Jane B. Alavi

Treatment of Primary CNS Lymphoma With Methotrexate and Deferred Radiotherapy: A Report of NABTT 96–07

PURPOSE A multicenter, phase II study of single-agent, intravenous methotrexate in newly diagnosed non-AIDS-related primary CNS lymphoma was conducted in the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. METHODS Methotrexate (8 g/m(2)) was initially administered every 2 weeks. The primary end point was radiographic CR or PR, as defined by standard radiographic criteria, and secondary end points were survival and drug-related toxicity. RESULTS Twenty-five patients were enrolled with a mean age of 60 years and median Karnofsky Performance Score of 80. Three of 14 patients who underwent lumbar puncture had malignant cells on CSF cytopathology, and five of 25 patients had ocular involvement. Two patients could not be evaluated for the primary end point because of the absence of measurable disease in one and death before radiologic imaging in another. All patients have completed the treatment program or progressed. Among 23 patients, there were 12 CR (52%), five PR (22%), one (4%) with stable disease, and five progressions (22%) while on therapy. Seven patients died of tumor progression, and two died of other causes. Median progression-free survival was 12.8 months. Median overall survival for the entire group had not been reached at 22.8+ months. The toxicity of this regimen was modest, with no grade 3 or 4 toxicity in 13 of 25 patients, grade 3 toxicity in eight of 25 patients, and grade 4 toxicity in four of 25 patients after 287 cycles of chemotherapy. CONCLUSION These results indicate that high-dose methotrexate is associated with modest toxicity and a radiographic response proportion (74%) comparable to more toxic regimens.

Positron emission tomography in patients with glioma. A predictor of prognosis.

Positron emission tomography (PET) studies have been performed using 18‐F‐fluorodeoxyglucose in 29 adult subjects with primary brain tumors. Seventy‐two percent of the patients were treated previously. The glucose metabolic state in the lesions was increased in 16 patients, and was normal or decreased in 13 patients. The hypermetabolic tumors tended to behave in a more malignant fashion. Patients with hypermetabolic tumors had a median survival of 7 months after PET scan, compared to 33 months for those with hypometabolic lesions. Among the high‐grade glioma patients, the PET results separated them into a good prognosis group (hypometabolic, with 78% 1‐year survival) and a poor prognosis group (hypermetabolic, with a 29% 1‐year survival after PET). These results suggest that glucose metabolic studies may provide an independent measure of the aggressiveness of a brain tumor, and may supplement pathologic grading.

Positron emission tomography imaging of regional cerebral glucose metabolism

The (F-18) fluorodeoxyglucose (FDG) technique to measure local cerebral metabolic rate for glucose (LCMRglu) is well accepted and widely used by many institutions around the world. A large number of studies has been carried out in normal volunteers and patients with a variety of CNS disorders. Several investigators have noted that no significant age-related changes in cerebral glucose use occur with normal aging. Some important and interesting findings have been revealed following sensory, motor, visual, and auditory stimulations. Functional imaging with FDG in certain neurologic disorders has dramatically improved our understanding of their underlying pathophysiologic phenomena. Some abnormalities detected on the positron emission tomography (PET) images have no corresponding changes on either x-ray computed tomograms (XCT) or magnetic resonance images (MRI). In patients with Alzheimers disease, primary sensorimotor, visual, and cerebellar metabolic activity appears relatively preserved. In contrast, parietal, temporal, and to some degree, frontal glucose metabolism is significantly diminished even in the early stages of the disease. Patients with Huntingtons disease and those at risk of developing this disorder have a typical pattern of diminished CMRglu in the caudate nuclei and putamen. In patients with stroke, PET images with FDG have demonstrated abnormal findings earlier than either XCT or MRI and with a wider topographic distribution. FDG scans have revealed interictal zones of decreased LCMRglu in approximately 70% of patients with partial epilepsy. The location of the area of hypometabolism corresponds to the site of the epileptic focus as determined by electroencephalography and microscopic examination of the resected tissue. Ictal scans during partial seizures demonstrate areas of hypermetabolism corresponding to the sites of seizure onset and spread. Several investigators have reported relative hypofrontal CMRglu in patients with schizophrenia. In our center, FDG scans from patients with schizophrenia were successfully differentiated from those obtained in normal controls. Finally, our preliminary data (using PET, XCT, and MRI) in patients with CNS disorders indicate that MRI provides excellent delineation of the structural abnormalities. It may prove to be superior to XCT in the evaluation of certain diseases such as cerebral ischemia and infarcts, head injury, tumors, and white matter lesions. Metabolic imaging with FDG provides functional information not obtainable with either MRI or NMR spectroscopy. Therefore, PET studies will play a complementary role to the anatomic imaging in the management of patients with CNS disorders.

