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H S Friedman

Publications and source records attributed to H S Friedman.

At least 127 records · Page 7Linked to original sources
PubMed1996

Monitoring of neoadjuvant therapy response of soft-tissue and musculoskeletal sarcoma using fluorine-18-FDG PET.

UNLABELLED: The purpose of this study was to investigate the potential role of FDG-PET in the monitoring of neoadjuvant therapy of soft-tissue and musculoskeletal sarcomas. METHODS: Nine patients were studied. Neoadjuvant therapy consisted of either chemotherapy or combined radiotherapy and hyperthermia. The FDG-PET studies were obtained, when possible, prior to therapy, 1-3 wk after commencement of therapy, and prior to surgery after completion of neoadjuvant therapy. In two patients, all three studies were completed. The remainder of patients underwent one or two studies at varying timepoints. RESULTS: In tumors treated with combined radiotherapy and hyperthermia, well-defined regions of absent uptake developed within responsive tumors, correlating pathologically with necrosis. Following treatment, a peripheral rim of FDG accumulation was found to correlate pathologically with the formation of a fibrous pseudocapsule. In tumors treated with chemotherapy, FDG accumulation decreased more homogeneously throughout the tumor, in responsive cases. Despite 100% tumor cell kill in some patients, persistent tumor FDG uptake was observed which correlated pathologically with uptake within benign therapy-related fibrous tissue. Significant FDG accumulation was also observed at the site of an uncontaminated incisional biopsy. CONCLUSION: These initial results demonstrate changes in tumor accumulation of FDG during and after neoadjuvant therapy; these changes are dependent on the type of neoadjuvant therapy administered. Prominent FDG accumulation was observed in benign tissues both within and adjacent to the treated tumor.

Adolescent↗
PubMed1996

Intrathecal 131I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results.

We aimed to determine the maximum tolerated dose (MTD) of 131I-labeled 81C6 in patients with leptomeningeal neoplasms or brain tumor resection cavities with subarachnoid communication and to identify any objective responses. 81C6 is a murine IgG monoclonal antibody that reacts with tenascin in gliomas/carcinomas but does not react with normal adult brain. 131I-labeled 81C6 delivers intrathecal (IT) radiation to these neoplasms. This study was a Phase I trial in which patients were treated with a single IT dose of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating doses of 131I (starting dose, 40 mCi; 20 mCi escalations) on 10 mg 81C6. MTD is defined as the highest dose resulting in serious toxicity in no more than two of six patients. Serious toxicity is defined as grade III/IV nonhematological toxicity or major hematological toxicity. We treated 31 patients (8 pediatric and 23 adult). Eighteen had glioblastoma multiforme. Patients were treated with 131I doses from 40 to 100 mCi. Hematological toxicity was dose limiting and correlated with the administered 131I dose. No grade III/IV nonhematological toxicities were encountered. A partial response occurred in 1 patient and disease stabilization occurred in 13 (42%) of 31 patients. Twelve patients are alive (median follow-up, > 320 days); five are progression free >409 days median posttreatment. The MTD of a single IT administration of 131I-labeled 81C6 in adults is 80 mCi 131I-labeled 81C6. The MTD in pediatric patients was not reached at 131I doses up to 40 mCi normalized for body surface area.

Adolescent↗
PubMed1995

A structural basis for a phosphoramide mustard-induced DNA interstrand cross-link at 5'-d(GAC).

Phosphoramide mustard-induced DNA interstrand cross-links were studied both in vitro and by computer simulation. The local determinants for the formation of phosphoramide mustard-induced DNA interstrand cross-links were defined by using different pairs of synthetic oligonucleotide duplexes, each of which contained a single potentially cross-linkable site. Phosphoramide mustard was found to cross-link dG to dG at a 5'-d(GAC)-3'. The structural basis for the formation of this 1,3 cross-link was studied by molecular dynamics and quantum chemistry. Molecular dynamics indicated that the geometrical proximity of the binding sites also favored a 1,3 dG-to-dG linkage over a 1,2 dG-to-dG linkage in a 5'-d(GCC)-3' sequence. While the enthalpies of 1,2 and 1,3 mustard cross-linked DNA were found to be very close, a 1,3 structure was more flexible and may therefore be in a considerably higher entropic state.

Base Sequence↗
PubMed1995

Intraarterial administration of melphalan for treatment of intracranial human glioma xenografts in athymic rats.

