Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma.

BACKGROUND: The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin-2 (IL-2) plus lymphokine-activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity. METHODS: Nineteen adults with recurrent malignant glioma (5 GBMs, and 4 anaplastic astrocytomas (AA)), Karnofsky performance status 60 or greater, were treated with intracavitary autologous LAK cells plus IL-2 after reoperation. Lymphokine-activated killer cells and IL-2 were given on day 1, and IL-2 alone was given 5 times during a 2-week cycle. This cycle was repeated at 2 weeks to constitute one 6-week course of therapy. Each two-cycle course of treatment was repeated at 3-month intervals for patients with stable disease or response to therapy. At the conclusion of immunotherapy, all patients were offered chemotherapy, generally carmustine or procarbazine, including responders. Corticosteroids were strictly limited during immunotherapy. Sequential reservoir aspirates were obtained for microbiologic and cytologic analyses. RESULTS: The maximal tolerated dose for a 12-dose course of therapy was 1.2 million international units (MIU) per dose. Dose-limiting, cumulative IL-2-related central nervous system (CNS) toxicity was observed at 2.4 MIU per dose. Three responses were confirmed by computed tomography scan during therapy: one complete response (CR) (1 AA), and two partial responses (PR) (2 GBM); as well as a significant increase in GBM survival. One additional CR (GBM) was observed at 17 months. The median survival for immunotherapy patients with GBM was 53 weeks after reoperation (N = 15) (mean, 87.9 +/- 21.4 weeks, standard error for the mean), with 8 of 15 surviving more than 1 year (53%). The median survival for 18 contemporary patients with GBM reoperated and treated with chemotherapy was 25.5 weeks (mean, 27.4 +/- 3.7 weeks), with 1/18 alive at 1 year (> 6%). Six of the 15 patients with GBM had additional surgery or biopsy, and chemotherapy after immunotherapy. The contribution of subsequent chemotherapy to survival cannot be discounted. CONCLUSIONS: Lymphokine-activated killer cells and IL-2 can be administered safely within the CNS resulting in improved long term survival in patients with recurrent glioblastoma. Increased survival was associated with significant biologic changes characterized by a regional eosinophilia, and extensive lymphocytic infiltration. A prospective randomized clinical trial is warranted.

Results of a randomized trial comparing intra-arterial cisplatin and intravenous PCNU for the treatment of primary brain tumors in adults: Brain Tumor Cooperative Group trial 8420A.

PURPOSE: To test the efficacy of intra-arterial (IA) cisplatin versus intravenous (IV) PCNU for treating primary brain tumors, in a randomized trial (Brain Tumor Cooperative Group [BTCG] Trial 8420A). METHODS: 311 adult patients (ages 19-79 years; median 45) with supratentorial tumors (confirmed histologically) were randomized by nine participating institutions. Patients were required to have completed radiotherapy (4500-6020 cGy to the tumor bed) before randomization. Patients were stratified as either nonprogressive (clinically and radiologically stable) or progressive. Results were analyzed for the 311 patients in the randomized population (RP), and for the 281 patients in the Valid Study Group (VSG) meeting protocol eligibility requirements. 56% of patients in the VSG had glioblastoma multiforme, 33% had other malignant glioma, and 11% had low-grade glioma. 64% were stratified as progressive. 12% had received prior chemotherapy. RESULTS: The group randomized to PCNU had the longer survival (p = 0.06 for the RP, p = 0.07 for the VSG). In the VSG, median survival was 10 months for the cisplatin group, 13 months for the PCNU group. The difference between treatment groups was significant (p < or = 0.02) when adjusted for important prognostic factors. PCNU lead to greater hematotoxicity; cisplatin lead to greater renal toxicity and some ototoxicity. Some cisplatin patients experienced complications associated with IA administration, including six cases of encephalopathy. CONCLUSION: The trial showed a survival advantage to the group randomized to PCNU, although the difference was modest. Coupled with previous BTCG results, these trails suggest that PCNU is an active drug for brain tumors.

Prognostic relevance of epidermal growth factor receptor (EGF-R) and c-neu/erbB2 expression in glioblastomas (GBMs).

Seventeen untreated primary adult glioblastomas were analyzed using immunocytochemistry for the expression of EGF-R, c-neu/erbB2, TGF-alpha, and phosphotyrosine. Patients were divided by median survival into long-term or short-term survivors (LTS, N = 10, median > 4 years; versus STS, N = 7, median 61 weeks). There were no significant differences between the two groups in terms of age, extent of resection, post-operative Karnofsky status, or treatment. Diagnostic sections from each tumor were stained with antibodies to EGF-R, c-neu/erbB2, TGF-alpha and phosphotyrosine. Double-labelling for TGF-alpha and EGF-R was also performed. All 10/10 LTS were considered to be EGF-R negative/scant, while 4/7 STS were EGF-R positive. EGF-R negativity significantly correlated with long-term survival. The differences in c-neu/erbB2 expression did not reach significance. However, 4/7 STS were positive for both proteins and 76% of the 17 cases were either double negative or positive for EGF-R and c-neu/erbB2. TGF-alpha and phosphotyrosine were frequently expressed, but neither were prognostic. Recurrent tumors were studied in 7 STS. EGF-R expression was increased in 4/7 of these cases and c-neu/erbB2 was increased in all 7 cases, compared to the pretreatment baselines. Increased expression of these proteins in glioblastomas may be associated with aggressive clinical behavior and treatment resistance.

