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© 2002 American Society for Clinical Oncology High Response Rate to Cisplatin/Etoposide Regimen in Childhood Low-Grade GliomaByFrom Pediatric Oncology, Radiodiagnostic E and Radiotherapy Unit, Istituto Nazionale Tumori; and Neurosurgery II and Development Pediatric Neurology Unit, Istituto Neurologico Carlo Besta, Milan; Pediatric Oncology and Neurosurgery Unit, Università Cattolica del Sacro Cuore–Policlinico Gemelli, Rome; Pediatric Neurosurgery Unit, Ospedale Infantile Regina Margherita, Torino; and Department Of Clinical Sciences and Bioimaging, Institute of Advanced Biomedical Technology G d A University, Chieti, Italy. Address reprint requests to Maura Massimino, MD, Pediatric Oncology Unit, Istituto Nazionale Tumori, Via Venezian, 1 20133 Milano, Italy; email: massimino{at}istitutotumori.mi.it
PURPOSE: The aim of this study was to avoid radiotherapy and to induce an objective response in children with low-grade glioma (LGG) using a simple chemotherapy regimen based on cisplatin and etoposide. PATIENTS AND METHODS: Thirty-four children (median age, 45 months) with unresectable LGG were treated with 10 monthly cycles of cisplatin (30 mg/m2/d on days 1 to 3) and etoposide (150 mg/m2/d on days 1 to 3). Tumor originated in the visual pathway in 29 patients, in the temporal lobe in two, in the frontal lobe in two, and in the spine in one. Eight children were affected by neurofibromatosis type 1. Objective tumor response and toxicity were evaluated by magnetic resonance imaging and neurologic and functional tests at 3-month intervals. RESULTS: An objective response was obtained in 24 (70%) of 34 patients, whereas the others had stable disease. None of the children were electively irradiated. In 31 previously untreated children, overall survival was 100% and progression-free survival was 78% at 3 years, with a median follow-up of 44 months. Acute toxicity was unremarkable; 28% patients evaluated for acoustic neurotoxicity revealed a loss of perception of high frequencies. CONCLUSION: Cisplatin and etoposide combined treatment is one of the most active regimens for LGG in children and allows avoidance of radiotherapy in the vast majority of patients.
LOW-GRADE GLIOMA (LGG) represents approximately one third of all childhood brain tumors. Whenever feasible, complete surgical removal appears to be the treatment of choice, resulting in cure in the vast majority in children. In the absence of any additional treatment, tumors that are not completely resectable may progress slowly over years. An accelerated growth rate is sometimes seen, however, especially in infiltrating lesions or in opticochiasmatic locations, mainly in children less than 5 years of age.1 When complete gross resection is impossible, radiotherapy and chemotherapy are therapeutic options to consider. In the relatively small series of children with LGG described so far, radiation therapy induced tumor shrinkage and prolonged progression-free survival.2-5 In young children with large tumors, or with diencephalic syndrome, the well-known harmful side effects of radiotherapy make this approach less appealing. In children with progressive disease or large symptomatic tumors, chemotherapy has been used with the purpose of delaying radiotherapy and its devastating effect on the developing nervous system. Although the efficacy of chemotherapy is not well established, it appears clear that some drugs such as vincristine, carboplatin, nitrosoureas, and etoposide are able to induce an objective tumor response in a high percentage of patients.6-9 The treatment protocol based on a combination of carboplatin and vincristine proposed by Packer et al1 and first reported in 1993 has achieved high objective response rates of 52% and 62%, respectively, in relapsed and newly diagnosed patients. Taking into account the antineoplastic effect observed in LGG treated by combinations containing either cisplatin or etoposide,10-13 we explored the possibility of treating LGG combining the two drugs into a simple and manageable monthly regimen. This schedule, which we had already applied successfully and with minimal acute and long-term toxicity in malignant brain tumors of young children,12 was first adopted in 1991 to treat a 33-month-old child with a large LGG of the chiasm that extended to the cerebral peduncles and the basal nuclei, and with subarachnoid dissemination. Because the child could not be operated on and was too young to receive safely a curative radiation treatment, we chose to explore whether the already known synergistic effect of cisplatin and etoposide could work also in low-grade histotypes. After the promising response observed in this child and in another seven young patients constituting a monoinstitutional pilot group with progression of large diencephalic tumors,13 we enrolled additional pediatric patients with large or symptomatic LGG, regardless of age. We report here on the response rate and treatment-related toxicity observed in the first 34 patients.
