Salvage Chemotherapy for Recurrent Primary Brain Tumors in Children
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Salvage chemotherapy for recurrent primary brain tumors in children Jan van Eys, PhD, MD, Tallie Z. Baram, MD, PhD, Ayten Cangir, MD, Janet M. Bruner, MD, and J. Martinez-Prieto, MD From the Departments of Pediatrics, Neurooncology, and Pathology, The Universityof Texas M, D. Anderson Cancer Center at Houston Sixty consecutive evaluable children with recurrent primary tumors of the central nervous system were treated with a regimen of vincristine, nitrogen mustard, procarbazine, and prednisone over a 12-year period. Tumor types included medulloblastoma (19), brain-stem glioma (16), astrocytoma (13), and a miscellaneous glioma (12). Responses and sustained survivals were achieved. Responses were highly dependent on tumor type. Disease progres- sion was halted in 73% of the children with medulloblastoma, and three have survived in complete remission for more than 10 years from the start of therapy with vincristine, nitrogen mustard, procarbazine, and prednisone. Two of four patients with anaplastic glioma, are long-term survivors. In contrast, less than one third of children with brain-stem gliomas responded. Toxicity consisted mainly of neutropenia, thrombocytopenia, infections, and rarely a procarba- zine rash. (J PEDIAI'R1988;113:601-6) Therapy for recurrent brain tumors in children remains METHODS unsatisfactory; most die of their disease regardless of Patients. Sixty-five children with a median age of 6 therapy, l We have repbrted on the responsiveness of years (range, 1 to 16 years) were treated with MOPP for recurrent brain tumors in children to chemotherapy with recurrent brain tumors. Sixty patients were eligible for vincristine, nitrogen mustard, procarbazine, and predni- evaluation; the other five patients were excluded because 1 sone. 2 A later prospective randomized trial confirmed the died before completion of the first MOPP course, the contribution of nitrogen mustard, although because of the ! greater toxicity, no difference in survival was observed CT Computed tomography [ between the two treatment regimens. 3 Since then we have MOPP Nitrogen mustard, vincristine, procarbazine extended the use of MOPP to primary therapy for infants and prednisone with brain tumors in whom radiotherapy may result in devastating sequelae. 4 The efficacy of MOPP as primary records of two others were not available, and two patients therapy for infants with medulloblastomas after surgery received intrathecal methotrexate concurrently with has been established. 5 MOPP. All patients had failed to respond to primary We now report on our experience of more than 10 years therapy consisting of either surgery, radiation, or both. with MOPP as salvage therapy for recurrent brain tumors Thirteen patients had also failed to respond to a previous in children. Our experience allows assessment of the chemotherapy regimen for tumor recurrence. Previous comparative responsiveness of different tumor types and chemotherapy consisted of one or more of the following shows the durability of the response in some children with drugs: vincristine, lomustine, methotrexate (systemic, medulloblastoma. A preliminary report has appeared. ~ intrathecal, or both), etoposide, and cisplatin. The distribution of tumor type6 and patients' ages and Reprint requests: Jan van Eys, PhD, MD, Department of Pediat- gender are listed in Table I. Tissue diagnoses were avail- rics, The University of Texas M.D. Anderson Hospital and Tumor able for all patients with medull0blastomas but for only 5 Institute, 1515 Holcombe Blvd., Houston, TX 77030. of 16 of those with brain-stem gliomas. Among the group 601 6 0 ~Z Van Eys et al. The Journal of Pediatrics September 1988 1.0, 0.9- 0.9 0.8 0.? O. 7 1 ---~ O. 6 (jt~ ^^ , r~ 0.5- t-- 0.5 vv ._o ~ ~,,~. "2 "1~ 0.4. o e.~ o.4. .o 13- o.s. 0.3 v v ~' 0.2. 7-7 0.1' 0.1 1 0.0' 10 ;tO 311 40 50 $0 70 I10 00 I00 I10 1211 1~10 140 150 0.0' , • , • , - , • , • , • , - i • i • , • i • , - , • , • i . i - i 10 20 30 '10 50 6(; "/0 80 90 lO0 110 120 130 140 150 160 Time in months Time in months Fig. 2. Meier-Kaplan curve for survival from initiation of Fig. t. Meier-Kaplan curve for survival from the time of diagno- MOPP therapy in patients with medulloblastomas (square), glio- sis in patients with medulloblastomas (square), gliomas (circle), mas (circle), brain-stem gliomas (diamond), and miscellaneous brain-stem gliomas (diamond), and miscellaneous tumors (star). tumors (star). Table I. Characteristics of patients treated with salvage MOPP regimen Gender Mean age at diagnosis Tumor type No. (range, yr) M F Medulloblastoma 19 7 (11/12-12) 16 3 Brain-stem glioma 16 7 (21/2-3½) 6 10 Astrocytoma 13 11 (7-15) 7 6 Glioblastoma mnltiforme 4 11 (7-13½) 3 1 Mixed glioma, anaplastic 4 lO (7-12) 1 3 Pilocytic/ganglioglioma/unknown 5 13 (12-15) 3 2 Miscellaneous 12 5 (9/12-15) 4 8 Ependymoma 4 8 (3-15) I 3 Primitive