Is [1-11C]putrescine useful as a brain tumor marker?

Our experience with 11C-putrescine underscores the difficulty of finding a selective brain tumor tracer, uniquely incorporated by neoplastic glia or metastatic cells within brain, but not by the proliferating, nontransformed cells which constitute a normal pathophysiological reaction to various disease processes. Thirty-three patients with 36 lesions were studied with 11C-putrescine to determine the specificity of labeled putrescine for tumor tissue. The uptake of 11C-putrescine was correlated with local cerebral glucose metabolic rate in various lesions, including different types of tumors, to assess the relationship between 11C-putrescine uptake and tumor biology. Carbon-11-putrescine uptake was similar in malignant tumor and benign, non-neoplastic lesions with blood-brain barrier breakdown, illustrating the lack of tumor specificity of this tracer. Carbon-11-putrescine was not well incorporated into poorly enhancing lesions, regardless of their pathology, emphasizing the requirement of a disrupted blood-brain barrier for 11C-putrescine uptake. The ratio of 11C concentration within lesions, compared to that in a region of interest in the contralateral brain, weakly correlated with an analogous ratio for local cerebral glucose metabolic rate in various lesions. Physiological processes not unique to tumors are associated with polyamine active transport and metabolism and contribute to the lack of tumor specificity of 11C-putrescine. Carbon-11-putrescine appear to have less diagnostic utility than 18FDG in brain tumors. The potential of 11C-putrescine for evaluating the effect of antineoplastic therapy and providing prognostic information on brain tumors remains to be investigated.

Temporal effects of dexamethasone on blood-to-brain and blood-to-tumor transport of 14C-alpha-aminoisobutyric acid in rat C6 glioma.

We used quantitative autoradiography (QAR) to evaluate the effect of systemically administered dexamethasone on capillary permeability in brain tumors and surrounding brain. Rats bearing unilateral right hemispheric C6 gliomas were studied at one and twelve hours after 10 mg/kg of intraperitoneal dexamethasone. Capillary permeability was determined by measuring unidirectional blood-to-brain and blood-to-tumor transport of 14C-alpha aminoisobutyric acid (14C-AIB) over fifteen minutes. 14C-AIB entry into tumor, brain adjacent-to-tumor (BAT), and ipsilateral and contralateral cortices was determined and expressed as a unidirectional transfer constant, K. Nontreated tumor K was more than two-fold greater than K for BAT and ten-fold greater than ipsilateral cortical K, confirming substantial barrier disruption in tumor. In addition, the K for BAT was also significantly greater than K for cortex, indicating that the barrier in the peritumoral region was also disrupted. One hour after dexamethasone treatment, tumor K fell to 63% of its pretreatment value (p less than 0.025). By twelve hours post-treatment, tumor K fell to 25% of the untreated value (p less than 0.001) and to 47% of the one-hour value (p less than 0.005). BAT K fell to 29% of its untreated value (p less than 0.02) and to 46% of its one-hour value (p less than 0.02). By 12 hours, ipsilateral cortical K fell to 67% of the untreated cortical value (p less than 0.05). Compared to untreated values, there was no significant difference between contralateral cortical K at either one or twelve hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma carcinoembryonic antigen as an indicator of cerebral metastases.

Four patients in whom the plasma CEA reflected the clinical course of intracranial disease are presented. We conclude that a search to explain an elevated CEA should include the central nervous system. In addition, in selected patients with brain metastases the plasma CEA is a helpful indicator of tumor control and of its response to radiation and chemotherapy.

Experimental meningeal carcinomatosis selectively depresses local cerebral glucose utilization in rat brain.

