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Keywords:

  • brainstem glioma;
  • radiotherapy;
  • radiosensitization;
  • carboplatin

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Ninety percent of children with diffuse intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit, and one way to potentially improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing. However, delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The goal of the current Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy.

METHODS

RMP-7 was given before the end of carboplatin infusion. Local radiotherapy (5940 centigrays) was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion, in cohorts of 3, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, whose median age was 7 years (range, 3–14 yrs).

RESULTS

One child died early in treatment of progressive disease and was not assessable for toxicity. Treatment for 3, 4, or 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. Of 3 children treated at the full duration of therapy (33 doses over 7 wks), 1 developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival period was 328 days, and 1 patient remained disease progression free > 400 days from initiation of treatment.

CONCLUSIONS

The results of the current study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy. Cancer 2005. © 2005 American Cancer Society.

Brainstem gliomas, comprising 10% of all childhood brain tumors, remain 1 of the most difficult brain tumors to treat successfully.1 Diffuse intrinsic tumors constitute most brainstem gliomas, commonly involving primarily the pons, often with infiltration into other regions of the brainstem and contiguous nonbrainstem sites. They characteristically present with multiple cranial nerve deficits, ataxia, and long tract dysfunction. With current means of neuroradiographic diagnosis, surgery is usually not needed for diagnosis. Most patients can be diagnosed reliably based on clinical and neuroradiographic findings.2 Radiotherapy remains the most effective treatment, resulting in at least transient disease control in most patients. However, 90% of children with diffuse intrinsic brainstem gliomas will experience disease recurrence after radiotherapy and will die of their disease. Alterations in dose and fractionations of radiotherapy have not improved survival.3 To date, addition of chemotherapy or other forms of therapy, before or after radiotherapy, has not improved disease control.1

Radiotherapy is the only effective, albeit transient, treatment for most children with diffuse intrinsic brainstem gliomas. One means to potentially improve the efficacy of radiotherapy is to couple it with radiosensitizers.4 Carboplatin has antineoplastic activity against several brain tumors including high-grade gliomas.5, 6 It also has radiosensitization properties.4, 7, 8 An important possible limitation to using carboplatin or any other form of chemotherapy to potentiate the effects of radiotherapy is adequate drug delivery to the primary tumor site.9, 10 The blood-brain barrier, a monolayer of specialized capillary endothelial cells, forms a relatively continuous barrier between the brain and circulating blood. Most diffuse intrinsic brainstem tumors do not enhance with intravenous agents such as gadolinium and are believed to have a relatively intact blood-brain barrier.2 Bradykinin causes transient relaxation of the blood-brain barrier's tight junctions.11, 12 Infusion of bradykinin into cerebral circulation transiently increases the permeability of the cerebrovasculature.11–13 There are 2 types of bradykinin receptors, B1 and B2, and the B2 receptors are expressed primarily in neuronal and vascular tissue types.11–13 RMP-7 (Cereport; Alkermes, Cambridge, MA) is a synthetic bradykinin analog and B2 receptor agonist.14, 15 B2 receptors functionally appear to be expressed predominantly in neuronal and vascular tissue. For this reason, RMP-7 seems to be a reasonable candidate to use with chemotherapy to deliver more therapy to the primary tumor and surrounding region. This approach also attempts to exploit the difference between normal brain and brain tumor blood vessels.15–20 In preclinical studies, RMP-7 caused rapid, reversible, and relatively selected permeability at the blood-brain barrier-tumor interface. This was rapid, transient, and autoregulated, and tachyphylaxis occurred with continuous administration. In animal central nervous system (CNS) tumor models, tumor levels of carboplatin were increased after the addition of RMP-7, regardless of intracarotid or intravenous administration.16, 17 There was an average 10-fold uptake increase in the tumor bed, and in experiments compared with hyperosmolar-induced permeability, there was a significant therapeutic advantage for RMP-7. RMP-7 did not increase cerebral blood flow or volume in the normal brain, but it increased permeability within 2 m surrounding the tumor, and did not significantly affect drug delivery to more distant brain tissue sites.

