Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Isoquinoline and peripheral-type benzodiazepine binding in gliomas: implications for diagnostic imaging.

Binding of the isoquinoline PK 11195 and of the benzodiazepines Ro5-4864 and flunitrazepam was compared in glioma cells and tissues. In human and rat glioma cell cultures [3H]PK 11195 bound with higher affinity (Kd = 14.01 and 15.76 nM, respectively) than either Ro5-4864 (Ki = 1200 and 84.9 nM, respectively) or flunitrazepam (Ki greater than 10,000 and = 848 nM, respectively). Autoradiograms of postmortem human brain sections containing glioma revealed that [3H]PK 11195 bound specifically to intact tumor cells and not to cells of normal cerebral cortex or necrotic areas of the tumor. Total [3H]Ro5-4864 or [3H]flunitrazepam binding to these sections was indistinguishable from nonspecific binding, and regions of tumor and normal brain could not be delineated. These results support the use of radiolabeled PK 11195 for clinical trials of imaging human gliomas by positron emission tomography.

Evaluating changes in tumor volume using magnetic resonance imaging during the course of radiotherapy treatment of high-grade gliomas: Implications for conformal dose-escalation studies.

OBJECTIVE: To determine whether changes in tumor volume occur during the course of conformal 3D radiotherapy of high-grade gliomas by use of magnetic resonance imaging (MRI) during treatment and whether these changes had an impact on tumor coverage. METHODS AND MATERIALS: Between December 2000 and January 2004, 21 patients with WHO Grades 3 to 4 supratentorial malignant gliomas treated with 3D conformal radiotherapy (median dose, 70 Gy) were enrolled in a prospective clinical study. All patients underwent T1-weighted contrast-enhancing and T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging at approximately 1 to 2 weeks before radiotherapy, during radiotherapy (Weeks 1 and 3), and at routine intervals thereafter. All MRI scans were coregistered to the treatment-planning CT. Gross tumor volume (GTV Pre-Rx) was defined from a postoperative T1-weighted contrast-enhancing MRI performed 1 to 2 weeks before start of radiotherapy. A second GTV (GTV Week 3) was defined by use of an MRI performed during Week 3 of radiotherapy. A uniform 0.5 cm expansion of the respective GTV, PTV (Pre-Rx), and PTV (Week 3) was applied to the final boost plan. Dose-volume histograms (DVH) were used to analyze any potential adverse changes in tumor coverage based on Week 3 MRI. RESULTS: All MRI scans were reviewed independently by a neuroradiologist (DGH). Two patients were noted to have multifocal disease at presentation and were excluded from analysis. In 19 cases, changes in the GTV based on MRI at Week 3 during radiotherapy were as follows: 2 cases had an objective decrease in GTV (> or =50%); 12 cases revealed a slight decrease in the rim enhancement or changes in cystic appearance of the GTV; 2 cases showed no change in GTV; and 3 cases demonstrated an increase in tumor volume. Both cases with objective decreases in GTV during treatment were Grade 3 tumors. No cases of tumor progression were noted in Grade 3 tumors during treatment. In comparison, three of 12 Grade 4 tumors had tumor progression, based on MRI obtained during Week 3 of radiotherapy. Median increase in GTV (Week 3) was 11.7 cc (range, 9.8-21.3). Retrospective DVH analysis of PTV (Pre-Rx) and PTV (Week 3) demonstrated a decrease in V(95%)(PTV volume receiving 95% of the prescribed dose) in those 3 cases. CONCLUSIONS: Routine MR imaging during radiotherapy may be essential in ensuring tumor coverage if highly conformal radiotherapy techniques such as stereotactic boost and intensity-modulated radiotherapy are used in dose-escalation trials that utilize smaller treatment margins.

A comparison of the predictive power for survival in gliomas provided by MIB-1, bromodeoxyuridine and proliferating cell nuclear antigen with histopathologic and clinical parameters.

