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© 2002 American Society for Clinical Oncology Phase II Study of Carboplatin in Children With Progressive Low-Grade GliomasByFrom the Duke University Medical Center, Durham, NC; Primary Children’s Medical Center, Salt Lake City, UT; Hospital Sainte-Justine, Montreal, Canada; and Royal Melbourne Children’s Hospital, Melbourne, Australia. Address reprint requests to Sridharan Gururangan, MRCP, The Brain Tumor Center at Duke, Duke University Medical Center, Box 3624, DUMC, Durham, NC 27710; email: gurur002{at}mc.duke.edu
PURPOSE: To assess the rate of tumor response and activity of carboplatin in stabilizing the growth of progressive low-grade gliomas. PATIENTS AND METHODS: Eligible patients received carboplatin 560 mg/m2 intravenously every 4 weeks for 1 year after maximum tumor response or until disease progression or unacceptable toxicity. RESULTS: Between October 1993 and October 2000, 81 children (median age, 79 months; range, 6 to 204) were enrolled onto this study. Patients received a median of 11 cycles of carboplatin (range, one to 29). Median follow-up from the time of enrollment was 55 months (range, 10 to 93). The overall objective response (complete response [CR] + partial response [PR] + minor response [MR]) and disease stabilization (CR + PR + stable disease + MR) rates to carboplatin treatment were 28% (95% confidence interval [CI], 18% to 38%) and 85% (95% CI, 74% to 93%), respectively. Eleven and 14 patients suffered progressive disease on study and after stopping therapy, respectively. Toxicity was predominantly myelosuppression and included grade 3/4 neutropenia in 56 patients and grade 3/4 thrombocytopenia in 40 patients. The 3-year failure-free survival (FFS) and overall survival (OS) for all patients were 64% (95% CI, 54% to 76%) and 84% (95% CI, 76% to 93%), respectively. Patients with diencephalic tumors had inferior FFS and OS compared with those with tumor at other sites (38% v 74% for FFS, P = .011; 54% v 91% for OS, P = .004). Neurofibromatosis type 1 patients with progressive low-grade glioma had a significantly better OS (95% v 80%; P = .052). CONCLUSION: Carboplatin, in the schedule used in this study, produced disease stabilization or improvement in a majority of children with progressive low-grade glioma, with manageable toxicity. Improved treatment strategies are particularly required for patients with diencephalic tumors.
PEDIATRIC LOW-GRADE gliomas of diverse histopathology and location constitute 30% to 40% of all CNS tumors diagnosed in this population.1 While the optimal initial treatment of such tumors is surgical resection either at diagnosis or relapse,2 therapies for unresectable or residual progressive gliomas are controversial. Although radiotherapy is a reasonable therapeutic option, its use, particularly in young children, may result in severe neurocognitive, endocrine, and vascular sequelae.3-6 In recent years, chemotherapy including vincristine, dactinomycin, cyclophosphamide, carboplatin, lomustine, and etoposide has been used individually or in combination in patients with progressive low-grade gliomas with the aim of stabilizing disease and avoiding or delaying radiotherapy.7-14 Carboplatin (cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)), a second-generation cisplatin analog, was found in preliminary clinical studies to be effective in children with low-grade gliomas.15,16 Based on these observations, a phase II study of carboplatin in children with progressive low-grade glioma was initiated in 1993 at Duke University Medical Center, Durham, NC, and three other centers in the United States, Canada, and Australia. The objectives of the study were to assess the response and disease stabilization rates to carboplatin in patients  18 years of age with progressive low-grade gliomas. We now report the results of this study and demonstrate that the drug was successful in stabilizing the tumor in most of these patients.
The study opened in October 1993 at Duke University Medical Center. Three other centers from Salt Lake City, UT, Montreal, Canada, and Melbourne, Australia, subsequently decided to participate in this study. Patient accrual was completed in October 2000. This report reflects the status of all patients as of September 2001.
Eligibility Requirements
Treatment Evaluation of response and toxicity. Patients received two cycles of treatment before the first assessment by clinical and imaging criteria (Table 1) and then at 3-month intervals. In patients with optic pathway tumors, visual acuity testing was performed before starting therapy, every 3 months thereafter, and at the end of therapy. Physical and neurologic examinations were performed in all patients before each cycle of treatment and at the end of therapy. Complete blood counts with manual differentials were obtained before each cycle and weekly thereafter. Renal and hepatic functions were checked before each cycle.
Dose modification. The dose of carboplatin was decreased by 25% for a platelet nadir of less than 50,000/µL during the previous course. The dose was increased by 25% once during the course of treatment if the platelet count was maintained at more than 100,000/µL in the previous course. No dose modification was made for severity of neutropenia. In patients with unusual or unacceptable nonhematologic toxicity, treatment was modified or stopped after discussion with the principal investigator.
