Chemotherapy for Progressive Low- Grade Gliomas in Children Older than Ten Years: The Dana-Farber Experience

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1 See discussions, stats, and author profiles for this publication at: Chemotherapy for Progressive Low- Grade Gliomas in Children Older than Ten Years: The Dana-Farber Experience Article in Pediatric Hematology and Oncology October 2003 Impact Factor: 1.1 DOI: / Source: PubMed CITATIONS 13 READS authors, including: Liliana C Goumnerova Harvard Medical School 135 PUBLICATIONS 5,416 CITATIONS SEE PROFILE Available from: Liliana C Goumnerova Retrieved on: 10 May 2016

2 Pediatric Hematology and Oncology, 20: , 2003 Copyright C Taylor & Francis Inc. ISSN: print / online DOI: / CHEMOTHERAPY FOR PROGRESSIVE LOW-GRADE GLIOMAS IN CHILDREN OLDER THAN TEN YEARS: The Dana-Farber Experience John A. Heath and Christopher D. Turner Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children s Hospital, Boston, Massachusetts, USA Tina Young Poussaint Department of Radiology, Dana-Farber Cancer Institute and Children s Hospital, Boston, Massachusetts, USA R. Michael Scott and Liliana Goumnerova Department of Neurosurgery, Dana-Farber Cancer Institute and Children s Hospital, Boston, Massachusetts, USA Mark W. Kieran Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children s Hospital, Boston, Massachusetts, USA The purpose of this retrospective study was to examine the clinical and radiographic response rates to and toxicity of chemotherapy for low-grade gliomas in children older than 10 years of age. Between June 1999 and January 2001, seven consecutive children between the ages of 10 and 18 were treated with vincristine and carboplatin ± thioguanine, procarbazine, CCNU [lomustine], and vincristine (TPCV) for progressive low-grade gliomas. All 7 children completed a 10-week induction course of vincristine and carboplatin; 3 were switched to TPCV during the maintenance phase of therapy after developing an allergic reaction to carboplatin. Overall, 4 patients had a radiographic response to treatment with chemotherapy (3 partial responses and 1 minor response: objective response rate of 57%), and 2 more showed stable disease. One patient progressed while on treatment and 1 patient progressed off treatment, and after 31 months had elapsed. The resulting progression-free survival at the time of this report was 71%. The median duration of follow-up was 32 months (range months). Hematologic toxicity was common, but did not result in cessation of therapy. No other significant treatment-related toxicities were observed. The results suggest that the clinical response/disease stabilization rate in children older than 10 years of age does not differ markedly from that observed in younger children. A prospective clinical trial of chemotherapy for progressive low-grade gliomas in children older than 10 years is therefore warranted. Keywords. astrocytoma, chemotherapy, children, low-grade glioma Low-grade gliomas are the most common brain tumor of childhood, with about a third occurring in children older than 10 years of age [1, 2]. Complete surgical resection may be curative but for many of these tumors, particularly those involving midline structures, such as the thalamus, hypothalamus, and optic chiasm, this is not possible. While radiation may be a useful therapeutic tool in the treatment of these incompletely resected low-grade gliomas [3], Received 9 December 2002; accepted 25 May Address correspondence to Dr. John A. Heath, MD, PhD, Department of Clinical Haematology and Oncology, Royal Children s Hospital, Flemington Road Parkville, Victoria 3052 Australia. john.heath@rch.org.au 497

