Progressive Brain Tumors Research Articles

A volumetric study of CyberKnife hypofractionated stereotactic radiotherapy as salvage for progressive malignant brain tumors: initial experience

Objective: Radiosurgery is frequently offered to patients with progressive malignant brain tumors if radiation therapy or chemotherapy fails to provide local control. The use of single-shot regimens, however, is limited by the risk of complications when the tumor is large, surrounded by edema or has been pre-treated with radiation. Hypofractionation may confer safety but has not been tested for these difficult tumors. We report the results of hypofractionation as an alternative option in a small cohort of progressive malignant brain tumors.Methods: Hypofractionated CyberKnife radiotherapy was chosen for 18 progressive malignant brain tumors (six high-grade gliomas and 12 metastatic lesions) in 15 patients because of size, previous treatment with radiation or surrounding edema. The mean dose was 21 ± 4 Gy and the number of fractions was 5 ± 0.6. The volume of each tumor at treatment was compared with the volume at follow-up.Results: Thirteen of the 18 tumors (72%) showed a volume decrease. The average volume change was a decrease of 16 ± 58% (median: 20%) with a follow-up of 180 ± 121 days (median: 172 days). Toxicity occurred in only one patient, with symptoms improving on steroids.Discussion: Progression of malignant brain tumors not ideal for single-shot radiosurgery can be arrested or reversed, at least for short periods, with minimal toxicity using hypofractionated radiotherapy. Longer studies will be needed to assess durability of this response in these difficult tumors.

Phase I and Pharmacokinetic Study of the Oral Farnesyltransferase Inhibitor Lonafarnib Administered Twice Daily to Pediatric Patients With Advanced Central Nervous System Tumors Using a Modified Continuous Reassessment Method: A Pediatric Brain Tumor Consortium Study

A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib (SCH66336) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.

Irinotecan and bevacizumab in progressive primary brain tumors: The Cleveland Clinic experience

2077 Background: High-grade gliomas are generally resistant to modern chemotherapy. In the case of glioblastoma multiforme, median overall survival has been less than 12 months and progression free survival of less than 4 months. For patients with recurrent GBMs, the 6 month progression free survival is 15–20%. The combination of irinotecan and bevacizumab is an active regimen in the treatment of this disease. Herein we report the experiences with this regimen at our institution with the objective of identifying a therapy with a better outcome than historical results. Methods: Single institutional, retrospective review of 27 patients with recurrent or progressive high grade gliomas treated at the Cleveland Clinic Brain Tumor Institute from 7/2005 through 10/2006. Patients had progressed on at least one prior chemotherapy. Patients with prior irinotecan or bevacizumab were excluded. Patients were analyzed on an intention-to-treat basis, and outcomes estimated by the Kaplan-Meier method. Results: The median age of the group was 46 years (range 5–69). The median number of prior therapies was 2 (range 1–10). Twenty of 27 patients have progressed (74%), and 11 of 27 patients have died (41%). Kaplan-Meier estimates for outcomes are summarized in the table . Progression-free survival at 6 months is 46 %, with median of 5.1 months. Overall survival at 6 months is 84%, with median of 12.6 months. In 7 patients, treatment was terminated early prior to progression. Significant toxicities include: one patient who developed hematuria, one patient with deep venous thrombosis and one patient who experienced intracranial hemorrhage. Conclusions: Our experience suggests that the combination of irinotecan and bevacizumab improves the 6-month progression-free survival when compared to historical figures. The rate of severe toxicities is consistent with prior reports and mandates careful selection of patients. Further randomized, phase 3 studies should be done to validate these results. [Table: see text] No significant financial relationships to disclose.