For these reasons, the current study (COG-ADVL0012) was undertaken by the Children's Oncology Group (COG) to evaluate the feasibility and potential efficacy of carboplatin and RMP-7 given concurrently with radiotherapy, for children with newly diagnosed, diffuse intrinsic brainstem gliomas.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Eligibility

Eligible patients were 3–21 years old, inclusive, with newly diagnosed, diffuse intrinsic brainstem gliomas. Patients with diffuse intrinsic tumors did not require tissue confirmation for entry, but were eligible based on neuroradiographic features. Patients with focal brainstem tumors, defined as tumors that occupied < 50% of a single brainstem structure, such as the medulla, pons, or midbrain, and tumors that were exophytic, defined as > 50% of the tumor lying outside the body of the brainstem, were only eligible if the tumor was a malignant glioma confirmed by biopsy results.

Before entry, patients must have received a magnetic resonance imaging (MRI) scan of the brain and spine, with and without gadolinium. All patients must have had measurable disease at the time of study. Lumbar cerebrospinal fluid (CSF) analysis was not required. However, for patients undergoing a spinal tap, CSF cytology must have been negative for tumor cells for eligibility. Patients with disseminated disease confirmed by an MRI scan or CSF cytology were ineligible.

Before entry, patients were required to have adequate bone marrow and liver function. Patients also were required to have normal renal function, defined as creatinine level less than the upper limit of normal for age, or a 24-hour creatinine clearance or glomerular filtration rate that was > 80 mL/min per 1.73 m2. All female patients were required to have a negative pregnancy test, if at childbearing age, and agree to use medically acceptable contraception if sexually active.

Patients who received any previous treatment other than surgery or corticosteroids were ineligible. Patients with neurofibromatosis type 1 also were ineligible. Patients could not have used the following medications in the 24 hours before RMP-7 administration: vasodilating compounds, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, antihistamines, aspirin, or beta blockers.

All patients must have signed an institutional review board-approved consent or assent forms (if appropriate) before entry, in accordance with the Declaration of Helsinki.

Treatment Overview

Patients were to begin therapy within 31 days of diagnosis (for those undergoing surgery, the diagnosis date was considered the date of surgery). Patients were to receive carboplatin and RMP-7 at the assigned duration, intravenously, on a Monday to Friday schedule, within 4 hours before treatment with radiotherapy. Doses of the drugs were identical at all durations of therapy.

The dose and duration of carboplatin and RMP-7 were assigned at entry. The first dose of both was to be administered on the first day of radiotherapy.

Dose Escalation

Patients were enrolled in cohorts of three. If none of the first three patients enrolled at a dose level experienced dose-limiting toxicity (DLT), the dose or duration was escalated as appropriate. If one of the first three experienced a DLT, three more were enrolled at the dose level. If any of the second cohort of three experienced DLT, the dose level was considered not tolerated. The dose was reduced one level and three patients were enrolled at that level, provided only three had been evaluated at the previous level. If two or more of the first three patients enrolled at a dose level experienced DLT, the dose level was considered not tolerated. The dose was reduced one level and three patients were enrolled at that level, provided only three patients had been evaluated at the previous level.

If no DLT was encountered, the duration of carboplatin administration was extended in subsequent cohorts, so that patients would receive carboplatin and RMP-7 during the first 4, 5, 6, and 7 weeks of radiotherapy, respectively. Later in the study, the trial was amended to collapse the 6th and 7th week of radiotherapy into 1 stratum, as Week 7 consisted of only 3 days of radiotherapy.

Dose-Limiting Toxicity

For the current study, DLTs were defined as an absolute neutrophil count of < 500 mm3 for 7 consecutive days; a platelet count of ≤ 20,000/mm3 for 7 consecutive days; fever and neutropenia for ≥ 7 days during the 7-day treatment cycle; any Grade 4 nonhematologic toxicity, with the exception of nausea and emesis, which could not be controlled within 7 days (a delay of 2 wks in completion of radiotherapy because of association with the carboplatin and RMP-7) or death while receiving therapy that was possibly, probably, or likely related to carboplatin and RMP-7.