3 498 J. A. Heath et al. the potential for long-term side effects, such as intellectual deficits, impaired endocrine function, vascular changes, and second malignancies, has led to a desire to delay or avoid radiation in children [4, 5]. The role of chemotherapy as first-line therapy for unresectable, progressive low-grade gliomas (particularly younger children) has therefore been increasing. Numerous single and combination chemotherapeutic agents have been used for this purpose. These include vincristine/actinomycin D, vincristine/etoposide, vincristine/cisplatin, cyclophosphamide, tamoxifen/carboplatin, and carboplatin alone [6 12]. Many of the reported studies have upper age limits of less than 18 years, however. More recently, the combinations of vincristine/carboplatin [11] and thioguanine, procarbazine, CCNU [lomustine], and vincristine (TPCV) [13] have found favor for use in young children with recurrent or progressive low-grade gliomas. In a recent series of 78 patients with newly diagnosed, progressive low-grade gliomas treated with vincristine/carboplatin, an overall progression-free survival of 68 ± 7% at 3 years was achieved [11]. In addition, children less than 18 years with newly diagnosed or progressive low-grade gliomas treated with TPCV and dibromodulcitol had a 36% objective response rate, with a further 59% showing stable disease [13]. However, current trials examining the role of chemotherapy for progressive low-grade gliomas are restricted to children less than 10 years old [14]. This cutoff is somewhat arbitrary, since there is no evidence that the biologic behavior of tumors in older children is different from those in younger children. In addition, while the effects of radiation are most severe in younger children, it is recognized that even focal radiation in adults can be associated with neurocognitive deficits and intellectual decline over time [15]. The risks of endocrine deficits, vascular change, and second malignancy also persist for older children and adults. This retrospective, single-institution study therefore examined the clinical and radiographic response of low-grade gliomas in children older than 10 years to chemotherapy. PATIENTS AND METHODS Patient Characteristics The study was a retrospective review of children older than 10 years treated with chemotherapy for progressive low-grade gliomas between June 1999 and January 2001 at Dana-Farber Cancer Institute and Children s Hospital, Boston, MA. Patients had histologically confirmed low-grade astrocytomas (pilocytic or fibrillary) or other low-grade gliomas (WHO grade I or II), and documented progression of tumor on serial magnetic resonance imaging following the initial surgical excision. Patients with an incomplete excision, and a necessity to begin treatment because of an unacceptable risk of neurologic impairment with progression, were also included. In addition, children with

4 Chemotherapy for Low-Grade Gliomas in Children over 10 Years 499 neurofibromatosis type 1 (NF1) who had optic pathway tumors (presumed to be low-grade gliomas) with definitive radiographic evidence of progression were eligible without pathologic diagnosis. Apart from surgery, no child had received any previous therapy. Before beginning chemotherapy, all children had a complete history, physical and neurological examination. A baseline MRI for all and an ophthalmology examination for those with optic pathway tumors were also performed. To monitor for toxicity, a complete blood count, measurement of serum electrolytes, creatinine, and liver function tests, an assessment of glomerular filtration rate ( 99 Tm nuclear medicine scan), and an audiology evaluation were also undertaken. Treatment Regimen All patients initially received a 10-week induction course consisting of 8 doses of intravenous carboplatin (175 mg/m 2 ) and 10 doses of intravenous vincristine (1.5 mg/m 2, maximum 2 mg weekly) (Table 1). For patients with an objective response to treatment or for those with stable disease, maintenance therapy was administered for up to 8 cycles (Table 1). All children received ondansetron as prophylaxis against emesis. The carboplatin was administered in the outpatient department as a 30-min infusion with 1 h of prehydration and 1hofposthydration. All patients received trimethoprim/ sulfamethoxazole as Pneumocystis carinii prophylaxis. Toxicities were graded using the National Cancer Institute Common Toxicity Criteria. The complete blood count was monitored approximately weekly throughout the treatment period. Chemotherapy was deferred until the absolute neutrophil count (ANC) was > /L and the total platelet count was >100, /L. If the patient did not meet these hematologic criteria, therapy was delayed for 1 week. If grade 3 or 4 hematological, renal, or hepatic toxicity was documented, the dose of carboplatin was reduced by 25% for subsequent cycles. Vincristine was held for symptoms of grade 3 or 4 peripheral neuropathy, TABLE 1 Treatment (Vincristine and Carboplatin) During Induction and Maintenance Week Induction Vincristine a Carboplatin b Maintenance (begins 2 weeks later); repeat 8 Vincristine a Carboplatin b Note. +, administered;, not administered. a IV push 1.5 mg/m 2 (maximum 2 mg). b 175 mg/m 2 IV infusion.

