
Response Rates and Toxicities A total of 44 patients were enrolled in the high-risk arm of the protocol, and 37 accepted and received both cycles of topotecan. One patient, who received topotecan, was subsequently found to have gliosis in the surgical cavity originally considered residual tumor more than 1.5 cm2, and hence was erroneously placed in the high-risk arm. The clinical characteristics of the assessable patients at diagnosis are listed in Table 1.
Of the 36 patients, six (16.6%) had a PR and four (11.1%) had a CR, indicated by complete disappearance of residual tumor on post-topotecan MRI imaging (response rate [PR + CR], 28%; 95% CI, 14% to 45%). Of the four patients who had a CR, three patients had positive CSF cytology as the only site of assessable disease. In addition, four patients (11.1%) had MR, 17 patients (47.2%) had stable disease, and five patients (13.9%) experienced disease progression while receiving topotecan. Toxicities observed during this protocol were primarily hematologic. No therapy-related fatalities occurred during treatment, and only one patient interrupted therapy prematurely, as a result of neurocortical toxicity, which manifested as intolerable irritability. The number of instances of grade 3 and 4 toxicities are listed in Table 2.
Pharmacokinetic Analysis A representative topotecan plasma concentration-time plot for a patient studied after the initial predetermined topotecan dosage (Fig 3A) shows the initial AUC value was below the target range. This value was considered a dosing failure because the topotecan dosage was predetermined. The topotecan ventricular CSF values obtained from this patient were above 1 ng/mL for 4.8 hours. On the basis of our pharmacokinetically guided approach, a dosage adjustment was made and the second topotecan AUC was within the target range; this second dose represents a pharmacokinetic targeting success (Fig 3B). More importantly, the topotecan CSF concentrations were above 1 ng/mL for 9.2 hours. This representative patient demonstrates a proof-of-principle that our pharmacokinetically guided dosage approach can achieve the plasma topotecan target and subsequently the topotecan CSF EDT.
The initial cohort (n = 10) received 20 5-day courses of topotecan as a 30-minute infusion and had 46 pharmacokinetic studies. Of this first group, data from the first patient enrolled onto the study was excluded from the pharmacokinetic analysis because of inconsistent handling of the topotecan infusion overfill volume, which was resolved in subsequent patients. The median topotecan dosage in the courses within the target range was 5.5 mg/m2 (range, 4 to 8 mg/m2). Twenty-seven patients were treated with topotecan as a 4-hour infusion, received 54 5-day courses, and 123 individual pharmacokinetic studies were obtained. On retrospective review of imaging data, we noted that one child from this group was erroneously placed in the high-risk arm. Another child encountered logistical problems with the infusion devices used during each course that made it impossible to achieve the desired topotecan target range. Thus, the topotecan pharmacokinetic data from these two patients were excluded from further analysis. The median topotecan dosage in the courses within the target range for this group was 3.2 mg/m2 (range, 1.9 to 6.5 mg/m2). Unexpectedly, we noted a statistically significant difference between the 30-minute group and the 4-hour infusion group in the topotecan volume of distribution, elimination rate constant, and systemic clearance (Table 3). No apparent reason was noted that could account for this difference between the two patient cohorts; however, despite this difference in topotecan systemic clearance, topotecan dosage individualization in each patient maintained the topotecan lactone AUC within the desired target range.