Determination of Cloretazine™ (VNP40101M) and its active metabolite (VNP4090CE) in human plasma by liquid chromatography electrospray tandem mass spectrometry (LC–ESI-MS/MS)

A sensitive method for the determination of Cloretazine™ (VNP40101M) and its metabolite (VNP4090CE) with an internal standard (ISTD) in human plasma was developed using high-performance liquid chromatographic separation with tandem mass spectrometric detection. Acidified plasma samples (500μL) were prepared using solid phase extraction (SPE) columns, and 25μL of the reconstituted sample was injected onto an Ascentis C18 HPLC column (3μm, 5cm×2.1mm) with an isocratic mobile phase. Analytes were detected with an API-3000 LC–MS/MS System at unit (Q1) and low (Q3) resolution in negative multiple reaction monitoring mode: m/z 249.0 (precursor ion) to m/z 114.9 (product ion) for both Cloretazine™ (at 3.64min) and VNP4090CE (at 2.91min), and m/z 253.0 (precursor ion) to m/z 116.9 (product ion) for the ISTD. The mean recovery for Cloretazine™ (VNP40101M) and its metabolite (VNP4090CE) was greater than 87% with a lower limit of quantification of 1.0ng/mL for Cloretazine™ (S/N=9.7, CV≤12%) and 0.5ng/mL for VNP4090CE (S/N=11.3, CV≤9.7%). This method was validated over a linear range of 1.0–1000ng/mL for Cloretazine™ and 0.5–100ng/mL for VNP4090CE, and results from a five day validation study demonstrated good within-day and between-day precision and accuracy. This method has been used to measure plasma Cloretazine™ and its metabolite concentrations in a Phase I study in children with recurrent progressive or refractory primary brain tumors.

Temozolomide (TMZ) for progressive primitive brain tumors: safety at 75 mg/m2 a day for 21 days every 28: A GICNO (Italian Neuro-Oncology Group) study

1541 Background: The activity of TMZ, at a standard schedule of 200 mg/m2 for five-days every 28, appears encouraging in patients with relapsed and newly diagnosed malignant gliomas. A continuous dose schedule of TMZ leads to DNA repair enzyme AGAT level depletion in tumor cells. AGAT, by removing TMZ-produced methyl adducts, contributes to the development of resistance to alkylating agents. The aim of the present study was therefore to determine the safety of continuous low-dose TMZ administration. Methods: From November 2003 to October 2004, 55 patients (34 male; mean age 52, range 28–71 years) with progressive brain tumors had oral TMZ 75 mg/m2 for 21 consecutive days, every 28. Forty-six pts (83.6%) had prior RT; 46 were chemo-naïve. Results: A total of 237 (median 4; range, 1–13) cycles were delivered. G2 and G3 toxicity were: lymphopenia, 27.5 and 17.6%; neutropenia, 1.9 and 3.9%; thrombocytopenia, 5.9% and 0; nausea, 3.6 and 3.6%; hepatic 3.6 and 1.8%, respectively. Two patients (3.6%) had reversible renal toxicity G1, and one, (1.8%) G2; one (1.8%) had prolonged G4 neutropenia; none had pneumocisti carinii pneumonia. TMZ was discontinued in 1 case (1.8%) due to G2 skin allergy. Seven (12.7%) patients converted to standard schedule TMZ: 1 had G2 renal toxicity which resolved and did not recur with standard schedule TMZ; 2, prolonged G2 thrombocytopenia and G3 neutropenia, respectively; 4 refused to continue with the continuous schedule. Conclusions: Continuous low-dose TMZ has an acceptable safety profile, but can incur renal reversible G1-G2 toxicity and cumulative lymphopenia. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough

Spectroscopic and perfusion magnetic resonance imaging predictors of progression in pediatric brain tumors.

In vivo biomarkers to predict progression of brain tumors are of great value in clinical practice. Therefore, the authors tested the hypothesis that changes in choline ratios by magnetic resonance (MR) spectroscopic imaging and/or relative tumor blood volume (rTBV) can differentiate clinically stable from progressive pediatric brain tumors. MR spectroscopic imaging examinations were performed on 27 children with neuroglial brain tumors during therapy on a 1.5-Tesla MR system. Normalized rTBV values were measured in 11 of 27 patients. Each examination was rated as stable or progressive by clinical and imaging criteria. The percent change in normalized choline (Cho) was significantly greater in patients who had progressive examinations compared with patients who had stable examinations (P = 0.03). The percent change in Cho/N-acetylaspartate (Cho/NAA) was significantly higher in patients who had progressive outcomes (n = 18 patients) compared with patients who had stable outcomes (n = 32 patients; P < 0.001; sensitivity, 0.89; specificity, 0.88) and was identified as the most important prognostic indicator of tumor progression by logistic regression (likelihood ratio test, 33.4; P < 0.001). The odds of tumor progression were approximately 55 times greater for patients who showed at least a 20% change in Cho/NAA. rTBV distinguished between progressing and stable tumors (P = 0.03), and Cho/NAA and rTBV values showed interaction to predict the probability of a progressing clinical outcome. The percent change in Cho/NAA by proton MR spectroscopic imaging, assisted by rTBV, was useful in predicting tumor progression in children with brain tumors.