5 500 J. A. Heath et al. TABLE 2 Treatment with TPCV(6-Thioguanine, Procarbazine, CCNU, and Vincristine) Chemotherapy Week Thioguanine a + Procarbazine b + CCNU c + Vincristine d + + Note. +, administered;, not administered. a Oral 30 mg/m 2 6-hourly for 12 doses. b Oral 50 mg/m 2 6-hourly for 4 doses. c Oral 110 mg/m 2. d IV push 1.5 mg/m 2 (maximum 2 mg). and only resumed at 66% dosage after symptoms improved to less than grade 2. Any patient who experienced an allergic reaction to carboplatin after receiving antihistamine and cortocosteroid premedication was switched to an alternative chemotherapy regimen of oral thioguanine, oral procarbazine, oral CCNU, and intravenous vincristine (TPCV) (Table 2). The initial and all subsequent cycles commenced after the ANC was > /L and platelets >100, /L. In cases of grade 3 or 4 hematological, renal, or liver toxicity, the doses of TPCV medications were reduced by 25% for subsequent cycles. Patients received up to 7 cycles of TPCV, depending on the total length of treatment and degree of myelosupression. Treatment was stopped if clinical or radiographic evidence of disease progression was documented. All patients and/or their responsible guardians provided written, informed consent for the treatment and all patients provided written assent to the treatment. Evaluation of Response All children had a complete physical and neurological examination prior to each course of chemotherapy. In addition, visual field testing was conducted every 3 months if clinically appropriate. An MRI scan of the tumor was undertaken every 3 months. Radiological response criteria were defined as follows: complete response (CR), the complete disappearance of tumor on imaging studies; partial response (PR), a reduction of 50% or more in tumor size, measured with maximum perpendicular diameters; minor response (MR), a reduction of at least 25% but less than 50% in tumor size; stable disease (SD), no change or a increase/decrease of less than 25% in tumor size; and progressive disease, any increase in tumor size greater than 25%. All radiographic studies were reviewed by one of the authors (TYP). Monitoring for toxicity included weekly complete blood counts and liver and renal

6 Chemotherapy for Low-Grade Gliomas in Children over 10 Years 501 function tests. In addition, repeat glomerular filtration rates and audiology were conducted every 3 months during treatment and initial follow-up. Statistical Analysis The primary objective of this review was to estimate the objective response rate (total number of CR, PR, and MR over total patients) of low-grade gliomas in children older than 10 years treated with chemotherapy. The secondary objective was to estimate the progression-free survival, measured from the date each patient was first administered chemotherapy to the date of excessive toxicity, progressive disease, death, or loss to follow-up. RESULTS From June 1999 to January 2001, seven consecutive children (5 boys, 2 girls) were treated with chemotherapy for progressive low-grade gliomas (Table 3). The median age at starting treatment was 14 years, 5 months (range 12 years, 9 months to 16 years, 3 months). At the time of this report, the median follow-up after initiation of chemotherapy was 32 months (range months). Response No child had a complete response to chemotherapy. Three patients had a partial response and 1 patient a minor response to chemotherapy, giving an overall objective response rate of 57%. Two patients showed this response after the completion of their induction therapy, while the other 2 showed continued shrinkage throughout the maintenance phase of therapy. A further 2 patients exhibited stable disease, resulting in an overall failure to progress rate of 86%. One patient (ganglioglioma) showed asymptomatic radiographic evidence of progression 3 months after commencing chemotherapy. He was subsequently taken off chemotherapy and treated with 5580 cgy TABLE 3 Clinical Characteristics of 7 Older Children Treated with Chemotherapy for Low-Grade Gliomas Age at Previous Time to Patient Sex treatment NF1 Diagnosis Site treatment progress 1 Female 12 y, 9 m Yes Glioma R optic nerve Nil 6 y, 9 m 2 Male 14 y, 9 m No Pilocytic L optic nerve Biopsy 1 y, 10 m 3 Male 14 y, 6 m No Ganglioglioma L temporal STR 2, 3y,8m 4 Female 12 y, 9 m No Pilocytic Brainstem STR 0 y, 3 m 5 Male 14 y, 5 m No Pilocytic Hypothalamic STR 4 y, 10 m 6 Male 16 y, 3 m No Pilocytic Hypothalamic Biopsy 0 a 7 Male 13 y, 2 m Yes Glioma Optic tract Nil 10 y, 2 m Note. y, years; m, months; STR, sub-total resection. a Patient was treated at the time of initial diagnosis.