In the 30-minute infusion group none of the patients achieved the target AUC with the initial topotecan dosage (ie, 2 mg/m2). We were encouraged that after our dosage individualization we observed a 75% targeting success rate for the 30-minute infusion group (ie, 24 AUC determinations in target of 32 assessable determinations). In the 4-hour infusion group only three of 26 patients (11%) achieved the target range with the initial topotecan dosage (ie, 5.5 mg/m2). After our dosage individualization we noted a 62% targeting success rate for this group (ie, 58 of 93). Because of logistical limitations we only collected ventricular CSF from six patients with pre-existing shunts. These six patients were in the 30-minute infusion group and had 18 CSF pharmacokinetic studies (total 50 CSF topotecan values). The topotecan plasma AUC was within the target range in nine of 18 studies. The EDT was not achieved in any of the nine pharmacokinetic studies that were outside the plasma target range. However, the CSF EDT was achieved in seven of nine pharmacokinetic studies in which the topotecan plasma AUC was within the target range. In four patients who had lumbar taps performed for diagnostic or other clinical purposes, we obtained lumbar CSF fluid and measured topotecan lactone concentrations in these samples. One patient had plasma, ventricular, and lumbar topotecan concentrations, and three patients had plasma and lumbar concentrations. Using initial estimates for lumbar CSF pharmacokinetic parameters from the nonhuman primate model,24 we found that in the three plasma studies outside the target AUC range the lumbar studies did not attain the EDT. However, the one plasma AUC within the target AUC was associated with a lumbar study that achieved the EDT in the lumbar CSF.
This study is the largest to use topotecan in a neoadjuvant setting in newly diagnosed medulloblastoma and CNS PNET, and we have observed an objective response rate of 28%. The primary toxicity was reversible myelosuppression, which was manageable. This is the first clinical trial in which pharmacokinetically guided dosing was used to account for interpatient variability in topotecan systemic clearance to achieve a desired topotecan exposure in the CSF compartment. With our strategy we achieved the desired CSF EDT (eg, 1 ng/mL for 8 hours) in seven of nine pharmacokinetic studies in which the topotecan plasma AUC was within the target range of 120 to 160 ng/mL·h. The favorable antitumor activity with manageable toxicity seen in this clinical trial suggests that when appropriately administered, topotecan is an effective agent in the treatment of children with medulloblastoma and PNET. Advances in the treatment of newly diagnosed medulloblastoma and PNET in the last 20 years can be attributed primarily to improved imaging and surgical approaches, given that few new drugs have been developed for front-line therapy. Our objective response rate of 28% compares with other upfront studies in older children that predominantly used platinating agents with etoposide (Table 4). Although response rates may seem higher in these studies, several reasons likely account for this difference, including small study populations, evaluation of response after prolonged chemotherapy, and use of computed tomography scans to evaluate response. In the four patients with MR, we observed a decrease in tumor size of 17% to 40%. It is conceivable that additional chemotherapy would have converted these responses to either a CR or PR. Neoadjuvant studies in infants with medulloblastoma and PNET have demonstrated response rates of 37% to 55% after either single-agent or combination chemotherapy; however, the sample sizes in the studies were small, with the exception of the study by Duffner et al.30 Although the majority of patients in our study had stable disease, it was difficult to evaluate several of them for response because they had only a thin film of leptomeningeal disease coating their neuraxis as their only assessable disease based on MRI scans. These patients were only assessable for response if they had a CR because it is difficult to quantitate either PRs or MRs in these patients. On the basis of our observations in this study, these patients may not be the best candidates for evaluating response in future studies.