Statistical Considerations
Patient Characteristics Patient characteristics are listed in Table 2. A total of 81 children were enrolled onto this study from all four centers. The median ages at diagnosis and enrollment were 49 months (range, 1 to 186 months) and 79 months (range, 6 to 204 months), respectively. Whereas most patients were entered onto this study based on PD noted on the MRI scan of the brain and spine, some patients had documented ataxia, seizures, or decreased vision based on the location of the tumor in the brain. Twenty-two patients had physical characteristics of NF-1, and all but two of these patients had optic pathway tumors (Table 2).
Patients received a median of 11 courses of carboplatin (range, one to 29 courses). The median follow-up of all patients remaining alive was 55 months (range, 10 to 93 months). The histologic types of low-grade gliomas and the sites of involvement are listed in Table 2.
Previous Treatment
Response to Carboplatin
Toxicity Toxicities observed in this study were graded according to the National Cancer Institute common toxicity criteria (version 2.0) and are summarized in Table 4. These were mainly hematologic and included grade 3 or 4 neutropenia in 55 patients and grade 3 or 4 thrombocytopenia in 40 patients. Additional but less frequent adverse events were allergic reaction to carboplatin in 14 patients (11%), grade 3 infection in 12 patients, grade 2 emesis in three patients, and grade 1 or 2 high-frequency hearing loss in two patients. One patient each has died secondary to pneumonia and shunt infection, respectively.
Salvage Therapy and Survival Of the 81 patients on the study, 25 patients (31%) suffered PD on or off treatment with carboplatin. After PD, six patients received focal irradiation only to the tumor site and 12 patients received chemotherapy only and subsequently achieved SD, whereas seven patients died before the institution of any salvage therapy. Thirteen patients have died: seven because of PD, two because of infection while on the study, and four who had SD at the completion of study but subsequently died of undocumented causes. With a median follow-up of 55 months (range, 10 to 93 months) for patients who are still alive, the 3-year OS and FFS were 84% (95% CI, 76% to 93%) and 64% (95% CI, 54% to 76%), respectively (Table 5, Fig 1).
Survival by Tumor Site Treatment failed for 13 of 21 patients with disease involving the diencephalon, compared with 18 of 60 patients with tumors at other sites (Table 5). The 3-year FFS and OS of patients with tumors located in the diencephalon were 38% (95% CI, 26% to 66%) and 61% (95% CI, 43% to 86%), respectively, compared with 74% (95% CI, 63% to 86%) and 91% (95% CI, 83% to 100%), respectively, for patients with tumors located at other sites (P = .011 for FFS and .004 for OS) (Table 5, Fig 2). A further analysis of each site other than the diencephalon was not performed because of inadequate numbers within each subgroup.
Survival by NF-1 Status Treatment failed in only seven of 22 patients with NF-1 and progressive low-grade glioma, compared with 24 of 59 patients without NF-1. The 3-year FFS and OS of NF-1 patients with low-grade gliomas were 72% (95% CI, 55% to 94%) and 95% (95% CI, 86% to 100%), respectively, compared with 62% (95% CI, 50% to 76%) and 80% (95% CI, 70% to 92%) for patients with low-grade gliomas and no NF-1, respectively (P = .39 for FFS and .052 for OS) (Table 5, Fig 3).
Survival by Age and Response to Treatment Age at treatment, categorized as younger than 5 years old or  5 years old, was not a statistically significant predictor of OS (P = .49) or FFS (P = .42). Similarly, there was no significant relationship between response seen at 9 months after study entry and subsequent FFS (P = .48).