Safety and efficacy of concurrent interstitial radiation and hyperthermia in the treatment of progressive malignant brain tumors

High activity 125I brachytherapy has efficacy in selected recurrent malignant brain tumors, but limited efficacy and risk of radiation necrosis have prompted investigation of additional adjunctive therapies. This study aims to assess the toxicity of interstitial conductive hyperthermia used concurrently with 125I brachytherapy for the treatment of recurrent brain malignancies. Twelve patients with recurrent malignant brain tumors were implanted using afterloading catheters intended to deliver 50 Gy at the isodose line encompassing the enhancing tumor with a 5-mm margin and heated to 41.5 degrees C for 48 h. The average implant volume was 18 cc with 5.3 catheters containing 9.4 sources with a total activity of 265 mCi. Serious toxicities included 8 motor deficits, 2 mood alterations, 4 seizures and 2 catheter wound cerebrospinal fluid leaks. Median survival was 10.35 months with the best responses being 6 with stable disease and 2 with partial responses. Reoperation rate for radiation necrosis was 33%. Concurrent conductive thermoradiotherapy is feasible but is associated with serious toxicity. There is no suggestion of improved survival with thermoradiotherapy over brachytherapy alone. Given the degree of toxicity observed, alternative approaches to improving local control of these tumors are being explored.

Second-line chemotherapy with the association of liposomal daunorubicin, carboplatin and etoposide in children with recurrent malignant brain tumors.

Progressive or recurrent high-grade gliomas are characterized by a very poor prognosis, and the relevance of second-line chemotherapy is still unassessed. Although it has been reported that liposomal anthracyclines and carboplatin show some activity in these patients, their association has never been investigated. We have treated six children with recurrent high-grade glioma after surgery, radiotherapy and chemotherapy, and one child with progressive teratoid/rhabdoid tumor with the combination of liposomal daunorubicin and carboplatin plus etoposide. Five out of seven children showed a major response and the 29 month progression-free survival was 38%. The above regimen was feasible and children showed only little and transient hematological toxicity. In our opinion, these results justify further investigation of the above combination chemotherapy for recurrent or progressive malignant brain tumors in children.

Interleukin-12-mediated induction of systemic immunity in the periphery and recruitment of activated T cells into the brain produce limited antitumor effects compared with interleukin-2

Interleukin-12 (IL-12) stimulates the type 1 helper T (Th1) cell responses and augments antitumor immunity. We examined possible antitumor effects of IL-12 secreted intracerebrally (i.c.) and/or subcutaneously (s.c.) in an experimental glioblastoma model and compared the effects with those of IL-2. Rat 9L gliosarcoma cells retrovirally transduced with the IL-12 or IL-2 gene (9L/IL-12 and 9L/IL-2, respectively) were completely rejected when they were s.c. inoculated. The transduced cells, implanted i.c., developed progressive brain tumors at reduced rates compared with 9L brain tumors and the growth retardation of 9L/IL-2 tumors was greater than that of 9L/IL-12 tumors. When rats were s.c. immunized with either 9L/IL-12 or 9L/IL-2 cells, the growth of 9L brain tumors developed in the rats was suppressed compared with that of 9L tumors in naive rats. Among various combinations of simultaneous inoculations of cytokine producers s.c. and i.c., 9L/IL-2 but not 9L/IL-12 cells inoculated i.c. were rejected when the rats were s.c. immunized with either 9L/IL-12 or 9L/IL-2 cells. The synergistic antitumor effects induced were correlated with the infiltration levels of CD8+ and CD4+ T cells into brain tumors. Tumor-specific cytotoxic activity was induced in the rats immunized s.c. with 9L/IL-2 but not fully in the rats with 9L/IL-12 cells. These results collectively suggest that the antitumor activity with IL-2 was superior to IL-12 both in the induction of cytotoxic T cells and in the recruitment of activated T cells into brain tumors.