Malignant gliomas will affect 15,000-17,000 Americans each year and carry a dismal prognosis. Adjuvant chemotherapy is hampered by inadequate drug delivery, systemic toxicity, and a markedly variable biological sensitivity. Intraarterial (i.a.) therapy may enhance selectivity by improving tumor drug delivery and reducing systemic toxicity. Using melphalan given i.a., we studied the therapy of intracranial human glioma xenografts in male athymic nude rats (mean weight, 300 g) which were inoculated intracerebrally with D-54 MG and D-456 MG. On Days 6 and 7 (D-54 MG) or Days 9 and 10 (D-456 MG), rats randomized by body weight and treated with single-dose melphalan given i.a. at 0.5 or 0.75 mg produced significantly higher median survival (D-54 MG, Days 33 and 32; D-456 MG, Days 52 and 54, respectively) compared with i.a. saline (D-54 MG, Day 14, P < 0.001; D-456 MG, Day 24, P = 0.000) or melphalan given i.v. at 0.75 mg and 0.9 mg (D-54 MG only; Day 19, P < 0.001; Day 23, P < 0.001, respectively) and at 0.5 and 0.75 mg (D-456 MG only; Day 26 for both doses, P = 0.00). Although a dose-dependent increase in median survival (D-54 MG, 0.25 mg, Day 18; 0.5 mg, Day 28.5; 0.75 mg, Day 32.5) was observed with i.a. administered melphalan, no significant difference was apparent between 0.5 and 0.75 mg in either tumor model (D-54 MG, P = 0.15; D-456 MG, P = 0.37). Toxicity studies in nontumor-bearing athymic rats yielded a maximum tolerated dose of 0.8 mg for i.a. administered melphalan. This dosage was superior in spite of different xenograft permeabilities (apparent mean blood-to-tissue transport [K] values for alpha-aminoisobutyric acid, 5.8 for D-54 MG and 1.3 for D-456 MG). Pharmacokinetic experiments demonstrated a significant first pass advantage for i.a. (versus i.v.) melphalan. The short plasma half-life, marked antiglioma activity, and lack of requirement for metabolic activation indicate that i.a. melphalan holds considerable promise for human glioma therapy.

Animals↗
PubMed1995

Activity of temozolomide in the treatment of central nervous system tumor xenografts.

The activity of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin- 4(3H)-one (temozolomide) in the treatment of a panel of xenografts derived from ependymoma, medulloblastoma, and childhood and adult high-grade glioma was evaluated in athymic nude mice bearing s.c. and intracranial tumors. Temozolomide administered daily for a total of five doses demonstrated marked activity against a panel of Mer+ xenografts despite marginal to moderate activity of 1,3-bis(2-chloroethyl)-1-nitrosourea. The growth delays produced by temozolomide in these xenografts were 1.8-7.5-fold greater than those produced by procarbazine. Although temozolomide demonstrated marginal activity against the Mer+ cell line D341 Med when a 5-day schedule was used, a high-dose 1-day schedule resulted in moderate activity. Temozolomide produced increases in median survival of 1285% (adult glioma D-54 MG), 323% (childhood glioma D-456 MG), and 68% (ependymoma D612 EP). Pretreatment of mice with O6-benzylguanine increased temozolomide-induced mortality, requiring reduction of the dosage from 1200 to 750 mg/m2 on the single-day regimen. O6-Benzylguanine pretreatment of mice bearing Mer+ D341 Med increased the growth delay of temozolomide, in duplicate experiments, from -3.1 to 4.8 and 1.1 to 4.9 days. These studies suggest that temozolomide may be active in the treatment of a broad spectrum of central nervous system cancers, including Mer+ tumors resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea.

Animals↗
PubMed1995

A phase II evaluation of thiotepa followed by other multiagent chemotherapy regimens in infants and young children with malignant brain tumors.