Preclinical studies in xenograft models had strongly suggested that efficacy of camptothecin analogs was best seen with protracted dosing.15 Early clinical trials with topotecan used continuous infusions in relapsed pediatric brain tumors,31,32 and no responses were seen in recurrent medulloblastoma patients. In contrast, we have shown that topotecan has antitumor activity in newly diagnosed medulloblastoma or PNET patients when administered on a fractionated schedule. Similar data were published in relapsed pediatric solid tumors where continuous-infusion topotecan failed to show efficacy,33 but fractionated schedules (eg, daily for 5 days, daily for 10 days) have shown efficacy in patients who experienced relapse and newly diagnosed patients.21,34,35 The current study emphasizes the importance of incorporating data from well-conducted preclinical studies into clinical protocols to avoid discarding an active drug. The concept underlying this study was to attain a plasma topotecan AUC between 120 to 160 ng/mL·h, which would achieve the desired CSF EDT. As we proposed, those studies with plasma AUC values below the target range did not achieve the CSF EDT, but when the plasma AUC was within the target range, the CSF EDT was achieved in seven of nine studies in the 30-minute infusion group. No patient in the 4-hour infusion group had an existing CSF shunt; therefore, we were unable to show proof of principle in these patients. However, in an adult patient, a 4-hour infusion yielded three-fold greater topotecan lumbar concentrations and 1.8-fold greater time above 1 ng/mL in ventricular CSF compared with a 30-minute infusion.36 In a few patients we measured topotecan concentrations in lumbar CSF obtained for clinical purposes, and we noted that in one study with the plasma AUC within the target range, the lumbar CSF value was within the EDT. Although we were unable to derive any conclusions from these limited data, our previous studies have emphasized the importance of lumbar CSF as a site of relapse.24 This was the first clinical trial to use pharmacokinetically guided dosing in the phase II setting.21 We were successful in this trial in achieving our plasma target range in 75% of studies for the 30-minute infusion group. However, our targeting success rate was 62% for the 4-hour infusion group. We evaluated factors that may have accounted for the difference in targeting success between the two infusion groups, including first-time targeting 4-hour infusion, difference in topotecan systemic clearance, and unidentified clinical differences in the two populations. However, no specific cause was apparent. Consistent with our previous studies of topotecan pharmacokinetics in children,37,38 we noted a wide interpatient variability in topotecan lactone systemic clearance, ranging from 8.2 to 71.7 L/h/m2. Many factors account for this range in clearance values, including newly diagnosed patients, age range, and drug-drug interactions. We have reported previously that phenytoin coadministration in patients receiving topotecan increases topotecan lactone and total clearance approximately 20%,39 and more recently have observed that concomitant dexamethasone administration also increases topotecan clearance by approximately 20%.40 However, we accounted for the range in clearance values, which could have translated into a wide range of plasma drug exposures with fixed drug dosing, by using our pharmacokinetically guided dosing approach. Thus, the benefit of this approach was that toxicity was avoided in patients with slow topotecan clearance, in whom fixed dosing might produce dose-limiting toxicity. Conversely, the topotecan dosage was increased in patients with rapid clearance values in whom fixed dosing may not have achieved the plasma systemic exposure necessary to achieve the CSF EDT. This study demonstrates that rational drug development using well-designed preclinical and clinical studies is mandatory so that any potentially new drug that has efficacy against pediatric tumors is not discarded because of suboptimal study design. We have shown that topotecan has efficacy in newly diagnosed medulloblastoma or PNET. On the basis of our data, additional development of topotecan is mandated in infants with medulloblastoma or PNET as part of a preradiation chemotherapy regimen, and in older children as part of postradiation adjuvant chemotherapy. Several institutions, including ours, have combined topotecan with alkylating agents in high-dose chemotherapy regimens with promising results.41 Thus, it is likely that topotecan will be used in combination regimens when used to treat infants and older children with medulloblastoma and PNET.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Clinton F. Stewart, GlaxoSmithKline; Peter J. Houghton, GlaxoSmithKline. Received more than $2,000 a year from a company for either of the last 2 years: Clinton F. Stewart, GlaxoSmithKline.
We thank the medical nursing team and Lisa Walters, Terri Kuehner, Sheri Ring, Margaret Edwards, and Paula Condy for their assistance, and Richard Heideman, MD, Andrew Walter, MD, David Reardon, MD, Steven Thompson, MD, and Doug Strother, MD, for providing excellent patient care.
Supported by Cancer Center Support (CORE) grant P 30 CA 21765 and grant P01 23099 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC). Authors’ disclosures of potential conflicts of interest are found at the end of this article.