Boswellic acids in the palliative therapy of children with progressive or relapsed brain tumors.

19 children and adolescents with intracranial tumors received a palliative therapy with H 15 at a maximum dose of 126 mg/kg BW/day. All patients had previously been treated with conventional therapy. No side effects were observed during a median 9 months application. The recently reported antiedematous effect of H 15 was documented by MRI in one patient with a peritumoral edema, thus sparing steroid therapy with its typical side effects. Five/19 children reported an improvement of their general health status; this might be a psychological effect of hope for tumor response during palliative care. Three/17 patients with malignant tumors showed a mainly transient improvement of neurological symptoms such as pareses and ataxia. Three further patients showed an increased muscular strength and one cachectic patient achieved a weight gain. These improvements might be attributed to the antiedematous effect of H 15. Because of the palliative situation of these patients, H 15 application was performed without prior rebiopsy for histological evaluation. Overlapping effects with a previous radiotherapy or chemotherapy may have occurred. An antiproliferative effect cannot be stated. To prevent an uncritical use of H 15, further studies with prospective central documentation have to be initiated to evaluate the clinical indications for H 15 in palliative therapy, optimal dosage and duration of application.

Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector--producer cells followed by intravenous ganciclovir administration

Object The outcome for children with recurrent malignant brain tumors is poor. The majority of patients die of progressive disease within months of relapse, and other therapeutic options are needed. The goal of this Phase I study was to evaluate the safety of in vivo suicide gene therapy in 12 children with recurrent, malignant, supratentorial brain tumors. Methods After optimal repeated tumor resection, multiple injections of murine vector--producing cells shedding murine replication--defective retroviral vectors coding the herpes simplex virus thymidine kinase type 1 (HSV-Tk1) gene were made into the rim of the resection cavity. Fourteen days after the vector-producing cells were injected, ganciclovir was administered for 14 days. The retroviral vector that was used only integrated and expressed HSV-Tk1 in proliferating cells, which are killed after a series of metabolic events lead to cell death. The median age of the patients was 11 years (range 2--15 years). Treated brain tumors included seven malignant gliomas, two ependymomas, and three primitive neuroectodermal tumors. The patients were treated with one of three escalating dose concentrations of vector-producer cells. Four transient central nervous system adverse effects were considered possibly related to the vector-producing cells. In no child did permanent neurological worsening or ventricular irritation develop, and tests for replication-competent retroviruses yielded negative findings. Conclusions This Phase I study demonstrates that in vivo gene therapy in which a replication-defective retroviral vector in murine vector--producing cells is delivered by brain injections can be performed with satisfactory safety in a select group of children with localized supratentorial brain tumors.

CLINICAL AND RADIOGRAPHIC RESPONSE IN THREE CHILDREN WITH RECURRENT MALIGNANT CEREBRAL TUMORS WITH HIGH-DOSE TAMOXIFEN

The purpose of this study was to deliver tamoxifen as antiangiogenic therapy to children with recurrent progressive malignant brain tumors. Tamoxifen was administered orally in very high dosage to one child as monotherapy and to two children in combination with oral etoposide and dexamethasone. One boy was diagnosed with high-grade astrocytoma in the brain stem, one girl with anaplastic ependymoma of the fourth ventricule, and one girl with high-grade astrocytoma in the midbrain. Conventional treatment with multiple surgeries, first- and second-line chemotherapy, and external beam therapy had failed. Tumor reduction was seen in radiographic images together with clinical improvement in 2 children, and clinical and radiographic halting of tumor progression was demonstrated in the patient with anaplastic ependymoma. None of the patients developed complications from the treatment. Follow up of the patients ranged from 15 to 30 months with a mean of 17 months. These encouraging preliminary results suggest a potential for this type of therapy. More studies are needed to start clinical trials and prove that angiostatic activity may contribute to the therapeutic effect of antiestrogens in estrogen receptor-negative tumors.