BACKGROUND: Chemotherapy may be used to delay the need for cranial irradiation in infants and young children with malignant central nervous system (CNS) tumors. The polyfunctional alkylator thiotepa (TT) possesses significant in vitro and in vivo activity in many central nervous system tumors. Before the introduction of a multiagent chemotherapy previously shown to be active in such tumors, thiotepa alone was evaluated in an upfront therapeutic window. METHODS: Twenty young children with CNS tumors (19 newly diagnosed, 1 recurrent) were treated with two cycles of TT before response evaluation. Patients on thiotepa without disease progression went on to receive further chemotherapy consisting of alternating cycles of cyclophosphamide plus vincristine, cisplatin plus etoposide, and further TT. Patients with disease progression received radiation therapy. RESULTS: Low objective rates of response and poor survival led to early study termination. Of 17 patients evaluable for response, 6 (35%) demonstrated disease progression during initial TT therapy. Only two objective responses were noted, both in patients with medulloblastoma. Among the 19 patients evaluable for survival, the overall and progression free survivals were 45% and 20%, respectively, at 3 years postdiagnosis. Myelosuppression was the dominant treatment-related toxicity. CONCLUSIONS: Although the numbers of patients were small, thiotepa as used in this study was associated with a poor objective response rate and an unacceptably high rate of disease progression. These results may be partly related to TT's significant myelosuppressive effects and the postponement of more effective chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25.

The high incidence of loss of chromosome 10 alleles in glioblastoma multiforme suggests the presence on this chromosome of a tumor suppressor gene that is important in glioma tumorigenesis and progression. Our initial deletion mapping studies using restriction fragment length polymorphism markers indicated a common deletion region in 10q24-qter. In an attempt to localize the deleted region further, we screened a panel of 117 gliomas for loss of heterozygosity for chromosome 10 loci using 10 microsatellite markers. Seventeen tumors showed partial loss of a copy of chromosome 10 and were further analysed using 28 additional microsatellite markers. Of these, 10 had terminal deletion in the q arm, three had deletions in both p and q arms, two contained interstitial deletion in 10q and two carried deletions in 10p. In the 15 tumors with deletions in 10q, the minimal overlapping deletion region was in distal 10q between markers D10S587 and D10S216. Loci D10S587 and D10S216 are approximately mapped to a 5 cM region in 10q25.1.

Brain Neoplasms↗
PubMed1995

Intrathecal administration of single-chain immunotoxin, LMB-7 [B3(Fv)-PE38], produces cures of carcinomatous meningitis in a rat model.

LMB-7 [B3(Fv)-PE38] is a single-chain immunotoxin constructed from the murine monoclonal antibody B3 and a truncated from of Pseudomonas exotoxin PE38. Antibody B3 recognizes a carbohydrate epitope found on solid tumors that frequently invade the intrathecal space and cause neoplastic meningitis. We tested the therapeutic value of intrathecally administered LMB-7 by using a model of human neoplastic meningitis in athymic rats. This model is representative of a clinical situation in that antibody B3 cross-reacts with a number of normal tissues that can be used to monitor potential systemic toxicity. Treatment was begun 3 days after A431 tumor implantation. Without treatment, the animals median survival was 10 days. Intrathecal administration of 10 micrograms of LMB-7 in 40 microliters on days 3, 5, and 7 produced 4 of 10 and 8 of 10 long-term survivors (> 170 days) in two experiments. Of the long-term survivors, 2 of 4 and 7 of 8 survivors had no microscopic evidence of tumor and were considered histologic cures. Lack of significant toxicity in the effective dose range and specificity make LMB-7 an excellent candidate for intrathecal treatment of neoplastic meningitis in humans.

Animals↗
PubMed1995

Lack of efficacy of postoperative chemotherapy and delayed radiation in very young children with pineoblastoma. Pediatric Oncology Group.

Eleven infants with pineoblastomas were treated with prolonged postoperative chemotherapy in an attempt to delay radiation and reduce neurotoxicity. These infants were part of the Pediatric Oncology Group infant brain tumor study but the outcome of infants with pineoblastomas was not previously reported. Ages ranged from 1 month to 35 months, with eight of 11 < or = 12 months at diagnosis. Four had + cytology and three had + myelograms at diagnosis. The majority had partial surgical resection (25-75% reduction in tumor) and 10 had shunts. Chemotherapy consisted of two 28-day cycles of cyclophosphamide plus vincristine, followed by one 28-day cycle of cisplatin plus etoposide. Craniospinal radiation was planned following completion of either 2 years of chemotherapy (children less than 24 months at diagnosis) or following one year (children 24-36 months at diagnosis). Neuroimaging results following two cycles of cyclophosphamide and vincristine were one partial response, five stable disease, and five progressive disease. There were no responders in the leptomeninges. All children ultimately failed chemotherapy (2 months-11 months). Nine failed in the primary site. Of those eight children in whom a metastatic workup was performed at time of progression, all had evidence of leptomeningeal disease. Six received radiation following failure on chemotherapy. All failed either in the primary site, leptomeninges or extraneurally (peritoneal cavity). All children died. Survival following diagnosis ranged from 4 months to 13 months. This chemotherapy regimen was neither effective in controlling tumor in the primary site nor in treating or preventing leptomeningeal spread.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Hematologic toxicity during craniospinal irradiation: the impact of prior chemotherapy.