Patients Population Patients younger than 21 years with a histologic or radiologic diagnosis of LLG were eligible for treatment. From May 1991 to December 2000, 34 children with LLG (16 males and 18 females) were treated. Table 1 lists the patients’ characteristics. Median age was 45 months, with a range from 4 to 198 months. Histologic diagnosis was available in 24 of 34 patients and was pilocytic astrocytoma in 20, desmoplastic infantile ganglioglioma in three, and oligoastrocytoma in one.
In 10 children, the diagnosis was made on the basis of radiologic and clinical grounds: six had neurofibromatosis type 1 (NF1) with typical visual pathway LGG, three had severe diencephalic syndrome with poor general conditions, and in one case the parents refused consent to biopsy. One child with visual pathway glioma presented with spinal metastases at diagnosis, whereas a meningeal subarachnoid enhancement was found in another three cases. Eight children had NF1. Twenty-nine patients were treated at Istituto Nazionale Tumori of Milan. Five additional children received the same chemotherapeutic program at Policlinico Gemelli in Rome. Disease in three of these had progressed after other medical treatment (carboplatin, vincristine, procarbazine, and carmustine for a median period of 6 months), after at least a 6-week washout period after the previous chemotherapy, before this regimen was administered.
Treatment Protocol The treatment has so far been completed in 28 children, who received a total of 10 cycles of chemotherapy. Twenty-five of 29 patients assessable for treatment setting received the chemotherapy on an outpatient basis. In two of four cases, the parents asked for a full-day admission; for one girl, poor social conditions prevented the discharge, and one patient’s psychotic syndrome made the day-hospital setting unsuitable. Neither young age nor diencephalic syndrome were obstacles to administering the chemotherapy on an outpatient basis.
Evaluation of Response Radiologic response was assessed according to International Society of Paediatric Oncology criteria: complete response is defined as no evidence of disease, partial response requires a reduction in size of more than 50% radiographically, and stable disease is the absence of tumor progression. In the particular evaluation of response used for LGG, we have added the category of volume reduction, which means less than 50% reduction of residual tumor size as obtained by the product of the diameter in the plane with the largest tumor extension, with the perpendicular one measured on the same scan.14 Stable disease was considered a positive response and chemotherapy was therefore continued. All patients are in active follow-up at the time of this report. Median follow-up is 44 months.
Statistical Analysis
At the time of starting treatment, all children suffered from radiologically proven progressive disease or obvious worsening of symptoms or deficiencies; the median interval from observation to treatment was 9 months (range, 1 month to 10 years). The only child treated soon after diagnosis presented with a severe diencephalic syndrome and rapid PEV deterioration since birth (Fig 1). One of the patients, a 10-year-old girl, had been diagnosed and operated on 7 years before for a pilocytic astrocytoma of the visual pathway: the residual disease had shown spontaneous shrinkage of at least a 50% in volume 2 years after surgery and had subsequently progressed again with rapid visual impairment 4 months before beginning the present treatment. Another 13-year-old girl with NF1 had received hormone-suppressive therapy to stop early pubertal development 7 years earlier, and then ophthalmologic and radiologic assessments revealed an optic glioma that had certainly not existed 7 years before.
Response All children were assessable for response to chemotherapy at the time of this report, with a median follow-up of 44 months (range, 10 to 120 months). Table 2 lists types of response according to volume, symptoms, and signs. Figure 2 illustrates a child with diencephalic syndrome (Fig 1) after metabolic improvement. According to International Society of Paediatric Oncology criteria,14 complete remission was reached in one child, partial remission in 11, volume reduction (less than 50%) in 12, and stable disease in 11. An objective response was therefore obtained in 24 (70%) of 34 patients. None had disease progression during treatment. The child with spine metastases attained remission both in the head and in the spine. Time to best response was between 4 and 18 months, with a median of 8 months after starting chemotherapy: three children had a transient increase in tumor volume (less than 25%) after two cycles of chemotherapy, followed by stabilization in one and tumor reduction in two. Table 3 lists best tumor responses for each patient. Neurologic/functional improvement has been recorded in 22 of 29 children so far assessable, whereas the situation has remained stable (ie, without worsening of any symptom or functional assessment) in seven of 29, judging from the neurologic and ophthalmologic evaluation. None of the children presented clinical signs of neurologic, metabolic, or functional deterioration while on treatment, thus achieving the goal of the protocol in all the patients.