LIPOSOMAL DAUNORUBICIN (DAUNOXOME) IN CHILDREN WITH RECURRENT OR PROGRESSIVE BRAIN TUMORS

Liposomal daunorubicin (DaunoXome = DNX) has been used in 14 children with recurrent or progressive growing brain tumor. DNX was given as a 1-h intravenous infusion with a dose of 60 mg/m2, once every 4 weeks, up to a cumulative dose of 600 mg/m2. At 3-month intervals the tumor process was evaluated on MRI or CT scan. Tumor response and toxicity of DNX were recorded according to the WHO guidelines. In 6 of the children a response has been established: 2 had complete responses, of which one relapsed again after 3 months; in 3 children a partial response was found. Two children showed stable disease. In 6 children the tumors grew progressively. In all responding children a remarkable subjective response was found. The toxicity of DNX at this dose was mild with a mild bone marrow depression and a slight but certain cardiotoxicity in 3 children. For the whole group the left ventricular function decreased with 13.8%. In 1 child the DNX treatment was stopped because of a decrease of the shortening fraction to 20%. In 4 children some hair loss was observed at the end of the treatment. In 3 children mental depression occurred that was associated with the administration of DNX. DNX is a well-tolerated and effective drug in the treatment of slowly progressive or recurrent brain tumors in children.

High-dose melphalan and cyclophosphamide with autologous bone marrow rescue for recurrent/progressive malignant brain tumors in children: a pilot pediatric oncology group study.

To determine the maximum-tolerated dose of cyclophosphamide (CTX) when administered sequentially with melphalan 60 mg/m2/d for 3 days, followed by autologous bone marrow rescue (ABMR), in children with recurrent or progressive malignant brain tumors, and to make preliminary observations on efficacy. Nineteen patients between the ages of 2 and 21 years were enrolled and 18 were assessable for effects of therapy. CTX was administered to seven patients at 750 mg/m2/d for 4 days, to five patients at 975 mg/m2/d, to three patients at 1,200 mg/m2/d, and to three patients at 1,500 mg/m2/d. All patients received ABMR. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was used in 15 patients. Toxicity, response to therapy, time to progression, and survival and monitored. The median time to a granulocyte count more than 500/dL was 19 days (range, 11 to 39), and for a platelet count more than 50,000/dL was 33 days (range, 16 to 60). Four heavily pretreated patients (22%) died of transplant-related complications. No dose-limiting, non-hematologic toxicities were defined for the study. Seven of 18 patients (39%) had a complete response (CR) or a partial response (PR). These included four patients with medulloblastoma (CR and three PRs), two with germinomas (two CRs), and one with ependymoma (one CR). The estimated 1-year survival rate was 39% (SE 12%). CTX, at a maximum total dose of 6,000 mg/m2, administered sequentially with melphalan and followed by ABMR was tolerable in children with recurrent brain tumors who had not been heavily pretreated. Responses were seen in patients with medulloblastoma and germinomas. Further trials in children with chemosensitive tumors, with minimal residual disease, are planned.

Stereotactic Injection of Herpes Simplex Thymidine Kinase Vector Producer Cells (PA317-G1Tk1SvNa.7) and Intravenous Ganciclovir for the Treatment of Progressive or Recurrent Primary Supratentorial Pediatric Malignant Brain Tumors. St. Jude Children's Research Hospital, Memphis, Tennessee

This study will evaluate the safety and efficacy of in vivo gene transfer of the herpes simplex thymidine kinase (HSV-Tk1) gene using PA317/G1Tk1SvNa.7 vector producer cells (VPC) in pediatric patients with progressive or recurrent primary supratentorial malignant brain tumors. Insertion of the HSV-Tk1 gene confers a sensitivity to the anti-herpes drug ganciclovir. It has been demonstrated that the direct injection of HSV-Tk vector producer cells into growing tumors in animals can result in their complete destruction with ganciclovir therapy. This selective destruction of growing tumors in situ is thought to result from the transfer of the HSV-Tk gene into the tumor cells and the production of toxic ganciclovir metabolites which result from the interaction of HSV-Tk and ganciclovir. This procedure can result in the cure of some experimental animals with limited systemic toxicity due to selective gene transfer into tumors. This clinical trial will focus on maximizing the relative number of vector producer cells to the tumor mass by stereotactically injecting VPCs into the tumor mass. Children with progressive or recurrent primary supratentorial malignant brain tumor which is accessible to stereotactic injection will be evaluated for the extent and location(s) of their disease before being entered into the study. Fifteen days after stereotactic injection of the tumor mass, ganciclovir will be administered at 5 mg/kg IV b.i.d. for 14 days. Upon completion of the treatment with HSV-Tk1 vector producer cells and ganciclovir, the patient will be followed monthly for the first three months, then every two months for the next twenty-one months, and annually for life thereafter.