neuroectodermal 4 4 (8/12-12) 3 1 One case each of meningeal sarcoma, 4 6 (9/12-13) 0 4 malignant meningioma, embryonal carcinoma, choroid plexus carcinoma with astrocytomas, five patients had glioblastoma multi- group of miscellaneous tumors included four ependymo- forme (World Health Organization criteria), 7 two had mas (one with ependymoblastoma features), four supra- anaplastic astrocytomas, two had mixed gliomas with an tentorial primitive neuroectodermal tumors, two of the aggressive astrocytic component, two had pilocytic tumors, pineal region, one meningeal sarcoma, one malignant and one had a ganglioglioma. In two cases of aggressive meningioma, one choroid plexus carcinoma, and one thalamic lesions, no tissue specimens were available. The embryonal carcinoma. Two patients with medulloblasto- Volume 113 MOPP for recurren t brain tumor# 6 0 3 Number 3 Table II. MOPP regimen*: Twenty-eight-day cycles for 2 years o.g. Dosage Drug (rng/m 2) Cycl e 1].8. Nitrogen mustard 6 Days 1, 8 Vincristin e 1.4 Days I, 8 "~ 1]. 7- Procarbazine 100 Days 1-I0 (/] Prednisone 40 Days 1-10, then tapered ~ 0.15. el. *Dose modificationfor hematopoietietoxicity: Leukocytes, 3000 to 00.5- 4000/mm3: 50% of procarbazine and nitrogen mustard. Platelets r- >100,000/mm3 and leukocytes, 2000 to 3000/mm3:25% of procarbazine and nitrogen mustard. Leukocytes, 1000 to 2000/mm3:no procarbazine e 1].4. 0 or nitrogen mustard and 50% of vincristine. Platelets, 50,000 to ~2 100,000Jmm3: 100% of vincristine and 25% of nitrogen mustard, no 0 procarbazine. Platelets <50,000/mm3:no therapy. mas had extraneural metastases, and seven had malignant cells in the Subarachnoid Space. Leptomeningeal 'spread was also documented in two patients with ependymoma and in two with primitive neuroectodermal tumors. O 10 2(] 30 40 50 16[] 70 80 go 100 It0 121] 1]0 140 IS0 Treatment. Before they began MOPP therapy, all Time in months Patients had complete clinical evaluations that included functional status and neuro!ogic examination. The need for Fig. 3. Time to tumor progression on MOPP therapy for patients with medulloblastomas (square), 'gliomas (circle), brain- steroids and the dosages given were recorded in each case. stem gliomas (diamond), and miscellaneous tumors (star). If dexamethasone (Decadron) was initially necessary, prednisone was omitted. Each patient had a computerized axial tomography scan of the brain. Cerebrospinal fluid was examined for malignant cells whenever required and regression (measured as sum of perpendicular diameters). permitted bY neurologic status. Laboratory examinations Stable disease or improvement is defined by tumor mass include d complete blood cell counts plus hepatic and renal reduction of <50% as already defined. Progressive disease function tests. is an increase in tumor mas s by >25%. All patients were treated with the standard MOPP These radiographic criteria are not useful for evalua- chemotherapy regimen every 28 days. The regimen was tions of brain-stem glioma. 7 Therefore for this patient modified for myelosuppression (Table II). Treatment was group, we used a combination of neurol0gi c and function continued for 2 years or until disease progression devel- status, steroid dependence, and CT appearance/ oped, whichever occurred first. Patients were followed (including full neurologic exam- RESULTS ination and CT scans of the brain) at regular intervals, Responses of patients with various tumor types to usually every 3 months, or whenever symptoms recurred. MOPP therapy are shown in Table ili. Survival from Blood counts were performed at weekly intervals early in diagnosis and initiation of therapy and time to tumor the course of treatment and then twice monthly. progression are depicted in Figs. 1 to 5. Disease progres- The Kaplan-Meier method was used to generate actuar- sion was halted in 14 of19 patients with medulloblasto- ial curves of Survival from diagnosis, survival from initia- mas. Mean time to tumor progression in 13 patients wile tion of MOPP therapy, and time to tumor progression had a relapse was 6 months (Fig. 3); yet of 12 patients from start of the therapy. followed up for more than 5 years from initiation of MOPP Response was defined according to the criteria recom- therapy, three have survived in complete c!inical remission mended by the American Cancer Society workshop at (12, 10, and t9 years, ~respetgively) (Fig. 2). MOPP Niagara Falls, 7 which are different from those used previ- therapy eliminated malignant cells in only one of seven ouslY by us. Complete response is absence of tumor on CT patients with medulloblastoma with leptomeningeal spread scan and in cerebrospinal fluid studies when applicable; and positive cytologic findings~ Of cerebrospinal fluid. In partial response is CT evidence of 50% tumor mass two patients with extraneural metastases, a femoral lesion 6 0 4 Van Eys et al. The Journal of Pediatrics September 1988 1.0. 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