1. Packer RJ, Goldwein J, Nicholson HS, et al: Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children’s Cancer Group Study. J Clin Oncol 17:2127-2136, 1999 2. Tarbell N, Friedman H, Kepner JL: Outcome for children with high stage medulloblastoma: Results of the Pediatric Oncology Group 9031. Int J Radiat Oncol Biol Phys 48:179, 2000 (abstr 134) 3. Bailey CC, Gnekow A, Wellek S, et al: Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma: International Society of Pediatric Oncology (SIOP) and German Society of Paediatric Oncology (GPO)—SIOP II. Med Pediatr Oncol 25:166-178, 1995[Medline] 4. Evans AE, Jenkin DT, Sposto R, et al: The treatment of medulloblastoma: Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72:572-582, 1990[Medline] 5. Hughes EN, Shillito J, Sallan SE, et al: Medulloblastoma at the joint center for radiation therapy between 1968 and 1984: The influence of radiation dose on the patterns of failure and survival. Cancer 61:1992-1998, 1988[CrossRef][Medline] 6. Tait DM, Thornton-Jones H, Bloom HJ, et al: Adjuvant chemotherapy for medulloblastoma: The first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer 26:464-469, 1990 7. Kortmann RD, Kuhl J, Timmermann B, et al: Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of the German prospective randomized trial HIT ’91. Int J Radiat Oncol Biol Phys 46:269-279, 2000[CrossRef][Medline] 8. Allen JC, Helson L: High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 55:749-756, 1981[Medline] 9. Friedman HS, Mahaley MS Jr, Schold SC Jr, et al: Efficacy of vincristine and cyclophosphamide in the therapy of recurrent medulloblastoma. Neurosurgery 18:335-340, 1986[Medline] 10. Gaynon PS, Ettinger LJ, Baum ES, et al: Carboplatin in childhood brain tumors: A Children’s Cancer Study Group Phase II trial. Cancer 66:2465-2469, 1990[CrossRef][Medline] 11. Kovnar EH, Kellie SJ, Horowitz ME, et al: Preirradiation cisplatin and etoposide in the treatment of high-risk medulloblastoma and other malignant embryonal tumors of the central nervous system. J Clin Oncol 8:330-336, 1990[Abstract]
12. Heideman RL, Kovnar EH, Kellie SJ, et al: Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors. J Clin Oncol 13:2247-2254, 1995
13. Taylor RE, Bailey CC, Robinson K, et al: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 Study. J Clin Oncol 21:1581-1591, 2003 14. Friedman HS, Houghton PJ: Treatment of central nervous system xenografts with camptothecins. Ann N Y Acad Sci 803:210-212, 1996[CrossRef][Medline] 15. Houghton PJ, Cheshire PJ, Hallman JD, et al: Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393-403, 1995[Medline]
16. Blaney SM, Cole DE, Balis FM, et al: Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates. Cancer Res 53:725-727, 1993 17. Baker SD, Heideman RL, Crom WR, et al: Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 37:195-202, 1996[CrossRef][Medline] 18. Pawlik CA, Houghton PJ, Stewart CF, et al: Effective schedules of exposure of medulloblastoma and rhabdomyosarcoma xenografts to topotecan correlate with in vitro assays. Clin Cancer Res 4:1995-2002, 1998[Abstract] 19. Stewart CF, Liu CY, Zamboni WC, et al: Population pharmacokinetics of topotecan in children and adolescents. Proc Am Soc Clin Oncol 2000;19:177a (abstr 687) 20. Tubergen DG, Stewart CF, Pratt CB, et al: Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A Pediatric Oncology Group study. J Pediatr Hematol Oncol 18:352-361, 1996[CrossRef][Medline]
21. Santana VM, Zamboni WC, Kirstein MN, et al: A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res 9:633-640, 2003 22. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982[Medline] 23. Friedman HS, Oakes WJ, Bigner SH, et al: Medulloblastoma: Tumor biological and clinical perspectives. J Neurooncol 11:1-15, 1991[CrossRef][Medline]