The purpose of this prospective study of 65 patients was to compare side-by-side the predictive power for survival of (a) MIB-1, (b) bromodeoxyuridine (BUDR), and (c) proliferating cell nuclear antigen (PCNA). They were compared (a) with each other, (b) with several clinical predictors, and (c) with histopathologic grade under actual clinical biopsy conditions in a study of 1993 World Health Organization (WHO) grade II to IV adult supratentorial gliomas. There was a strong positive relationship between MIB-1 and BUDR by Spearman Rank correlation. In univariate analysis, MIB-1 (logrank p = 0.06) was more predictive of survival than BUDR or PCNA. Longer survivors were distinguished from others by the lowest MIB-1 labeling indices (LI < or = 2.5%) better than by the lowest histopathologic grade. However, histopathologic grades were highly predictive among the entire group (logrank p < 0.0001). Young age (p < 0.0001) and high Karnofsky performance status (p < 0.0001) were the clinical factors most predictive of longer survival. Female gender correlated with longer survival (logrank p = 0.02). In multivariate Cox proportional hazards models, age, Karnofsky performance status, and histopathologic grading remained statistically significant after full reduction of the model. We conclude that Ki-67 measured by MIB-1 monoclonal antibody was superior to other markers of proliferation. When all factors are considered simultaneously over all 3 grades of malignancy, greatest predictive power resides in histopathologic grade and clinical variables. MIB-1 is expected to be most important in cases where clinical or histopathologic factors are ambiguous or where they cannot be fully assessed.

Nuclear parameters as prognostic indicators in glioblastoma patients.

The objective of this study was to determine whether nuclear parameters were associated with prognosis in glioblastoma multiforme. DNA indices, cell cycle parameters, and nuclear population densities were compared with patient survival. Selection criteria included the pathologic diagnosis of a cerebral glioblastoma multiforme, absence of therapy before surgery, and adequate tissue to measure each nuclear parameter studied. Nine cases accrued over a two year period. The amount of DNA per nucleus was quantified in fresh tissue specimens by nuclear-isolation flow cytometry in Vindelov's solution. One particular association was significant when tested by Cox models: The percentage of nuclei with S-phase amounts of nuclear DNA was a significant predictor of decreased survival (regression coefficient = 0.20, p = 0.04). The percentage of nuclei in the G0/G1 peak was marginally associated with longer survival. These data are evidence of an association between nuclei in certain phases of the DNA cell cycle and postoperative survival.

In vivo measurement of regional brain and tumor pH using [14C]dimethyloxazolidinedione and quantitative autoradiography.

Using [14C]dimethyloxazolidinedione ([14C]-DMO) and quantitative autoradiography, we estimated tissue pH (pHt) and intracellular pH (pHi) in nine regions of the normal rat brain and in intracerebrally implanted RG-2 gliomas. Calculations of regional pHt, based on equilibrium tissue and arterial plasma [14C]DMO concentration, ranged from 6.83 to 6.94; pHi, calculated assuming an extracellular water volume of 0.15 ml/g for gray matter and 0.11 ml/g for white matter, ranged from 6.61 to 6.78. No consistent difference was found in pHt or pHi between white and gray matter regions. Tumor tissue water content was determined by drying to constant weight, and extracellular space water volume (Ve) was estimated with [14C]sucrose in nephrectomized rats using quantitative autoradiography. Tumor pHt ranged from 7.08 to 7.18. For Ve = 0.17 (measured), pHi was 6.94-7.06; for Ve = 0.30 (assumed), the corresponding range for pHi was 6.63-6.90. Thus, the RG-2 glioma is not more "acidic" than adjacent brain tissue and its "alkaline" pHt probably reflects a large extracellular water content and plasma-like extracellular pH.

Mixing in the human carotid artery during carotid drug infusion studied with PET.

The safety and efficacy of drug infusion into the carotid artery require adequate mixing of the infused solution with carotid blood. Using positron emission tomography (PET), we studied the mixing of solutions infused into the human carotid artery in seven patients by analyzing the distribution of [15O]H2O infused into the carotid artery and by vein. At four infusion rates ranging from 0.5 to 10 ml/min, the variability in distribution averaged 16.5-17.8% among the pixels in a large volume of interest, without dependence on the infusion rate. The overall correlation between [15O]H2O influx with arterial infusion and [15O]H2O influx with venous injection was 0.78-0.82 at the four infusion rates, with no trend toward higher correlations at the faster infusion rates. The distribution into the anterior, middle, and posterior cerebral artery territories differed from distribution throughout the entire carotid territory by an average of 6.2-9.6% at the four infusion rates, with no trend toward smaller differences at the faster infusion rates. Infusions performed into a vinyl tube simulating the carotid artery indicated that at 0.5 ml/min, the velocity of fluid exiting the catheter makes no apparent contribution to mixing. We conclude that with infusions at the carotid bifurcation, mixing in the human carotid artery is complete or nearly complete over a wide range of infusion rates. The mixing appears to result from the patterns of blood flow within the artery, and not from jet effects at the catheter tip.

Effects of xenon and krypton on regional cerebral blood flow in the rat.