This phase II study of carboplatin in children with progressive low-grade gliomas demonstrates that it is possible to stabilize disease with this agent given in this dosage schedule in a significant majority of patients with acceptable toxicity. The treatment also allowed delay or avoidance of radiotherapy in most patients. Carboplatin was chosen for this study after observation of its improved toxicity profile over its parent analog cisplatin and the preliminary activity seen in children with low-grade glioma.15,16 The dose and schedule used in this study were based on a phase I trial of carboplatin reported by Gaynon et al.19 Approximately a quarter of patients demonstrated an objective response in the form of CR, PR, or MR in this study, and a higher proportion of patients (85%) achieved SD for a median time period of almost 2 years. This is comparable to other large studies of carboplatin in children with low-grade gliomas.20,21 In a Pediatric Oncology Group study of carboplatin given every 4 weeks in young children with progressive optic pathway tumors, 39 (78%) of 50 children had SD or better, although only two patients demonstrated a PR in this study.20 In another large multi-institutional study of young children with progressive low-grade gliomas, Packer et al21 administered carboplatin combined with vincristine in children with previously untreated progressive low-grade gliomas. Forty-four (56%) of 78 patients demonstrated an objective response (four CR; 22 PR; and 18 MR) to treatment, and 73 (93%) of 78 patients had disease stabilization with a 3-year progression-free survival of 68%. The reasons for a lower objective response rate in our study compared with that reported by Packer et al21 are difficult to assess but may be related to difference in patient population, chemotherapy schedule, and response assessment. Nevertheless, the disease stabilization and FFS rates are similar in these two studies. The monthly schedule of carboplatin has several advantages over the weekly schedule in that the toxicity is tolerable, the rate of allergic reaction is lower, and it is more convenient to the patients and families. A randomized trial comparing these two schedules of carboplatin administration should be performed to accurately assess the superiority of one regimen over the other. In our study, patients with diencephalic tumors (defined as tumors involving the thalamus, hypothalamus, and basal ganglia) had a significantly worse FFS and OS compared with those with tumors located at other sites. Such tumors comprise approximately 5% of all low-grade gliomas,22 are typically large, and difficult to resect because of the presence of important surrounding structures. They are often poorly responsive to chemotherapy as well. A recent Pediatric Oncology Group study also reported poor outcomes in 25 patients with hypothalamic tumors.20 Similarly, in a study from the Children’s Hospital of Philadelphia, of 46 young children with optic pathway and hypothalamic/chiasmatic gliomas initially treated with vincristine plus dactinomycin or focal irradiation, patients with diencephalic tumors had a 5-year FFS of only 19%.23 The high failure rates for patients with diencephalic tumors may be related to the presence of unresectable bulky disease in a central location and a higher risk for leptomeningeal dissemination.13,22,24 In contrast, Packer et al21 have observed an impressive response rate of 69% in patients with diencephalic tumors (33 of 48 patients with CR, PR, or MR) after treatment with carboplatin plus vincristine and no difference in progression-free survival compared with patients with tumors in other locations. Although the incidence of optic pathway tumors is patients with NF-1 is approximately 15%, the disease is asymptomatic in half of these patients and is seen only as an incidental finding on a MRI scan of the brain.25,26 All but two of the 22 patients with NF-1 in our study had optic pathway tumors and were treated with carboplatin based on visual deterioration and/or increase in size of tumor on surveillance MRI scan of the brain. These patients had a slightly better OS compared with those without NF-1, but the FFS between the two groups was not significantly different. Packer et al21 have similarly not observed a difference in progression-free survival in their cohort of patients with or without NF-1. However, other reports have demonstrated a relatively indolent clinical course for optic pathway gliomas in children with NF-1,13,22,23,27 and many patients experience disease stabilization without any treatment.26 A similar benign clinical course has also been reported in NF-1 patients with brainstem tumors.28-30 In the context of an increased risk of malignancies in patients with NF-131,32 and the possibility of disease stabilization even without treatment, convincing evidence of PD should be established before instituting therapy. The use of carboplatin to control PD seems to be reasonable in such patients because secondary malignancies have not yet been reported using this agent in this group of patients, despite a long period of follow-up. In contrast to its parent compound cisplatin, the dose-limiting toxicity with carboplatin is myelosuppression, particularly, thrombocytopenia.15,19 Not surprisingly, toxicity in our study was predominantly myelosuppression with 68% and 49% of patients suffering at least grade 3 neutropenia or thrombocytopenia, respectively. Two of these patients died as a consequence of infection during the neutropenic phase. In contrast, Mahoney et al20 reported at least grade 3 myelosuppression in only 33% of their patients, none of whom had previous therapy and were treated with carboplatin in the same dosage schedule as in our study. The reasons for the higher incidence of bone marrow toxicity in our study could be related to previous myelosuppressive therapy, with 23 patients receiving chemotherapy or radiotherapy before study entry. The incidence of allergic reactions to carboplatin in our study was 11% and is comparable to the rate of 2% to 30% reported in other studies.16,20,21,33 Variations in the reported incidence of hypersensitivity to this agent could be related to the schedule of administration, with a higher risk of allergic reactions associated with more frequent exposure to the drug.34 The occurrence of allergic reaction in our study was dependent on the duration of treatment, with symptoms occurring for the first time after a median of 11 cycles of therapy. While desensitization therapy for carboplatin allergy has been previously reported from our institution,35 none of our patients in our study received desensitization for this adverse reaction but were instead removed from study. Other toxicities caused by carboplatin observed in our study were infrequent and included mild hearing loss and emesis. The incidence of ototoxicity in two (2.5%) of 81 patients in our study is low, as expected from the toxicity profile of this drug, and is comparable to the incidence reported in other studies.15,19 The results of our phase II study demonstrate that monthly carboplatin is an effective therapy in patients with progressive low-grade gliomas. The majority of the children in this study achieved disease stabilization with predictable and manageable toxicities. This in turn allowed these children to avoid completely or substantially delay radiotherapy that might likely contribute to improved neurocognitive function. Although these data are encouraging, further refinements in therapy are required for patients with progressive low-grade gliomas, especially those with diencephalic tumors.
Presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
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Packer RJ, Lange B, Ater J, et al: Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol 11: 850-856, 1993 11. Reddy AT, Packer RJ: Chemotherapy for low-grade gliomas. Childs Nerv Syst 15: 506-513, 1999[CrossRef][Medline] 12. Packer RJ: Chemotherapy: Low-grade gliomas of the hypothalamus and thalamus. Pediatr Neurosurg 32: 259-263, 2000[CrossRef][Medline] 13. Garvey M, Packer RJ: An integrated approach to the treatment of chiasmatic-hypothalamic gliomas. J Neurooncol 28: 167-183, 1996[Medline] 14. Pons MA, Finlay JL, Walker RW, et al: Chemotherapy with vincristine (VCR) and etoposide (VP-16) in children with low-grade astrocytoma. J Neurooncol 14: 151-158, 1992[Medline] 15. Friedman HS, Krischer JP, Burger P, et al: Treatment of children with progressive or recurrent brain tumors with carboplatin or iproplatin: A Pediatric Oncology Group randomized phase II study. J Clin Oncol 10: 249-256, 1992[Abstract] 16. Moghrabi A, Friedman HS, Burger PC, et al: Carboplatin treatment of progressive optic pathway gliomas to delay radiotherapy. J Neurosurg 79: 223-227, 1993[Medline] 17. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-480, 1958[CrossRef] 18. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35: 1-39, 1977[Medline] 19. Gaynon PS, Ettinger LJ, Moel D, et al: Pediatric phase I trial of carboplatin: A Childrens Cancer Study Group report. Cancer Treat Rep 71: 1039-1042, 1987[Medline] 20. Mahoney DH Jr, Cohen ME, Friedman HS, et al: Carboplatin is effective therapy for young children with progressive optic pathway tumors: A Pediatric Oncology Group phase II study. Neuro-oncol 2: 213-220, 2000[Abstract] 21. Packer RJ, Ater J, Allen J, et al: Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 86: 747-754, 1997[Medline] 22. Allen JC: Initial management of children with hypothalamic and thalamic tumors and the modifying role of neurofibromatosis-1. Pediatr Neurosurg 32: 154-162, 2000[CrossRef][Medline] 23. Janss AJ, Grundy R, Cnaan A, et al: Optic pathway and hypothalamic/chiasmatic gliomas in children younger than age 5 years with a 6-year follow-up. Cancer 75: 1051-1059, 1995[CrossRef][Medline] 24. Mamelak AN, Prados MD, Obana WG, et al: Treatment options and prognosis for multicentric juvenile pilocytic astrocytoma. J Neurosurg 81: 24-30, 1994[Medline] 25. Listernick R, Charrow J, Greenwald M, et al: Natural history of optic pathway tumors in children with neurofibromatosis type 1: A longitudinal study. J Pediatr 125: 63-66, 1994[CrossRef][Medline] 26. Listernick R, Charrow J, Gutmann DH: Intracranial gliomas in neurofibromatosis type 1. Am J Med Genet 89: 38-44, 1999[CrossRef][Medline] 27. Listernick R, Darling C, Greenwald M, et al: Optic pathway tumors in children: The effect of neurofibromatosis type 1 on clinical manifestations and natural history. J Pediatr 127: 718-722, 1995[CrossRef][Medline]
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Molloy PT, Bilaniuk LT, Vaughan SN, et al: Brainstem tumors in patients with neurofibromatosis type 1: A distinct clinical entity. Neurology 45: 1897-1902, 1995 31. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: A population-based UKCCSG study. Br J Cancer 70: 969-972, 1994[Medline] 32. Doorn PF, Molenaar WM, Buter J, et al: Malignant peripheral nerve sheath tumors in patients with and without neurofibromatosis. Eur J Surg Cancer 21: 78-82, 1995 33. Chang SM, Fryberger S, Crouse V, et al: Carboplatin hypersensitivity in children: A report of five patients with brain tumors. Cancer 75: 1171-1175, 1995[CrossRef][Medline] 34. Yu DY, Dahl GV, Shames RS, et al: Weekly dosing of carboplatin increases risk of allergy in children. J Pediatr Hematol Oncol 23: 349-352, 2001[CrossRef][Medline] 35. Broome CB, Schiff RI, Friedman HS: Successful desensitization to carboplatin in patients with systemic hypersensitivity reactions. Med Pediatr Oncol 26: 105-110, 1996[CrossRef][Medline] Submitted December 3, 2001; accepted March 21, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