RMP-7/Carboplatin Dosing Guidelines

RMP-7 was given at a dose of 0.3 mg/kg of ideal body weight (300 ng/kg of ideal body weight per day) as a 10-minute intravenous infusion beginning 5 minutes before the end of the 15-minute carboplatin infusion. The RMP-7 infusion was to be completed 5 minutes after the end of the 15-minute carboplatin infusion. The carboplatin dose, at all durations of therapy, was 35 mg/m2 per day.

Radiotherapy

Patients were to be treated with a linear accelerator with nominal photon energy between 4 and 10 MV. Electrons could not be employed. Any 2-dimensional (2-D) or 3-dimensional (3-D) treatment technique was allowed. For 2-D planning, the margin was to be 1.5 cm2. For 3-D planning, a margin of 1 cm in all directions was allowed. The treatment plan was to completely involve the planning target volume within the 95% isodose surface. The total dose of radiotherapy was to be 5940 centigrays (cGy) in 180-cGy dose fractions (33 fractions).

Required Observations during and after Treatment

Because of potential blood pressure problems associated with RMP-7, blood pressure levels were measured every 15 minutes for the first hour before each dose of RMP-7 to establish baseline average systolic and diastolic blood pressure levels. Blood pressure levels were monitored every 5 minutes during RMP-7 infusion and for 20 minutes after completion of the schedule. If the patient experienced dose-limiting hypotension, the blood pressure level was monitored every 2 minutes until it returned to a level that did not meet DLT.

On-Study Evaluation

Patients underwent physical and neurologic examinations weekly throughout radiotherapy and blood counts and liver functions were to be evaluated twice weekly during radiotherapy. Blood chemistry evaluation was performed at baseline and at Weeks 3 and 5 of treatment. Toxicity was coded according to the National Cancer Institute Common Toxicity Criteria, version 2. The maximum grade of each toxicity type observed during the 6-week period of protocol therapy was reported.

Six weeks after radiotherapy, patients were to undergo repeat neurologic and physical examinations and brain MRI scans with and without gadolinium. Patients also were to be evaluated by complete blood counts, serum chemistries, and an audiogram. Patients were then observed at 3-month intervals for the first 2 years after therapy, then at 6-month intervals for the next 5 years.

Statistical Methods

Patients enrolled and eligible were considered in the calculation of risk of disease progression and risk of death. Disease progression-free survival (PFS) was defined as the time from study enrollment until disease progression, death, or last contact, whichever came first. A progression event was patient death or disease progression. Survival was defined as the time from study enrollment until death or last patient contact. A survival event was defined as patient death. Disease PFS and survival as a function of time since enrollment were calculated using the Kaplan–Meier method.21 Confidence intervals for median survival were calculated by the method of Brookmeyer and Crowley.22

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Thirteen patients with a median age of 7 years (range, 3–12 yrs) were enrolled between February 2001 and October 2003. Twelve patients completed treatment and one child died of tumor progression during radiotherapy. Thus, 12 patients were fully evaluable for toxicity.

Toxicity

There were no DLTs at the first three strata. Therefore, patients were able to complete 3, 4, and 5 weeks of carboplatin and RMP-7 and concurrent radiotherapy without delays (Table 1). At the 4th dose level (33 days of concurrent therapy), 1 patient developed Grade 3 hepatotoxicity (elevated levels of alanine aminotransferase and aspartate aminotransferase) and Grade 3 neutropenia, which did not resolve over a 2-week period. Because there was no resolution, this was considered to be a DLT. Radiotherapy was continued, with a 3-day interruption for that patient, who ultimately completed therapy at a 25% reduced dose of carboplatin and RMP-7. As stated, 1 patient at dose level 2 (who was to receive 4 wks of RMP-7 and carboplatin) developed progressive disease within 3 weeks of initiating treatment. Therapy was discontinued and the child died. Death was not believed to be related to carboplatin and RMP-7 infusion. All other strata had only three patients entered.