7 502 J. A. Heath et al. TABLE 4 Clinical and Radiographic Evaluation of the Response to Chemotherapy in 7 Children Older Than 10 Years Treated with Chemotherapy for Low-Grade Gliomas Patient Cycles VC (I a ) TPCV (M b ) Before therapy (cm) After induction (cm) Therapy completed (cm) Response Follow-up c (months) PR PR PD SD MR SD PR 27 Note. Patient 2 suffered an asymptomatic radiographic progression at 31 months and 5s rece5v5ng f6ca3 5rrad5at56n. a Weeks of induction treatment. b Maintenance cycles. c Measured from commencement of therapy. focal irradiation with good effect. No patient with an optic tract tumor showed a deterioration on visual field testing and no child showed clinical neurologic deterioration while on chemotherapy. Five of 6 children with either an objective response to treatment or stable disease remain unchanged or improved at the time of submission of this report. One child (who initially had a partial response) showed asymptomatic radiologic progression 31 months after the commencement of chemotherapy and is currently being treated with 5580 cgy focal irradiation (Table 4). Toxicity In addition to the 10-week vincristine/carboplatin induction chemotherapy, a total of 29 vincristine/carboplatin maintenance cycles and 18 TPCV cycles were given. There were a total of 8 episodes of grade 3/4 hematologic toxicity in those patients receiving vincristine/carboplatin (Table 5). Three children had an allergic reaction to carboplatin (hives and/or bronchospasm) that was not responsive to premedication. This necessitated a switch to TPCV chemotherapy. Patients treated with TPCV after commencing on vincrisine/carboplatin suffered a total of 10 episodes of grade 3/4 TABLE 5 Worst Toxicity in 7 Children Older Than 10 Years Receiving Chemotherapy for Progressive Low-Grade Gliomas Number (/7) Number (/3) Hematological toxicity vincristine/carboplatin TPCV Grade 3 or 4 neutropenia 3 2 Grade 3 or 4 thrombocytopenia 0 2 Grade 3 or 4 anemia 1 0 Note. Carboplatin allergy = 3, vincristine neuropathy = 4.

8 Chemotherapy for Low-Grade Gliomas in Children over 10 Years 503 hematologic toxicity. Additionally, there were 5 episodes of vincristine-related neuropathy severe enough to require dose reduction. No patient experienced significant hearing loss or any impairment of renal or liver function throughout the treatment or in the follow-up period. No child has developed a second malignancy. DISCUSSION Based on this small series, children older than 10 years of age with progressive low-grade gliomas appear to have similar clinical response/disease stabilization rates to chemotherapy when compared to those reported in younger children. Of the 7 children treated in this retrospective study, 4 had an objective radiographic response to the chemotherapy and 2 more exhibited stable disease. Given previous experience showing there is no difference in disease control in patients who had a complete or partial response to chemotherapy compared to those who had a minor response or stable disease [6], our results are encouraging for the longer term. Previously, children less than 5 years treated with vincristine/carboplatin have been reported to have 3-year progression-free survival rates of 74 ± 7%, compared to a rate of 39 ± 21% for older children [6]. The reason for the poorer response in older children is not clear, and to date has not been corroborated in any subsequent study. In fact, older children with optic chiasm gliomas treated with carboplatin alone (560 mg/m 2 monthly) have been reported to have an 83% progression-free survival at 39 months [16]. While not all of our cohort have been followed for this length of time, the 2-year progression-free survival rate of 86% (n = 7) is not inconsistent with a positive long-term outcome. Only 1 of our 6 patients who initially showed a partial response has progressed 31 months after the commencement of chemotherapy. To date, the 2 patients with NF1 have avoided exposure to radiation therapy entirely. While the number is small, it may be an important finding, given the recognized susceptibility for malignant transformation in these patients [17]. Even if the relapse rate for the remaining patients were to increase with time, the delay in exposure to radiation therapy may still be a worthwhile endpoint. Clearly, more detailed studies of the age-related effects of radiation therapy will be needed to clarify this. It is of interest that the only tumor that progressed in spite of chemotherapy was the single case of ganglioglioma within the cohort. Whether this reflects an inherent biologic difference in the tumor remains to be seen, and is the subject of a separate ongoing evaluation. The 2 chemotherapy regimens used appeared to be well tolerated with only moderate and reversible toxicities observed. The high incidence of allergic reactions to carboplatin makes its use somewhat problematic, however. Our experience is very similar to that observed in younger children, where weekly exposure to intravenous carboplatin has been associated with allergic