The purpose of this work was to determine the frequency of hematologic toxicity during craniospinal radiation (CSI) and the impact of preirradiation chemotherapy on this frequency. The charts of 37 patients who received CSI were reviewed. Twenty did not have prior chemotherapy (CT-), while 17 did receive 1 to 18 (mean 5) cycles of multi-agent systemic chemotherapy (CT+). Leukopenia/thrombocytopenia necessitating treatment interruptions occurred in 1/20 (5%) in the CT- group, compared to 8/17 (47%) among the CT+ group. This difference was statistically significant, P < 0.0001 (Fisher's exact two-tailed test). The duration of treatment interruption in the CT+ patients was 4-24 days (mean 14). Compared to the CT- group, the CT+ group had a statistically significant greater decline in their white blood cell count (WBC), platelet count, and hematocrit (HCT) during CSI (percent reduction per Gy; (P = 0.018, 0.006, and 0.047, respectively). Although not statistically significant, the CT+ group also experienced lower nadir ratios (nadir count/baseline count) in terms of WBC and platelets (P = 0.07 and 0.22, respectively). While the mean pretreatment baseline blood counts were lower in the CT+ group compared to the CT- group, these differences reached statistical significance for the HCT (P = 0.02), but not the WBC (P = 0.59) or platelets (P = 0.43). Leukopenia and thrombocytopenia are very common in patients who receive craniospinal irradiation following multi-agent systemic chemotherapy. This appears to be due to more rapid and marked reductions in counts during CSI. Since this toxicity may cause treatment interruptions that are potentially therapeutically disadvantageous, aggressive hematologic support with transfusions and growth factors may be necessary. This problem may become more common as combined modality therapy is used more frequently.

Adolescent↗
PubMed1995

The effect of L-amino acid oxidase on activity of melphalan against an intracranial xenograft.

We have previously shown that diet restriction-induced depletion of large neutral amino acids (LNAAs) in murine plasma to 46% of control significantly enhances intracranial delivery of melphalan without enhancing delivery to other organs. Studies have now been conducted to determine whether more substantial LNAA depletion could further enhance intracranial delivery of melphalan. Treatment with L-amino acid oxidase (LOX) significantly depleted murine plasma LNAAs: phenylalanine, leucine, and tyrosine (> 95%); methionine (83%); isoleucine (70%); and valine (46%). Experiments evaluating the intracellular uptake of melphalan and high-pressure liquid chromatography quantitation of melphalan metabolites revealed, however, that melphalan is rapidly degraded in the presence of LOX, and that the timing of the administration of melphalan following the use of LOX to deplete LNAAs is crucial. Conditions were found under which LOX-mediated degradation of melphalan was minimized and LNAA depletion was maximized, resulting in a potentiation of the antitumor effect of melphalan on human glioma xenografts in nude mice. Such potentiation could not be obtained using diet restriction alone.

Amino Acid Oxidoreductases↗
PubMed1995

Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors.

The efficacy of protracted schedules of therapy of the topoisomerase I inhibitors 9-dimethyl-aminomethyl-10-hydroxycamptothecin (topotecan) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (irinotecan; CPT-11) were evaluated against a panel of 21 human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas, representing an intrinsically chemorefractory malignancy, six lines derived from childhood rhabdomyosarcoma (three embryonal, three alveolar) representing a chemoresponsive histiotype, sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine and melphalan, and three pediatric brain tumors. All tumors were grown at the subcutaneous site. Topotecan was administered by oral gavage 5 days per week for 12 consecutive weeks. The maximum tolerated dose (MTD) was 1.5 mg/kg per dose. Irinotecan was given by i.v. administration daily for 5 days each week for 2 weeks [(d x 5)2](one cycle of therapy), repeated every 21 days. The MTD for three cycles was 10 mg/kg per dose. Treatment was started against advanced tumors. Topotecan caused a high frequency of objective regressions in one of eight colon tumor lines, whereas irinotecan caused complete regressions (CR) of all tumors in three colon lines and a high frequency of CRs in three additional lines. Both drugs demonstrated similar activity against rhabdomyosarcoma xenografts. Topotecan caused CR of all tumors in four of six lines, and irinotecan in five of six lines evaluated. Both agents retained full activity against tumors selected for primary resistance to vincristine, but only irinotecan retained activity against a tumor selected for primary resistance to melphalan. Both agents demonstrated good activity against brain tumor xenografts with irinotecan causing CR in two of three lines and topotecan inducing CR in one of three lines. Results indicate that low-dose protracted schedules of daily administration of these topoisomerase I inhibitors is either equi-effective or more efficacious than more intense shorter schedules of administration reported previously.