Table 1. Non–Dose-Limiting Toxicities Observed during Protocol Therapy According to Dose Level and Grade
ToxicityGradeDose level
15 doses over 3 wks20 doses over 4 wks25 doses over 5 wks33 doses over 7 wks
naNnN
  • AST: aspartate aminotransferase; ALT: alanine aminotransferase.

  • a

    Number of patients who demonstrated the noted toxicity.

Hemoglobin level1 1  
Lymphopenia3 1  
Neutrophils/granulocytes2  1 
Platelets1 11 
Sinus tachycardia13 1 
Partial thromboplastin time1 1  
Fatigue (lethargy, malaise, asthenia)1 1  
Alopecia2   1
Flushing13212
Rash/desquamation1 1  
Hot flashes/flushes11   
Constipation11   
Nausea111 1
Emesis11  1
 2  1 
Gastrointestinal other2 1  
Epistaxis11   
AST1 1  
ALT111  
 2 1  
Infection without neutropenia2   1
Hypocalcemia11   
Dizziness/lightheadedness111  
Hallucinations3   1
Mood alteration-anxiety, agitation2   1
Mood alteration-depression2   1
Ocular/visual-other (specify)11   
Abdominal pain or cramping1   1
Headache112  
Urinary frequency/urgency12   

Grade 1 tachycardia and flushing were common at all doses. Other toxicities such as headache, gastrointestinal upset, and nausea occurred at various levels. None were DLT.

Because of drug availability, the last cohort (Weeks 6–7 of radiotherapy) could not be expanded to ascertain the maximum tolerated dose (MTD) of carboplatin at 35 mg/m2 per day and RMP-7, the protocol-defined maximum dose.

Response

The radiographic response was determined 6 weeks after radiotherapy. As noted, one child developed progressive disease early during radiotherapy. Of the remaining 12 patients, 2 had a partial response (a > 50% reduction in tumor area determined by the product of the 2 greatest dimensions), 2 had minor responses (a > 25%, but a < 50% change in area), 7 had stable disease, and 1 had progressive disease. One child with stable disease had a marked increase in tumoral enhancement, but no change in tumor size 6 weeks after radiotherapy (a concurrent positron emission tomography [PET] scan showed no increased uptake). Possible intratumoral necrosis was noted 6 weeks after treatment in 3 patients, but was not associated with clinical worsening. One child had what we believed was leptomeningeal dissemination (brain and spine meningeal enhancement) 6 weeks after radiotherapy, associated with increased tumor size. The increased enhancement remained stable for the ensuing 6 months, and the child ultimately died of progressive local disease, raising the issue of whether this represented leptomeningeal tumor spread or increased enhancement due to alterations in the blood-brain barrier.

Outcome

The estimated median survival period was 329 days, with a 95% confidence interval of 258–394 days. One patient remained disease progression free > 400 days from the initiation of treatment, and 1 was alive at this writing after disease progression (Figs. 1 and 2). Of 10 patients who had disease recurrence, 3 had disseminated disease. Two had diffuse leptomeningeal recurrence involving the brain and spine, and one developed multiple discrete lesions throughout the cerebral cortex and cerebellum.

thumbnail image

Figure 1. Progression-free survival from study enrollment for patients evaluable for dose-limiting toxicity.

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Figure 2. Overall survival from study enrollment for patients evaluable for dose-limiting toxicity.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The blood-brain barrier precisely regulates the CNS microenvironment, which is critical for normal neuronal function. Lack of fenestrations, decreased pinocytotic activity, tight junctions, and specific receptor-mediated transport mechanisms preserve this microenvironment.9 Protection is the blood-brain barrier's most critical function. However, by excluding toxic substances, it can prevent active anticancer agents from reaching their targets.9 This is an important deterrent to successful treatment of brain tumors with relatively intact barriers, such as diffuse intrinsic brainstem gliomas. Although many mechanisms increase blood-brain barrier permeability nonspecifically, such as hypertension, hypercapnia, seizures, and hyperosmolar substances, they tend to be transient.10, 23, 24 Osmotic disruption has been attempted to enhance treatment efficacy for children with brain tumors, with equivocal success.10 Osmotic disruption is nonselective and because tumors usually have inherently leakier blood-brain barriers, the increase in permeability is not as great as in normal brain tissue and brain tissue that surrounds the tumor.