The effects of high inspired concentrations of xenon and krypton on regional CBF (rCBF) were assessed in the rat using [14C]iodoantipyrine and quantitative autoradiography. Inhalation of 80% xenon for 1 or 2 min and inhalation of 40% xenon for 2 min were found to have significant effects on rCBF, including average increases of 75-96% in cerebral neocortical regions. Inhalation of 40% xenon for 1 min and of 80% krypton for 2 min had no significant effect on rCBF in most brain regions studied. If xenon inhalation produces effects on rCBF in humans similar to those observed in the rat, such effects could be an important source of error in xenon computed tomography rCBF studies.

A relationship between metabolism in frontal lobes and cerebellum in normal subjects studied with PET.

Lesions of one cerebral hemisphere are associated with decreased glucose metabolism, oxygen metabolism, and blood flow in the contralateral cerebellar hemisphere. We used positron emission tomography to look for a functional relationship in cerebral metabolism between the cerebral cortex and the contralateral cerebellum in normal human subjects. Twenty-four normal subjects were scanned with [18F]fluoro-2-deoxy-D-glucose while in a resting state. Asymmetry in local CMRglu (LCMRglu) in the frontal cortex was strongly correlated with asymmetry in LCMRglu in the opposite direction in the cerebellar hemispheres (r = -0.60, p less than 0.001). Widespread subregions of the frontal cortex were found to contribute to this relationship. Considering these results together with previous studies demonstrating that frontal lesions are associated with decreased metabolism in the contralateral cerebellum, we conclude that the frontal cortex exerts a strong modulating influence on metabolism in the contralateral cerebellum in normal subjects, and that this influence may be asymmetrical.

Clinical outcome in aggressively treated meningeal carcinomatosis.

OBJECTIVE: To critically evaluate the clinical outcome of patients with cytologically proved meningeal carcinomatosis and to identify factors associated with an improved outcome. DESIGN: A consecutive series of patients was identified from a cytopathology data base. The study period was from 1985 to 1990. Case records and results of radiologic investigations were reviewed; all patients were followed up until their deaths. SETTING: University hospital with a cancer center. PATIENTS: Thirty-six consecutive patients with cytologically proved meningeal carcinomatosis. Patients with lymphoma or leukemia were excluded. INTERVENTIONS: External beam radiation therapy, intrathecal chemotherapy via a ventricular catheter, and intravenous chemotherapy. MAIN OUTCOME MEASURES: Clinical assessment and survival. RESULTS: Symptoms improved in 15% of 33 treated patients. Response to treatment had no clear relationship with the age, site of involvement, or tumor type. Median survival for treated patients was only 9 weeks. Patients who received more than five intrareservoir chemotherapy treatments had a median survival of 23 weeks. Median survival for patients with breast carcinoma who received intravenous chemotherapy was 20 weeks, significantly better than that of patients not receiving intravenous chemotherapy. CONCLUSIONS: Survival is poor despite aggressive treatment. Intravenous chemotherapy may improve survival in patients with chemoresponsive primary tumors and deserves further study.

Characteristics of the dysarthria of multiple system atrophy.

OBJECTIVE: To characterize the dysarthria in patients with multiple system atrophy (MSA). DESIGN: Motor speech examinations, consisting of oral motor, oral agility, and perceptual speech analysis, were performed on 46 patients with MSA. SETTING: University department of neurology referral center. RESULTS: All patients had dysarthria with combinations of hypokinesia, ataxia, or spasticity. Thirty-two patients had all 3 components, 13 had 2 components, and 1 had only 1 component. In most patients the hypokinetic components were the most severe. Hypokinetic components predominated in 22 patients (48%), whereas ataxic components predominated in 16 (35%), and spastic components in 5 (11%). In 1 patient (2%) the hypokinetic and spastic components were equal and greater than the ataxic components, and in 1 patient (2%) the hypokinetic and ataxic components were equal and greater than the spastic components. One patient (2%) had only ataxic dysarthria. The predominant type of dysarthria corresponded well to the subtype of MSA. CONCLUSIONS: The finding of a mixed dysarthria with combinations of hypokinetic, ataxic, and spastic components is consistent with both the overall clinical and the neuropathologic changes in MSA. Motor speech examination can provide helpful information in evaluating patients who might have MSA.

The Marinesco-Sjögren syndrome examined by computed tomography, magnetic resonance, and 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography.

The Marinesco-Sjögren syndrome is an autosomal recessive degenerative disorder characterized by congenital cataracts, cerebellar ataxia, spasticity, mental deficiency, and skeletal abnormalities. We studied two adult siblings with Marinesco-Sjögren syndrome using anatomic and metabolic brain imaging techniques to characterize the pattern and nature of abnormalities in the brain. Computed tomographic and magnetic resonance imaging showed diffuse brain atrophy of mild to moderate degree, involving primarily the white matter of the cerebrum, cerebellum, brain stem, and cervical spinal cord. The pattern of atrophy resembled that seen in diffuse leukoencephalopathies. Measurements of local cerebral glucose metabolic rates with positron emission tomography revealed no statistically significant differences from normal control subjects in most regions, but metabolic rate was decreased in the thalamus in one patient. The findings support a diffuse white matter disorder in Marinesco-Sjögren syndrome.