Disease has progressed in four children so far, all at the primitive tumor site, a mean of 22 months since beginning chemotherapy: one has undergone surgery, with total removal of a cystic component and is progression-free at 74 months; one has had debulking surgery and is on second-line chemotherapy at 38 months; one has refused further treatment and is still alive at 64 months; and one is free from progression after debulking 51 months after diagnosis. Only one 14-year-old boy with stable disease after partial remission was treated with radiotherapy at another institution, at the parents’ request, and is alive with disease, whereas another boy was able to undergo complete resection of an uncal neoplasm after two cycles of chemotherapy. None of the children with NF1 has relapsed so far. The overall survival of the 31 previously untreated children is 100%, and progression-free survival (PFS) is 78% at 3 years (Fig 3); PFS for the eight NF1 patients is 100% and 73% for the other 23 patients (P = NS); PFS is 87% and 33%, respectively (P = .02) for the 24 children older than 1 year and the seven children younger than 1 year of age (Fig 4). Taking 5 years of age as a cutoff for prognosis, PFS was 100% for the 12 children above 5 years and 66% for the 19 patients younger than 5 years (P = NS). Moreover, PFS was 78% for the 20 children who had a volume reduction and 83% for those 11 cases whose neoplasm remained stable in volume during chemotherapy. Considering only children with visual pathway glioma, their PFS was 73% at 3 years. None of the children has died so far, from disease or any other cause.
Toxicity Audiometric tests were performed serially in 28 of 34 children already out of treatment: 20 of 28 have normal hearing function, and eight (28%) have impairment at high frequencies that is monolateral in four cases and bilateral in the other four. One girl showed a functional auditive improvement at the audiometric test performed 4 years after the first pathologic test. Fourteen blood transfusions and four platelet transfusions were required in 253 assessable cycles; however, 10 transfusions of blood and three of platelets were administered to one patient only with a severe diencephalic syndrome. World Health Organization grade 3 to 4 neutropenia was documented in one child only, who had been treated previously. Kidney function was normal in all children throughout the treatment course and at subsequent follow-up. No child has shown signs of myelodysplastic syndrome in the peripheral blood. The 18 children that have already reached school age are attending state schools and following a standard program: four are supported by an additional teacher, who has to help with writing because of the visual loss in two children. Eight children who had undergone a thorough neurocognitive evaluation before starting treatment have shown no cognitive impairment after chemotherapy.
In case of progressive residual LGG not amenable to repeated surgery without severe sequelae, radiotherapy has been the most often-used therapeutic tool and is still the first-line adjuvant treatment at many institutions.2-5,16,17 New techniques have been adopted (eg, conformational or stereotactic fractionated radiotherapy) that have contributed in terms of precision and sparing of the normal tissue, but still carry the risks of late effects on the irradiated target and surrounding normal brain, which is always included in the irradiated field at various dosage levels.16,17 Moreover, the long-term follow-up of children with LGG treated in this way is not sufficient for us to know whether or not late effects relating to loss of sensitivity, neurocognitive disabilities, somatic defects, vascular impairment risk, and second tumors will be negligible. Among all patients, moreover, children affected by NF1 are known to form a particular group that seem to have a better prognosis and a more favorable response to chemotherapy, together with a greater susceptibility to thrombogenic side effects of radiotherapy.6,18-20 Also, older children and adolescents who are traditionally submitted to radiotherapy for progressive residual LGG remain at risk of severe sequelae from radiotherapy, especially considering that total treatment doses, applied despite the histotype of LGG, are generally not lower than 50 Gy, and that the risk of malignant transformation can reach 10%.21,22 The role of chemotherapy in reducing LGG volume is well known, although there is still debate as to the optimal drug association, the duration and intensity of the treatment, and the prospective utility of chemotherapy as the definitive treatment for LGG. LGG consists of a group of tumors that have different histologies and different sites of origin, aspects that can make interpretation of incoming data particularly difficult. The rationale for the duration and modulation of the treatment adopted in this schedule was based on the period when relapse is most likely and on the model of other schedules.1,23,24 Because the response was progressive and continuous, a high dose intensity did not seem useful, and slowing down the schedule made hematologic and subjective toxicity less severe and more tolerable. Experience with the largest series published to date also shows that the best responses achievable with carboplatin and vincristine are appreciated more during the less intense maintenance period of their administration than during the induction phase.6,7,19,20,24,25 The recently published article by Mahoney et al,26 regarding the Pediatric Oncology Group phase II study on the use of monthly carboplatin in 50 children, refers to a schedule designed to last a total of 18 months. Partial response was achieved in two and stable disease was achieved in 37, whereas six of 11 with progressive disease died; in the initial small group