Using quantitative autoradiography, we investigated the effect of meningeal carcinomatosis on local cerebral glucose utilization (LCGU). A rat model of meningeal carcinomatosis using Walker 256 tumor was used. LCGU was evaluated using 14C-2-deoxy-D-glucose according to the Sokoloff method. Thirty-one neuroanatomic structures were evaluated, both separately and as part of five functional or neuroanatomic groups: olfactory, auditory, visual, limbic, and white matter. The relationship between tumor and LCGU of underlying brain was examined. Compared with controls, there was no global change of LCGU in the experimental group that applied to all structures. However, mean LCGU was significantly depressed in olfactory cortex, temporal cortex, olfactory tubercle, amygdala, caudate/putaman, inferior colliculus, medial geniculate, anterior commissure, and corpus callosum, and the functional groups that make up the olfactory and auditory systems. There was no correlation between extent of regional tumor burden and degree of depression of LCGU in underlying structures. In meningeal carcinomatosis, tumor results in selective regional depression of LCGU. This occurs both in structures underlying tumor and those anatomically remote, but in certain cases, functionally related to structures subadjacent to tumor. These data may help to explain the diversity of neurologic dysfunction seen in patients with meningeal cancer.

Pharmacokinetics of tumor cell exposure to [14C]methotrexate after intracarotid administration without and with hyperosmotic opening of the blood-brain and blood-tumor barriers in rat brain tumors: a quantitative autoradiographic study.

Using quantitative autoradiography, we investigated the entry over 90 min of [14C]methotrexate (MTX) into C6 gliomas implanted bilaterally into Wistar rat brains. The [14C]MTX was administered into the right carotid artery, yielding ipsilateral "arterial" brain and tumor concentrations and contralateral "systemic" concentrations. In a separate group of tumor-bearing rats, mannitol 1.6 M was given into the right carotid artery prior to administering the [14C]MTX to disrupt the blood-brain barrier on the ipsilateral side. [14C]MTX tissue concentrations were measured in regions of 50 x 50 x 20 microns in tumor, peritumoral brain tissue (brain adjacent to tumor), and cerebral cortex. In the nonmannitol experiments, tissue concentrations from the rats at each time interval were fitted using a nonlinear curve fitting program, and the pharmacokinetic values of influx and efflux of [14C]MTX into the three compartments were calculated. The influx rate constant K1 for [14C]MTX ranged from 1.3 to 8.2 microliters/g/min in the tumor. Influx rate constants in the cortex were 1.3-1.9 microliters/g/min and in the brain adjacent to tumor were 1.7-2.8 microliters/g/min. The efflux rate constant k2 was approximated for each tissue but was less reliable than the K1 values. The k2 for tumor, brain adjacent to tumor, and cortex was always higher than the corresponding K1. Peak [14C]MTX concentrations in the tumor were highest after arterial infusion with hyperosmolar barrier disruption, lower after arterial administration without barrier modification, and lowest after systemic administration. However, cortical [14C]MTX concentration was also highest after arterial administration with barrier modification and higher than the highest tumor concentration. Furthermore, tissue exposure (concentration x time) was also highest in the cortex after barrier disruption. The [14C]MTX concentration x time (micrograms/min/g x 90 min +/- SEM) ratio between tumor and cortex after systemic administration was 33.4 +/- 4.1:15.7 +/- 1.9; after arterial administration it was 96.3 +/- 11.7:30.3 +/- 3.1; after arterial administration with barrier disruption it was 266.6 +/- 28.8:311.2 +/- 15.9. The greatest tumor:cortex ratio (3.1:1) occurred with arterial drug administration without barrier disruption. Disrupting the barrier enough to permit increased tumor exposure actually increased cortical exposure to a greater degree. The resulting poorer therapeutic ratio would not appear to support this technique in humans, at least for neurotoxic drugs.

Opening the blood-brain and blood-tumor barriers in experimental rat brain tumors: the effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow.

Using quantitative autoradiography, we investigated the effect of intracarotid infusions of hyperosmolar mannitol solutions on capillary permeability and blood flow. Capillary permeability, expressed in terms of a blood-to-tissue transfer constant (K), was determined in two rat brain tumor models by measuring the entry of 14C-alpha aminoisobutyric acid into brain tumor, into brain tissue adjacent to tumor, and into cortex. Cerebral blood flow was determined by measuring the uptake of 14C-iodoantipyrine in one rat brain tumor model. Blood flow was examined in the same regions as K, as well as in the corpus callosum. Before mannitol administration, K values in both Walker 256 (W256) carcinosarcoma and C6 gliomas were much higher than those in cortex. C6 gliomas were about three times more permeable than were W256 tumors. There was a direct correlation between tumor size and increased capillary permeability. Mannitol at a concentration of 1.37 M did not increase the K values for either tumor or adjacent tissue. At 1.6 M, mannitol increased the K values for both tumors (1.7-fold in C6 glioma and 13-fold in W256) as well as for adjacent tissue. At both concentrations, mannitol markedly increased cortical K values in all groups: by 48- to 72-fold at 1.37 M and by 90- to 105-fold at 1.6 M. The net effect of the mannitol was to reverse the tumor-to-cortex permeability relationship. Cortical blood flow increased modestly after intracarotid mannitol administration on both sides of the brain. These data provide little justification for using intracarotid mannitol during chemotherapy of human brain tumors.