rmp-7 and Astrocytoma

In recurrent malignant glioma, early imaging response to two courses of chemotherapy is generally considered to be predictive of good survival. We studied the relationships between initial tumour volume and speed of imaging response to chemotherapy in malignant glioma.. In 43 chemotherapy naïve patients, 26 glioblastoma multiforme (GBM) + 17 anaplastic astrocytoma (AA), median age 45 years, MRI responses to intravenous cereport and carboplatin were assessed at baseline, then at 2 monthly intervals. Patients were classified as fast responders if they had reached a partial response (PR) after two courses, and slow responders if PR was achieved after three or more courses of chemotherapy.. PR occurred in four patients with GBM (15%) and nine patients with AA (53%). Likelihood of response was related to initial tumour enhancing volume in GBM but not in AA. PR occurred in four of five GBM patients (80%) with initial volume < 15,000 mm3 and none of the 21 cases with an initial volume > 15,000 mm3. In patients achieving a PR, there was no association between speed or duration of response and eventual survival. Fast responders with AA were significantly older than slow responders (p = 0.033).. Initial enhancing volume of GBMs may be an important predictor of imaging response. This has implications where response rates of phase II studies are reported and in stratification for phase III trials. Further work is necessary to confirm these findings with other types of chemotherapy and examine the relationship between proliferation markers and speed of response.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Astrocytoma; Bradykinin; Brain Neoplasms; Carboplatin; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Predictive Value of Tests; Prognosis; Treatment Outcome

Cereport (RMP-7) is a novel bradykinin agonist which is being developed as a modulator of the blood-brain barrier (BBB). In order to investigate the pharmacokinetics of carboplatin in combination with Cereport, we performed pharmacological studies in conjunction with early clinical trials.. Pharmacokinetic samples were collected from eight patients in a phase I study (Cereport 100-300 ng/ kg) and ten patients in a phase II study (Cereport 300 ng/kg). Pharmacokinetic parameters for carboplatin were compared with respect to the dose of Cereport and with historical controls.. Cereport combined with carboplatin was well-tolerated, with mild haematological toxicities consistent with the target area under the concentration time curve (AUC) of 7 mg/ml x min. Although the clearance of carboplatin was within the range reported for this drug alone, the addition of Cereport resulted in a higher than expected carboplatin AUC. This effect was related to the dose of Cereport in the phase I study (AUC values 104-133% of target, Spearman rank correlation coefficient = 0.71, P < 0.001). The higher than expected AUC value was confirmed in the phase II study (AUC values 106-189% of target).. Co-administration of Cereport with carboplatin may result in a greater than predicted AUC. The mechanism of this possible interaction remains to be determined, although this did not result in any increased toxicity. Thus, the clinical potential of this combination in the treatment of brain tumours warrants further investigation.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Area Under Curve; Astrocytoma; Blood Proteins; Blood-Brain Barrier; Bradykinin; Brain Neoplasms; Carboplatin; Female; Glioblastoma; Glioma; Half-Life; Humans; Male; Middle Aged; Protein Binding

The results of animal studies suggest that superselective intra-arterial infusion allows the permeation of a high concentration of chemotherapeutic agents within intracranial neoplasms. In the present report, we review our clinical experience with the 100 intra-arterial infusions of carboplatin in intracranial neoplasms not responsive to other treatment modalities.. Carboplatin was infused in 100 separate sessions (24 patients) as a mean dose of 286+/-60 mg/m2 (range 34-377 mg/m2). RMP-7, a bradykinin analog, was used as an adjunct in 28 sessions (6 patients). The infusions were performed through superselective microcatheterization of the following arteries: internal carotid (n = 39), middle cerebral (n = 61), posterior cerebral (n = 21) and anterior cerebral (n = 10). The frequency of neurological and non-neurological complications, and survival were recorded. In a subset of 10 patients, tumor volume was measured by serial magnetic resonance images to assess therapeutic response to therapy.. The mean age of the patients was 44.5 years (range 26-67 years); 13 were men. The tumors were classified as glioblastoma multiforme (n = 12), metastatic tumor (n = 1), high-grade astrocytoma (n = 6), and anaplastic mixed glioma (n = 5). Follow-up was available for 23 patients (mean 22 months, range 2-69 months). Survival beyond 1 year after initiation of intra-arterial carboplatin therapy was documented in 12 of the 23 patients. A total of 13 neurological complications including seizures (n = 7), transient neurological deficits (n = 5), and ischemic stroke (n = 1) were observed in 100 procedures. A lower frequency of complications occurred in men and in patients who received adjunctive RMP-7. Volumetric analysis of serial magnetic resonance images demonstrated tumor mass reduction in 3 out of 10 patients. An increase in tumor mass ranging from 23% to 230% was observed in the other 7 patients over a period ranging from 2.3 to 37.7 months since initiation of carboplatin therapy.. Superselective intra-arterial administration of carboplatin appears feasible and was associated with predominantly transient neurological complications. The addition of RMP-7 to carboplatin therapy appears to be at least as safe as the administration of carboplatin alone and requires further investigation as a means of chemotherapeutic dose intensification.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Astrocytoma; Bradykinin; Brain Neoplasms; Carboplatin; Carotid Arteries; Cerebral Arteries; Female; Follow-Up Studies; Glioma; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Retrospective Studies; Time Factors