Structural and functional brain imaging in Friedreich's ataxia.

BACKGROUND: Although the major neuropathologic changes in Friedreich's ataxia (FA) affect the spinal cord and peripheral nerves, we previously found abnormally increased glucose metabolism in the cerebral hemispheres in ambulatory patients and a return toward normal metabolism in nonambulatory patients. OBJECTIVE: To determine whether brain atrophy accompanies the decline in cerebral glucose metabolism in FA and whether the degree of atrophy and the extent of decline in cerebral glucose metabolism are related to clinical severity. DESIGN: Prospective series. SETTING: University referral center. PATIENTS: Twenty-two patients with FA and 26 patients with dizziness, headache, or minor acute head trauma, serving as control subjects, who underwent computed tomographic scans that were interpreted as normal. MEASURES: In patients with FA and control subjects, regional atrophy was assessed using subjective and objective measures on computed tomographic scans. In patients with FA, local cerebral glucose metabolism was measured with positron emission tomography, and clinical severity was assessed with a clinical rating scale. RESULTS: Atrophy in the cerebral hemispheres, cerebellum, and brain stem was significantly greater in patients with FA than in control subjects, and the degree of atrophy correlated with the clinical severity. Local cerebral metabolic rate for glucose declined significantly from the initially elevated levels in the thalamus, cerebellum, and brain stem in correlation with increasing clinical severity. CONCLUSIONS: The structure and function of wide-spread brain regions including the cerebral hemispheres are abnormal in FA, and these abnormalities correlate with the clinical severity.

Neuropsychological changes in olivopontocerebellar atrophy.

We used standardized neuropsychological measures of intellectual, cognitive, psychomotor, and emotional functioning to compare 39 patients with olivopontocerebellar atrophy and 25 normal controls of similar age. The patients reflected greater depression, anxiety, and subjective emotional discomfort than did the control subjects. While 4 of the patients had below-normal IQ scores (Wechsler Adult Intelligence Scale [WAIS-R] Full-Scale IQ [FSIQ] less than 80), their clinical histories suggested lifelong functioning at such levels. As a group, the patients were not abnormal in general intellectual functioning and related cognitive abilities (WAIS-R FSIQ, mean [+/- SD], 93.46 +/- 13.19; Wechsler Memory Scale mental quotient, 108.95 +/- 17.43). These scores were lower than those of the normal controls (WAIS-R FSIQ, 113.72 +/- 12.68; mental quotient, 127.80 +/- 12.40); however, the controls were a highly educated group with intelligence levels that were higher than those of the average population. Moreover, when education and motor dysfunction were statistically covaried, no significant differences between the patients and the normal controls were apparent on the cognitive and intellectual tasks. Further analysis of specific memory performance in a subgroup of patients and controls matched for age, sex, and education yielded findings that were comparable with the overall group analysis. We conclude that motor dysfunction and depressed mood could leave patients with olivopontocerebellar atrophy appearing to be impaired in memory, even demented, when they are not.

Impaired upper limb coordination in alcoholic cerebellar degeneration.

BACKGROUND: Alcoholic cerebellar degeneration (ACD) is a disorder resulting from severe chronic alcoholism and malnutrition and is characterized by cognitive disturbances, ataxia of gait, and truncal instability, with generally preserved coordination of the upper extremities. OBJECTIVES: To determine whether cognitive deficits in patients with ACD are the same as those seen in patients with severe chronic alcoholism without ACD and to determine whether upper limb motor coordination is different in the 2 groups. DESIGN: We examined cognitive function and upper limb coordination in 56 patients with severe chronic alcoholism, 13 with ACD and 43 without ACD, who had comparable levels of total alcohol intake. Neuropsychological and motor function was measured using an expanded Halstead-Reitan Neuropsychological Test Battery, including the Tactual Performance Test and Grooved Pegboard Test. RESULTS: Neither group had impaired coordination of upper limb function on clinical neurological examination. Both groups had impaired performance on neuropsychological tests involving executive function, but the patients with ACD had greater impairment of upper limb coordination than the patients without ACD as measured by the Tactual Performance Test and Grooved Pegboard Test. CONCLUSIONS: The findings suggest that these 2 groups have similar cognitive deficits but that upper extremity motor functions are more significantly impaired in the ACD group and that quantitative tasks of motor function reveal these impairments.