Adenocarcinoma↗
PubMed1995

Prognostic implications of chromosome 17p deletions in human medulloblastomas.

DNA derived from medulloblastoma biopsies was analyzed to determine if deletions of the 17p region, mutations of the TP53 gene, or amplification of the c-myc, N-myc, EGFR (epidermal growth factor receptor), or MDM2 (murine double-minute-2) genes was indicative of a poor prognosis. Loss of heterozygosity for 17p, observed in 8/28 (29%) paired samples, was associated with a shortened survival period (p = 0.045 by the logrank test). TP53 mutations occurred in 2/46 (4.3%) tumor samples. c-myc Amplification was seen in 3/43 (6.9%) cases, while none of the tumors contained amplified N-myc, EGFR, or MDM2 genes. These results demonstrate that, while only rare medulloblastomas contain TP53 gene mutations or amplification of the c-myc gene, loss of heterozygosity on chromosome 17p is indicative of a significantly worse prognosis among patients with these tumors. Further, these results provide a strong impetus for a prospective analysis of loss of heterozygosity in a cooperative group setting, which would include tumor staging, a selection of treatment modalities, and multivariate analyses.

Adolescent↗
PubMed1995

Cyclophosphamide therapy of medulloblastoma: from the laboratory to the clinic and back again (and again and again).

Medulloblastoma, the most common malignancy of childhood, was originally shown to be sensitive to cyclophosphamide in 1981. We have used combined laboratory and clinical investigations to demonstrate the synergy of cyclophosphamide and vincristine in the treatment of this tumor, the therapeutic gain associated with escalation of the dosage of cyclophosphamide, the consequence of and mechanisms underlying resistance of medulloblastoma to cyclophosphamide, the emerging importance of the neuraxis as a site of relapse of medulloblastoma, and newer approaches, including intrathecal 4-hydroperoxycyclophosphamide and busulfan, to treat neuraxis disease. These studies serve as a paradigm for laboratory-clinical translational research.

Animals↗
PubMed1995

Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab')2--a preliminary report.

The advent of monoclonal antibody (MAb) technology has made Ehrlich's postulate of the 'magic bullet' an attainable goal. Although specific localization of polyvalent antibodies to human gliomas was demonstrated in the 1960s, the lack of specific, high affinity antibody populations and of defined target antigens of sufficient density precluded therapeutic applications. Not until the identification of operationally specific tumor-associated antigens (present in tumor tissue but not normal central nervous system tissue); production of homogeneous, high affinity MAbs to such antigens; and the use of compartmental administration (intrathecal or intracystic), has the promise of passive immunotherapy of primary and metastatic central nervous system neoplasms been recognized. We report here preliminary data from Phase I studies of the compartmental administration of the anti-tenascin MAb 81C6 and F(ab2)2 fragments of MAb Me1-14, which recognizes the proteoglycan chondroitin sulfate-associated protein of gliomas and melanomas, to patients with primary central nervous system tumors or tumors metastatic to the central nervous system. Phase I dose escalation studies of intracystically administered 131I-labeled anti-tenascin MAb 81C6 to either spontaneous cysts of recurrent gliomas or surgically created cystic resection cavities have resulted in striking responses. Of five patients with recurrent cystic gliomas treated, four had partial responses, clinically or radiographically. Similarly, in patients with surgically created resection cavities, a partial response at the treatment site and extended stable disease status has been obtained following intracystic administration of 131I-labeled 81C6. No evidence of hematologic or neurologic toxicity has been observed in either patient population, with the exception of transient exacerbation of a pre-existing seizure disorder in a single patient. Dosimetry calculations indicated high intracystic retention for four to six weeks with little or no systemic dissemination; estimated total doses intracystically ranged from 12,700-70,290 rad. Intrathecal administration of labeled MAbs to patients with neoplastic meningitis is more difficult to assess in terms of clinical responsiveness. Of patients so treated with either 131I-labeled 81C6 or 131I-labeled Me1-14 (F(ab)2, cerebrospinal fluid and radiographic responses have been achieved, and survival prolongation through maintenance of stable disease has been observed in several cases. Initial results from pHase I dose escalation trials are encouraging in terms of the proportion of cases of disease stabilization and partial and complete responses obtained. Importantly, neurotoxicity has been virtually nonexistent, and hematologic toxicity rare and rapidly responsive to treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Meta-[131I]iodobenzylguanidine uptake and meta-[211At]astatobenzylguanidine treatment in human medulloblastoma cell lines.