Treatment of recurrent gliomas and metastatic brain tumors with a polydrug protocol designed to combat nitrosourea resistance.

The study was undertaken to evaluate a chemotherapy protocol against recurrent malignant gliomas that was designed to combat presumed chloroethyl-nitrosourea (NU) resistance. All patients had malignant gliomas and had failed prior therapy. Patients were stratified as having either glioblastoma multiforme (GM) or anaplastic gliomas (AG) and as having failed radiotherapy (RT) only or both RT and chemotherapy. Chemotherapy consisted of six drugs: before lomustine (CCNU), thioguanine (TG), dibromodulcitol (mitolactol; DBD), and procarbazine (PCB) were given to enhance CCNU-induced tumor-cell kill and to reduce alkyltransferase repair of ethylated DNA. A fluorouracil-hydroxyurea (FUHU) combination was given 2 weeks later to kill cells that began to cycle after the challenge of the first four drugs (TPDC-FUHU chemotherapy). Of the 88 assessable patients, 37 had GM, 38 had AG, and 13 had other primary and metastatic brain tumors. For GM patients, 61% had a partial response (PR) or stable disease (SD) for a median of 9.3 months if RT only failed, and 58% had a PR or SD for a median of 5.1 months if they had previously been treated with an NU. For AG patients, 92% had a PR or SD for a median of 15 months if RT only had failed, but only 38% had a PR or SD for a median of 10.6 months if they had been previously treated with a NU. Activity was also seen against other recurrent or progressive primary and metastatic brain tumors. TDPC-FUHU chemotherapy is a highly effective form of chemotherapy for both recurrent GM and AG patients. This study suggests but does not prove that this combination may be superior to other NU-based treatments for recurrent malignant glioma patients who fail RT. Because of the activity of this chemotherapy, we intend to evaluate more fully this approach in a randomized study.

Treatment of children with progressive or recurrent brain tumors with carboplatin or iproplatin: a Pediatric Oncology Group randomized phase II study.

The Pediatric Oncology Group (POG) conducted a randomized phase II study to evaluate the activity of carboplatin and iproplatin in children with progressive or recurrent brain tumors. The study was designed to evaluate the activity of these agents and to compare the toxicities associated with their use. Treatment consisted of carboplatin 560 mg/m2 at 4-week intervals or iproplatin 270 mg/m2 at 3-week intervals. The major toxicity observed was myelosuppression, particularly thrombocytopenia, for both agents. Ototoxicity (grade 1 or 2) was seen in 2.5% of patients treated with carboplatin and 1.3% of patients treated with iproplatin. The majority of patients with low-grade astrocytic neoplasms treated with carboplatin (nine of 12 patients) or iproplatin (eight of 12 patients) demonstrated tumor response or prolonged stable disease that persisted off-therapy. The duration of stable disease produced by carboplatin was particularly striking, ranging from 2 months to 68 + months (median, 40 + months). Neither drug demonstrated appreciable activity in the treatment of medulloblastoma (two of 26 responses to carboplatin, one of 14 responses to iproplatin), ependymoma (two of 17 responses to carboplatin, none of seven responses to iproplatin), high-grade glioma (two of 19 responses to carboplatin, one of 14 responses to iproplatin), or brain-stem tumors (one of 23 responses to carboplatin, none of 14 responses to iproplatin). Carboplatin is active against low-grade gliomas. Further evaluation of the role of carboplatin in the preirradiation treatment of children with low-grade gliomas of the optic pathway is currently underway in a clinical trial.

Recombinant interferon beta: a phase I-II trial in children with recurrent brain tumors.