In a 68Ga ethylenediaminetetraacetic acid (EDTA) PET scan study of 9 adult patients with cortical recurrent malignant gliomas, RMP-7 was shown to selectively increase transport of 68Ga EDTA into brain tumors without increasing transport into normal tissue.2598Ga EDTA and carboplatin have a similar molecular size, charge, weight, and water solubility. When the current study began, Phase I studies in children had shown that RMP-7 infusion with carboplatin was well tolerated over 10 minutes.26 Phase I and Phase II adult trials and preliminary results of a Phase I pediatric study of recurrent brain tumors suggested that carboplatin might be more effective with RMP-7.26, 27 The toxicity profile of the combination seemed reasonable, primarily including vasodilatation, tachycardia, headaches, and nausea.

The rationale for carboplatin with radiotherapy included intrinsic efficacy in many different tumors, including gliomas, and radiosensitization.4, 6, 7 Cytotoxicity of platinum compounds is partially a function of unbound drug that reaches the tumor. Carboplatin binds more slowly to plasma proteins, with a half-life of 6 hours, and continuous infusion is not necessary to ensure free platinum during radiotherapy. Carboplatin was given daily with radiotherapy to patients with other types of cancer, including nonsmall cell lung carcinoma, with improved survival.8 It was also delivered at 33 mg/m2 per day for 5 days during Weeks 1 and 4 of involved-field accelerated radiotherapy for glioblastoma multiforme, with reasonable tolerance.28 In a Phase I study, carboplatin was given twice weekly during hyperfractionated radiotherapy for children with brainstem gliomas and 280 mg/m2 per week for 7 weeks was the MTD.29 Despite responses, disease PFS was 8 months and the overall survival was only 12 months.29

Overall, the study was performed well. Carboplatin with RMP-7 was well tolerated during radiotherapy. There were frequent minor side affects such as flushing and tachycardia that occurred during and at all durations of the therapy, which was similar to that seen for carboplatin and RMP-7 without radiotherapy in a pediatric Phase I study.26 Therapy was somewhat inconvenient for patients and caregivers. Patients must have received therapy within 4 hours of radiotherapy initiation. At most sites, chemotherapy and radiotherapy were given in different places, creating logistic difficulties. Also, the need to carefully monitor blood pressure levels to ensure safety involved significant caregiver time before and after infusion. Despite drawbacks, therapy was given successfully according to protocol.

One of the rationales for RMP-7 and carboplatin was its possible increased efficacy, compared with carboplatin alone, in adults with high-grade gliomas. A study by Gregor et al.27 for the RMP-7 European study group demonstrated stable disease or response in 79% of patients with recurrent high-grade gliomas who had not received chemotherapy. A randomized, double blind, placebo-controlled Phase II study of RMP-7 with carboplatin, versus carboplatin alone, in adults with recurrent high-grade gliomas was completed while our study was underway, and RMP-7 did not improve carboplatin efficacy.30 A Phase III study of RMP-7 and carboplatin with radiotherapy in patients with newly diagnosed high-grade gliomas also was underway. When preliminary results of that study demonstrated no increased efficacy for RMP-7/carboplatin concurrent with radiotherapy, the study was closed and, subsequently, the drug supply became limited.

Conclusions concerning efficacy cannot be drawn reliably from the current study. Disseminated disease in three children early after treatment was worrisome and raised the issue of whether blood-brain barrier disruption could lead to a higher incidence of tumor dissemination via vascular spread of tumor cells. Because of drug availability, the last cohort could not be expanded to ascertain MTD, but we demonstrated the potential use of blood-brain barrier disruptive agents with chemotherapy during radiotherapy for a tumor highly resistant to treatment and the ability to deliver a bone marrow toxic chemotherapy daily during radiotherapy.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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