Uptake of radioiodinated meta-iodobenzylguanidine (MIBG) has been demonstrated in the neural crest tumors, including neuroblastoma, pheochromocytoma, and carcinoid tumors, and is presently in use diagnostically and therapeutically in these settings. Cells comprising medulloblastoma, the most common central nervous system malignancy in childhood, may be derived from a common germinal neuroepithelial cell as neural crest tissue, and as a result, also may have the capacity for accumulating MIBG. To investigate this hypothesis, we measured the in vitro binding of [131I]MIBG to 9 medulloblastoma-derived cell lines and the SK-N-SH neuroblastoma line known to accumulate MIBG. Seven of the medulloblastoma lines exhibited MIBG binding. The cell line with the greatest uptake, D384 Med, bound 11.2 +/- 0.9% of added [131I]MIBG activity compared with 47.1 +/- 2.3% for the SK-N-SH cell line. When 2 of the cell lines, D384 Med and D458 Med, were treated with the alpha-particle emitting analogue meta-[211At]astatobenzylguanidine ([211At]MABG), as much as a 3-log cell kill was observed in limiting dilution clonogenic assays. Exposure to considerably higher activity levels of [211At]astatide was required to achieve a similar degree of cell kill, suggesting that this cytotoxicity was not related to nonspecific effects of alpha-particle irradiation. We conclude that the uptake capacity of medulloblastoma cell lines for [131I]MIBG uptake in vitro, while lower than that seen in SK-N-SH neuroblastoma cells, is sufficient to permit [211At]MABG to be used with significant therapeutic effectiveness.

3-Iodobenzylguanidine↗
PubMed1995

A phase II study of every other day high-dose ifosfamide in pediatric brain tumors: a Pediatric Oncology Group Study.

Despite reported activity in many other solid tumors, high-dose ifosfamide produces few objective responses in recurrent pediatric brain tumors. Alkylating agents such as cyclophosphamide (CYCLO) possess good activity in many of solid tumors, including brain tumors. Although Ifosfamide (IFOS), a structural congener of CYCLO, has been suggested to have greater activity in several tumors, its activity in brain tumors is uncertain. We conducted a phase II trial of every-other day IFOS (3 gm/M2/qod x 3) in 87 recurrent pediatric brain tumors. Responses were evaluable in 71 patients. Partial responses occurred in 1/6 patients with low grade astrocytoma, 1/16 with malignant glioma, 1/16 with medulloblastoma, 1/3 with pineoblastoma and 1/12 patients with ependymoma. No responses occurred among 10 patients with brain stem gliomas or 8 patients with other brain tumors. Despite the poor objective response rate, 23/71 patients were clinically and imaging stable for periods of 8-62 weeks. There was no relationship between prior CYCLO treatment and subsequent response or failure with IFOS. The predominant toxicity was myelosuppression. Although generally reversible, prolonged suppression and sepsis were responsible for the deaths of 3 heavily pretreated patients. Renal toxicity was uncommon; 2 patients had grade III, and one grade IV renal tubular dysfunction. One patient had grade IV hematuria. Neurotoxicity was less common than in studies of daily ifosfamide; only 1 patient had grade IV neurotoxicity. Three patients had grade III or IV IFOS related hyponatremia. Despite the good stable disease rate, the poor rate of objective response suggests that IFOS monotherapy possesses little clinically meaningful activity in brain tumors.

Adolescent↗