of six children reported, disease had been stable in all during carboplatin administration.27 Considering disease stabilization and volume reduction as a positive response, we obtained a 100% response (ie, no tumor progression). Of course, nephrotoxicity and ototoxicity caused by cisplatinum are real risks to bear in mind, but they depend on cumulative dose, means and time of administration, and unknown individual characteristics.28-30 None of our patients had acute or permanent signs of nephrotoxicity, whereas 28% revealed a hearing disability after completing the schedule. This cannot be considered a major disability because it was never appreciable in the speech frequencies range. Because the efficacy of cisplatin is so high, we think that the effort should be to use it by lowering its late effects in the best possible way.30 We can also hypothesize that the progressive increment of time among chemotherapy courses contributed to lower cisplatinum toxicity despite the total dose administered. Replacing cisplatin by carboplatin, which is less toxic on the ear and kidney, does not seem convincing because this drug is also less effective.31-33 Moreover, allergic reaction to carboplatin, especially during repeated administrations, and myelotoxicity, even at the doses used for LGG, are far from negligible side effects.23,26 After allergic manifestations, there is the actual risk of withdrawing chemotherapy, and thus the loss of efficacy,23 with the adoption of more toxic therapeutic tools. The schedule we applied reached a cumulative dose of 4.5 g/m2 of etoposide, which is still within the safe cumulative range, whereas its administration on 3 consecutive days in a month (instead of intermittently and chronically, once or twice weekly) should prevent the risk of bone marrow transformation.35 Moreover, the association with cisplatin has not been depicted so far as one of those enhancing the cumulative risk of iatrogenic leukemias.34,35 Children with NF1 are per se at risk of developing juvenile chronic myelomonocytic leukemia because the NF1 allele acts as a tumor suppressor in myeloid cells.36 They deserve therefore a keen hematologic follow-up even if secondary leukemias after epipodophyllotoxins have a mean latency period of 2 years and have not been associated with any genetic predisposition also including germline NF1 mutations.37 None of our patients were electively submitted to radiotherapy on relapse because re-excision or other chemotherapeutic schedules were preferred. In dealing with LGG, surgery can take advantage of the intratumoral debulking of disease38,39 and can sometimes lead to a spontaneous reduction in the neoplastic mass.39-41 Although we cannot say that the good response to chemotherapy correlated with a better PFS, as many other authors have pointed out,6,8,42 we can emphasize that the radiotherapy-free survival was 100%. Assessment of response is a difficult task in these neoplasms, because of the tendency to grow asymmetrically in three dimensions. Moreover, the course of the disease is sometimes indolent, and it is easier to appreciate the functional response rather than the radiologic response. In the series reported to date, a better prognosis is attributed to the children with NF1: our data confirm this observation,43-45 with a 100% PFS for this group. Conversely, the six children younger than 1 year of age represent a higher risk group, with a PFS of 33% at 3 years as opposed to 87% for the rest of the group considered. The youngest children are at greatest risk of developing the diencephalic syndrome, which seems to correlate with metastatic deposits46,47 and thus with a worse prognosis. It is worth emphasizing, conversely, that all four patients with disseminated disease achieved remission and none of the four children whose disease progressed after completing treatment had presented with subarachnoid dissemination at diagnosis, whereas two had diencephalic syndrome. Unlike the findings of Packer et al,1 the children over 5 years of age did not fare worse than younger patients: none of them progressed so far. The best volumetric and symptomatic response was obtained after a median of 6 months. This interval is remarkably long for childhood brain tumors and also for all other diseases encountered by pediatric oncologists. Being too anxious to find out how the treatment is working during the early cycles of chemotherapy might therefore lead to mistakes in the physician’s and patient’s subsequent behavior (eg, giving up on chemotherapy or, even worse, adopting more toxic treatments). This group of tumors has certain unique features, meaning that none of the usual diagnostic or therapeutic models are suitable for approaching these patients. The diagnosis and treatment of LGG is a difficult task, and there is still little consensus regarding treatment guidelines.48 LGG includes also categories of rare tumor types with unpredictable histories and sometimes even spontaneous regression. In dealing with a disease that does not immediately kill patients, we should carefully weigh the risks of treatment and of the chances of the cure being more harmful than the disease. Chemotherapy side effects appear less severe if compared with damage induced by radiotherapy. We have shown, as have others, that chemotherapy can modify the natural history of LGG, inducing high rates of tumor stabilization or regression.1,6-9 Monthly cisplatin and etoposide is probably one of the most active regimens in the pharmacologic treatment of LGG in children, thus allowing avoidance of radiotherapy and its severe devastating late effects in the vast majority of patients. Our next task will be to reduce single-drug doses with the aim of maintaining the same response rate together with lowering the actual and possible toxicity of cisplatin and etoposide.