A multicenter phase I-II trial of intravenous (IV) human recombinant interferon beta (rIFN-beta; Betaseron; Triton Bioscience Inc, Almeda, CA) was conducted in children with recurrent or progressive primary brain and spinal cord tumors. A total of 29 patients were enrolled: high-grade astrocytoma (12), brainstem glioma (nine), and primitive neuroectadermal tumor (three), ependymoma (two), germ cell (two), and spinal cord astrocytoma (one). Betaseron was given by IV infusion over 30 minutes 3 times per week (Monday-Wednesday-Friday [MWF]). Four dose levels were studied, and at least three patients were entered at each dose level. The treatment plan began with a three-step dose escalation for each patient over 6 weeks (initiation phase). The dose-escalation schema for the four dose levels was: 50-100-200, 100-200-400, 200-300-500, and 300-400-600 x 10(6) (M) IU/m2. Patients experiencing an objective response or stable disease after 6 weeks entered the maintenance phase at the final escalated dose, ie, 200, 400, 500, or 600 mlU/m2 (MWF). Common transient effects included chills, fever, and fatigue. Dose-limiting toxicities were hematologic, hepatic, and CNS. The maintenance maximum-tolerable dose (MTD) was 500 mlU/m2, ie, dose level 3. Response was assessed at completion of the initiation phase and at 2-month intervals during the maintenance phase. Objective partial responses were seen in patients with high-grade astrocytoma (two) and brain-stem glioma (two). Thus, four of 21 (19%) assessable patients had partial responses for a median of 4 months. Eight patients had stable disease for a median of 5+ (2 to 14+) months. Antineoplastic activity has been identified in children with high-grade astrocytomas and brainstem gliomas in a dose-intensive regimen.

A Pilot Clinical and Pharmacokinetic Study of Intracarotid Cisplatin and Bleomycin

Fifteen patients with progressive primary malignant or metastatic brain tumors were treated on a clinical and pharmacokinetic study with intracarotid cisplatin and bleomycin. Toxicity was tolerable and consisted mainly of nausea and vomiting. Neurologic toxicity included focal seizures (1), leukoencephalopathy (1), and motor weakness (1). Five patients had improvement in CT scans and four patients had stabilization of disease. Recommended dosage for future clinical trials are cisplatin 60 mg/m2 and bleomycin 100 units. Pharmacokinetics of intracarotid cisplatin revealed the jugular vein concentration was twice the peripheral vein level at the end of infusion. Cisplatin is a drug which has demonstrated in vitro activity against malignant gliomas (1). Clinical trials with intravenous administration of cisplatin has shown definite, although limited antitumor activity against primary brain tumors (2,3,4) and metastatic brain tumors (5,6). To enhance its antitumor effect, cisplatin has been administered by the intracarotid route (7,8,9). The results appear encouraging, but neurological and ophthalmological toxicity may occur (8). In our initial study with intracarotid cisplatin, 35 patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation +/- chemotherapy were treated. Of 20 evaluable patients with primary tumors, 6 responded to therapy and 5 had stable disease. Five of 10 evaluable patients with brain metastases responded and 2 had stable disease. For responding primary brain tumor patients the median time to progression was 33 weeks. The recommended dose for intracarotid cisplatin was 60-75 mg/m2 administered every 3-4 weeks (7,8). Higher cisplatin doses produced more central neurological toxicity. There is limited data on the central nervous system pharmacology of cisplatin.(ABSTRACT TRUNCATED AT 250 WORDS)

A phase II study of diaziquone in children with recurrent or progressive primary brain tumors: A report from the Childrens Cancer Study Group

Seventy-five children with recurrent, progressive or metastatic primary brain tumors were treated with aziridinylbenzoquinone (AZQ; Diaziquone) at 9 mg/m2/day by 30-minute intravenous infusion for five days every three weeks. Sixty-six patients were evaluable for response by imaging studies. There were five partial responses and one complete response for a combined response rate of 9%. A complete response lasting for 35+ months occurred in one of twelve patients with metastatic or locally recurrent ependymoma. Objective responses were also seen in patients with primitive neuroectodermal tumors (PNET) (1/8), low-grade glioma (1/6), and primary central nervous system lymphoma (1/1). Stable disease of greater than six months duration was seen in patients with ependymoma, PNET and medulloblastoma. Profound and prolonged myelo-suppression was the significant toxicity observed. As administered in this study, AZQ has marginal activity and severe toxicity.