9 504 J. A. Heath et al. reaction rates as high as 50% [18]. Fortunately, all 3 patients who switched over to TPCV were able to complete 18 months of chemotherapy and have not progressed to date. Clearly, the length of follow-up in this study is short; older children have been followed for between 25 and 42 months. This period of time may well be critical for the population under study, however, given that a delay in or omission of radiation through the period of puberty may well improve growth. Further follow-up will be required to determine whether treatment with chemotherapy has a longer term effect on tumor growth and if indeed a significant reduction in long-term morbidity can be achieved. We conclude that further prospective clinical trials examining the role of chemotherapy in the treatment of older children with progressive low-grade gliomas are warranted. REFERENCES 1. Giles FH, Consortium CBT. A study of childhood brain tumors based on surgical biopsies from ten North American institutions: sample description. Childhood Brain Tumor Consortium. J Neurooncol. 1988;6: Farwell JR, Dohrmann GJ, Flannery JT. Central nervous system tumors in children. Cancer. 1977;40: Fisher BJ, Bauman GS, Leighton CE, Stitt L, Cairncross JG, Macdonald DR. Low-grade gliomas in children: tumor volume response to radiation. J Neurosurg. 1998;88: Packer RJ, Meadows AT, Rorke LB, Goldwein JL, D Angio G. Long-term sequelae of cancer treatment on the central nervous system in childhood. Med Pediatr Oncol. 1987;15: Constine LS, Woolf PD, Cann D, et al. Hypothalamic pituitary dysfunction after radiation for brain tumors. N Engl J Med. 1993;328: Packer RJ, Sutton LN, Bilaniuk LT, et al. Treatment of chiasmatic/hypothalamic gliomas of childhood with chemotherapy: an update. Ann Neurol. 1988;23: Pons MA, Finlay JL, Walker RW, Puccetti D, Packer RJ, McElwain M. Chemotherapy with vincristine (VCR) and etoposide (VP-16) in children with low-grade astrocytoma. J Neurooncol. 1992;14: Kato T, Sawamura Y, Tada M, Ikeda J, Ishii N, Abe H. Cisplatin/vincristine chemotherapy for hypothalamic/visual pathway astrocytoms in young children. J Neurooncol. 1998;37: Kadota RP, Kun LE, Langston JW, et al. Cyclophosphamide for the treatment of progressive low-grade astrocytoma: a Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol. 1999;21: Walter AW, Gajjar A, Reardon DA, et al. Tamoxifen and carboplatin for children with low-grade gliomas: a pilot study at St. Jude Children s Research Hospital. J Pediatr Hematol Oncol. 2000;22: Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997;86: 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-oncology. 2000;2: Prados MD, Edwards MS, Rabbitt J, Lamborn K, Davis RL, Levin VA. Treatment of pediatric low-grade gliomas with a nitrosourea-based multiagent chemotherapy regimen. J Neurooncol. 1997;32: Ater JC, and Children s Cancer Group. Protocol A9952: chemotherapy for progressive low-grade astrocytoma in children less than ten years old. A Phase III Intergroup CCG/POG Study. 1997: al-mefty O, Kersh JE, Routh A, Smith RR. The long-term side effects of radiation therapy for benign brain tumors in adults. J Neurosurg. 1990;73: Aquino VM, Fort DW, Kamen BA. Carboplatin for the treatment of children with newly diagnosed optic chiasm gliomas: a phase II study. J Neurooncol. 1999;41: Korf BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000;5: Yu DY, Dahl GV, Shames RS, Fisher PG. Weekly dosing of carboplatin increases risk of allergy in children. J Pediatr Hematol Oncol. 2001;23:

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