1. 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 2. Fisher BJ, Bauman GS, Leighton CE, et al: Low-grade gliomas in children: Tumor volume response to radiation. J Neurosurg 88: 969-974, 1998[Medline] 3. Karim ABM, Maat B, Hatlevoll R, et al: A randomised trial on dose-response in radiation therapy of low-grade cerebral gliomas: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys 36: 549-556, 1996[CrossRef][Medline] 4. Gajjar A, Sanford RA, Heideman R, et al: Low-grade astrocytoma: A decade of experience at St. Jude Children’s Research Hospital. J Clin Oncol 15: 2792-2799, 1997[Abstract] 5. Strojan P, Petric-Grabnar G, Zupancic N, Jereb B: Concomitant chemoradiotherapy for incompletely resected supratentorial low-grade astrocytoma in children: Preliminary report. Med Pediatr Oncol 32: 112-116, 1999[CrossRef][Medline] 6. Packer R, Sutton LN, Bilaniuk LT, et al: Treatment of chiasmatic/hypothalamic gliomas of childhood with chemotherapy: An update. Ann Neurol 23: 79-85, 1988[CrossRef][Medline] 7. Petronio J, Edwards SB, Prados M, et al: Management of chiasmal and hypothalamic gliomas of infancy and childhood with chemotherapy. J Neurosurg 74: 701-708, 1991[CrossRef][Medline] 8. Prados MD, Edwards MSB, Rabbitt J, et al: Treatment of pediatric low-grade gliomas with a nitrosourea-based multiagent chemotherapy regimen. J Neurooncol 32: 235-241, 1997[CrossRef][Medline] 9. Castello MA, Schiavetti A, Padula A, et al: Does chemotherapy have a role in low-grade astrocytoma management? A report of 13 cases. Med Pediatr Oncol 25: 102-108, 1995[Medline] 10. Durand RE, Goldie JH: Interaction of etoposide and cisplatin in an in vitro tumor model. Cancer Treat Rep 71: 673-679, 1987[Medline] 11. Kobayashi T, Yoshida J, Ishiyama J, et al: Combination chemotherapy with cisplatin and etoposide for malignant germ-cell tumors: An experimental and clinical study. J Neurosurg 70: 676-681, 1989[Medline] 12. Massimino M, Gandola L, Cefalo G, et al: Management of medulloblastoma and ependymoma in infants: A single-institution long-term retrospective report. Childs Nerv Syst 16: 15-20, 2000[CrossRef][Medline] 13. Massimino M, Gefalo G, Luksch R: CDDP/VP16 chemotherapy for childhood low-grade gliomas: A mono-institutional study. 8th International Symposium on Pediatric Neuro-Oncology, Rome, Italy, May 6-9, 1998 14. Gnekow AC: Recommendations of the Brain Tumor Subcommittee for the reporting of trials: SIOP Brain Tumor Subcommittee—International Society of Pediatric Oncology. Med Pediatr Oncol 24: 104-108, 1995[Medline] 15. Kaplan E, Meyer P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 16. Lunsford LD, Samaza S, Kondziolka D, Flickinger JC: Survival after stereotactic biopsy and irradiation of cerebral non anaplastic non pilocytic astrocytoma. J Neurosurg 82: 523-529, 1995[Medline] 17. Miralbell R, Blart J, Matias G, Molet J, Ariza A, Craven-Bartle J: Radiotherapy for supratentorial low-grade gliomas: Results and prognostic factors with special focus on tumor volume parameters. Radiother Oncol 27: 112-116, 1993[CrossRef][Medline] 18. Hoffman HJ, Humphreys RP, Drake JM, et al: Optic pathway/hypothalamic gliomas: A dilemma in management. Pediatr Neurosurg 19: 186-195, 1993[Medline] 19. Listernick R, Louis DN, Packer RJ, Gutmann DH: Optic pathway gliomas in children with neurofibromatosis 1: Consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann Neurol 41: 143-149, 1997[CrossRef][Medline] 20. Grill J, Couanet D, Cappelli C, et al: Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 45: 393-396, 1999[CrossRef][Medline] 