Clinical outcome in aggressively treated meningeal gliomatosis.

We reviewed 11 consecutive patients with an antemortem cytologic diagnosis of meningeal gliomatosis. In three patients, meningeal gliomatosis was diagnosed before surgical resection of the glioma. Three of five patients with anaplastic astrocytoma and one with oligodendroglioma improved with treatment. Patients with glioblastoma multiforme did not respond and had a median survival from the diagnosis of meningeal gliomatosis of only 8 weeks. Meningeal gliomatosis can be an early finding in gliomas. Treatment response is probably related to tumor histology and grade.

Acute pandysautonomic neuropathy.

Acute pandysautonomic neuropathy is characterized by severe postganglionic sympathetic and parasympathetic dysfunction, with relative or complete sparing of motor and sensory function. Of four reported cases with sural nerve biopsies, two were normal and two abnormal, revealing loss of small myelinated and unmyelinated fibers. We present a patient with pandysautonomic neuropathy and elevated CSF protein whose sural nerve biopsy showed active axonal degeneration.

Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure.

The Brain Tumor Study Group has shown procarbazine (PCB) to be as effective an adjuvant treatment as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We treated 35 patients with recurrent malignant astrocytomas after radiation and nitrosourea failure with successive courses of PCB 150 mg/m2/d for 28 days every 8 weeks. After 2 courses, 2 patients had complete responses, 7 had partial responses, 11 had stable disease, and 15 had progression. Significantly more patients receiving PCB had complete or partial responses or stable disease than a similar group of patients in a previous trial who received intra-arterial (IA) cisplatin (DDP). There is a significant advantage in time to disease progression for those receiving PCB compared with those receiving IA diaziquone (AZQ). Our results suggest that PCB is a more effective 2nd agent than IA DDP or AZQ following radiation and nitrosourea failure.

Chemotherapy response criteria in malignant glioma.

No one has ever proven a relationship between the extent of response to chemotherapy in malignant glioma and time to progression or survival. We studied the predictive value of "imaging response" following two courses of nitrosourea-based chemotherapy in 136 patients with recurrent astrocytoma/malignant glioma. We performed image analysis by blinded side-to-side comparison of sequential studies, and categorized response into: partial response (PR) (>50% reduction), minor response (MR) (25-50% reduction), stable disease (SD) (<25% change), progressive disease (PD) (>25% increase). Patients with PR, MR, and SD did not differ with respect to time to progression (TTP) (p > 0.2) or survival (p > 0.2). Median TTP was 27 weeks for SD, 43 weeks for MR, and 30 weeks for PR. Patients with PD had a significantly reduced survival (p < 0.001). Median survival was 21 weeks for PD, 53 weeks for SD, 63 weeks for MR, and 48 weeks for PR. The lack of relationship between response and TTP may be due to early relapses in patients with response, a cytostatic benefit of chemotherapy in some patients who do not have an objective response, or a relatively favorable natural history in some tumors that do not respond to chemotherapy. Our data do not support the validity of current response grading, assessed after two courses of chemotherapy. Further research and validation of response criteria is necessary.

Age influences chemotherapy response in astrocytomas.

OBJECTIVE: In patients with cerebral astrocytomas treated with nitrosourea-based chemotherapy, to determine whether age is predictive of response, time to progression, survival, or rate of complications. DESIGN: Retrospective analysis of neuroimaging studies and clinical data. SETTING: University hospital with a busy neuro-oncology service. PATIENTS: One hundred forty-eight patients with pathologically confirmed malignant astrocytomas or recurrent astrocytomas. RESULTS: Partial response occurred in 39% of patients aged < 40 years, in 17% of those aged 40 to 59, and in only 5% of those aged > or = 60 (p < 0.001). Median time to progression after chemotherapy was 23 weeks in patients aged < 60 and 6 weeks in patients aged > or = 60 (p < 0.001). Median survival after chemotherapy was 43 weeks in patients aged < 60 but only 24 weeks in patients aged > or = 60 (p < 0.001). Differences between age groups in response rate, time to progression, and survival persisted with adjustment for tumor grade. The risk of myelosuppressive complications requiring hospitalization was significantly related to age (p = 0.03); such complications occurred in 35% of patients aged > or = 60 and 16% of patients under 60 years. CONCLUSION: Age is strongly predictive of the likelihood of a response to chemotherapy, time to progression, survival, and risk of myelosuppressive complications. Patients aged > or = 60 have a lower change of benefit and an increased risk of myelosuppressive complications from chemotherapy for astrocytomas compared with younger patients.