24. Zamboni WC, Gajjar AJ, Mandrell TD, et al: A four-hour topotecan infusion achieves cytotoxic exposure throughout the neuraxis in the nonhuman primate model: Implications for treatment of children with metastatic medulloblastoma. Clin Cancer Res 4:2537-2544, 1998 25. Yeoh EJ, Cunningham JM, Yee GC, et al: Topotecan-filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells. Bone Marrow Transplant 28:563-571, 2001[CrossRef][Medline] 26. Pratt CB, Stewart CF, Santana VM, et al: Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol 12:539-543, 1994[Abstract]
27. Zamboni WC, Stewart CF, Thompson J, et al: Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts. J Natl Cancer Inst 90:505-511, 1998 28. D’Argenio DZ, Schumitzky A: ADAPT II User’s Guide (ed 1). Los Angeles, CA, Biomedical Simulations Resource, USC, 1990
29. Strother D, Ashley D, Kellie SJ, et al: Feasibility of four consecutive high-dose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: Results of a collaborative study. J Clin Oncol 19:2696-2704, 2001
30. Duffner P, Horowitz M, Krischer JP, et al: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328:1725-1731, 1993
31. Blaney SM, Balis FM, Cole DE, et al: Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion. Cancer Res 53:1032-1036, 1993 32. Kadota RP, Stewart CF, Horn M, et al: Topotecan for the treatment of recurrent or progressive central nervous system tumors: A pediatric oncology group phase II study. J Neurooncol 43:43-47, 1999[CrossRef][Medline]
33. Blaney SM, Needle MN, Gillespie A, et al: Phase II trial of topotecan administered as 72-hour continuous infusion in children with refractory solid tumors: A collaborative Pediatric Branch, National Cancer Institute, and Children’s Cancer Group Study. Clin Cancer Res 4:357-360, 1998 34. Nitschke R, Parkhurst J, Sullivan J, et al: Topotecan in pediatric patients with recurrent and progressive solid tumors: A Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol 20:315-318, 1998[CrossRef][Medline]
35. Pappo AS, Lyden E, Breneman J, et al: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: An intergroup rhabdomyosarcoma study. J Clin Oncol 19:213-219, 2001
36. Zamboni WC, Luftner DI, Egorin MJ, et al: The effect of increasing topotecan infusion from 30 minutes to 4 hours on the duration of exposure in cerebrospinal fluid. Ann Oncol 12:119-122, 2001
37. Furman WL, Stewart CF, Kirstein M, et al: Protracted intermittent schedule of topotecan in children with refractory acute leukemia: A pediatric oncology group study. J Clin Oncol 20:1617-1624, 2002 38. Stewart CF, Zamboni WC, Crom WR, et al: Topoisomerase I interactive drugs in children with cancer. Invest New Drugs 14:37-47, 1996[CrossRef][Medline] 39. Zamboni WC, Gajjar AJ, Heideman RL, et al: Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma. Clin Cancer Res 4:783-789, 1998[Abstract] 40. Gajjar A, Kirstein MN, Santana VM, et al: Concomitant dexamethasone (DXM) increases topotecan (TPT) clearance in children. Proc Am Assoc Cancer Res 42:653, 2001 (abstr 3512) 41. Hale GA, Benaim E, Stewart CF, et al: A phase I study of cyclophosphamide and topotecan in patients with high risk malignancies undergoing autologous hematopoietic stem cell transplantation. Med Pediatr Oncol 37:175, 2001 (abstr O49) 42. Mastrangelo R, Lasorella A, Riccardi R, et al: Carboplatin in childhood medulloblastoma/PNET: Feasibility of an in vivo sensitivity test in an "up-front" study. Med Pediatr Oncol 24:188-196, 1995[Medline] 43. Loeffler JS, Kretschmar CS, Sallan SE, et al: Pre-radiation chemotherapy for infants and poor prognosis children with medulloblastoma. Int J Radiat Oncol Biol Phys 15:177-181, 1988[Medline] Submitted October 15, 2003; accepted May 17, 2004. This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
) was determined by use of a log-linear trapezoidal method.
) concentrations are plotted; solid lines represent best-fit curves.