21. Jenkin D, Angyalfi S, Becker L, et al: Optic glioma in children: Surveillance, resection, or irradiation? Int J Radiat Oncol Biol Phys 25: 215-225, 1992 22. Bataini JP, Delanian S, Pouvert D: Chiasmal gliomas: Results of irradiation management in 57 patients and review of literature. Int J Radiat Oncol Biol Phys 21: 615-623, 1991[Medline] 23. Gnekow AK, Kaatsch P, Kortmann R, et al: HIT-LGG: Effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood—An interim report. Klin Padiatr 212: 177-184, 2000[CrossRef][Medline] 24. Chan MY, Foong AP, Heisey DEM, et al: Potential prognostic factors of relapse-free survival in childhood optic glioma: A multivariate analysis. Pediatr Neurosurg 29: 23-28, 1998[CrossRef][Medline]
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32. Go RS, Adjei AA: Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 17: 409-422, 1999 33. Bin P, Boddy AV, English MV, et al: The comparative pharmacokinetics and pharmacodynamics of cisplatin and carboplatin in pediatric patients: A review. Anticancer Res 14: 2279-2283, 1994[Medline] 34. Miser J, Krailo M, Smith M, et al: Secondary leukaemia (SL) or myelodysplastic syndrome (MDS) following therapy for Ewing’s sarcoma (ES). Proc Am Soc Clin Oncol 16: 1863, 1997 (abstr) 35. Smith MA, Rubinstein L, Auderson JR, et al: Secondary leukemia or myelodisplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17: 275-281, 1999 36. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: A population-based UKCCSG study. Br J Cancer 70: 969-972, 1994[Medline] 37. Felix CA: Secondary leukemias induced by topoisomerase-targeted drugs. Biochim Biophys Acta 1400: 233-255, 1998[Medline] 38. Sutton LN, Molloy PT, Sernyak H, et al: Long-term outcome of hypothalamic/chiasmatic astrocytomas in children treated with conservative surgery. J Neurosurg 83: 583-589, 1995[Medline] 39. Schmandt SM, Packer RJ, Vezina LG: Spontaneous regression of low-grade astrocytomas in children. Pediatr Neurosurg 32: 132-136, 2000[CrossRef][Medline] 40. Kernan JC, Horgan MA, Piatt JH, D’Agostino A: Spontaneous involution of a diencephalic astrocytoma. Pediatr Neurosurg 29: 149-153, 1998[CrossRef][Medline] 41. Balkhoyor KB, Bernstein M: Involution of diencephalic pilocytic astrocytoma after partial resection. J Neurosurg 93: 484-486, 2000[Medline] 42. 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] 43. Rossi LN, Pastorino G, Scotti G, et al: Early diagnosis of optic glioma in children with neurofibromatosis type 1. Childs Nerv Syst 10: 426-429, 1994[CrossRef][Medline] 44. Janss AJ, Grundy R, Cnaan A, et al: Optic pathway and hypothalamic/chiasmatic gliomas in children younger than 5 years with a 6-year follow-up. Cancer 75: 1051-1059, 1995[CrossRef][Medline] 45. Listernick R, Charrow J, Tadanori T, Goldman S: Carboplatin therapy for optic pathway in tumors in children with neurofibromatosis type-1. J Neurooncol 45: 185-190, 1999[CrossRef][Medline] 46. Perilongo G, Carollo C, Salviati L, et al: Diencephalic syndrome and disseminated juvenile pilocytic astrocytomas of the hypothalamic-optic chiasm region. Cancer 80: 142-146, 1997[CrossRef][Medline] 47. Gropman AL, Packer RJ, Nicholson HS, et al: Treatment of diencephalic syndrome with chemotherapy. Cancer 83: 166-172, 1998[CrossRef][Medline] 48. Lee AG, Dutton JJ: A practice pathway for the management of gliomas of the anterior visual pathway: An update and an evidence based approach. Neuroophthalmology 22: 139-155, 1999 Submitted August 13, 2001; accepted June 19, 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