New grading system of cerebral gliomas using positron emisson tomography with F-18 fluorodeoxyglucose

SummaryPositron emission tomography (PET) using fluorine-18 (18F)-fluorodeoxyglucose (FDG) has been reported to be a powerful diagnostic and prognostic tool in patients with primary brain tumors. This study was undertaken to compare the prognostic value of: (1) visual grading of [18]FDG uptake in the tumor, (2) the absolute glucose metabolic rate of the tumor (TMRglc), (3) the ratio of glucose metabolism between the tumor and whole brain (T/WB) and (4) between the tumor and contralateral cerebellum (T/CBL). Each of these four parameters was correlated with the survival time in 20 patients with malignant cerebral gliomas. Excellent correlation was obtained with visual grading and reasonably good correlation was obtained with T/WB or T/CBL, but TMRglc alone was only a fair prognostic indicator. Thus, visual grading provides a qualitative analysis and T/WB provides a semi-quantitative analysis neither of which requires arterial blood sampling for quantification of absolute metabolic rates for glucose.

Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma

Penicillamine is an oral agent used to treat intracerebral copper overload in Wilsons disease. Copper is a known regulator of angiogenesis; copper reduction inhibits experimental glioma growth and invasiveness. This study examined the feasibility, safety, and efficacy of creating a copper deficiency in human glioblastoma multiforme. Forty eligible patients with newly diagnosed glioblastoma multiforme began radiation therapy (6000 cGy in 30 fractions) in conjunction with a low-copper diet and escalating doses of penicillamine. Serum copper was measured at baseline and monthly. The primary end point of this study was overall survival compared to historical controls within the NABTT CNS Consortium database. The 25 males and 15 females who were enrolled had a median age of 54 years and a median Karnofsky performance status of 90. Surgical resection was performed in 83% of these patients. Normal serum copper levels at baseline (median, 130 microg/dl; range, 50-227 microg/dl) fell to the target range of <50 microg/dl (median, 42 microg/dl; range, 12-118 microg/dl) after two months. Penicillamine-induced hypocupremia was well tolerated for months. Drug-related myelosuppression, elevated liver function tests, and skin rash rapidly reversed with copper repletion. Median survival was 11.3 months, and progression-free survival was 7.1 months. Achievement of hypocupremia did not significantly increase survival. Although serum copper was effectively reduced by diet and penicillamine, this antiangiogenesis strategy did not improve survival in patients with glioblastoma multiforme.

Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-α delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas

Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this phase 2 study, aprinocarsen was administered to patients with recurrent high-grade gliomas by continuous intravenous infusion (2.0 mg/kg/day for 21 days per month). Twenty-one patients entered this trial. Their median age was 46 years (range, 28-68 years), median Karnofsky performance status was 80 (range, 60-100), median tumor volume was 58 cm3 (range, 16-254 cm3), and histology included glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), and anaplastic astrocytoma (n = 1). The number of prior chemotherapy regimens included none (n = 3), one (n = 10), and two (n = 8). No tumor responses were observed. Patients on this therapy rapidly developed symptoms of increased intracranial pressure with increased edema, enhancement, and mass effect on neuroimaging. The median time to progression was 36 days, and median survival was 3.4 months. The observed toxicities were mild, reversible, and uncommon (grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy or CNS bleeding resulted from this therapy. Plasma concentrations of aprinocarsen during the infusion exhibited significant interpatient variability (mean = 1.06 mug/ml; range, 0.34-6.08 mug/ml). This is the first study to use an antisense oligonucleotide or a specific PKC-alpha inhibitor in patients with high-grade gliomas. No clinical benefit was seen. The rapid deterioration seen in these patients could result from tumor growth or an effect of aprinocarsen on bloodbrain barrier integrity.

Sickle Cell Anemia: Pathophysiology and Treatment

Current concepts of the pathophysiology of the sickling process are reviewed. New approaches to treatment - including induced hyponatremia, membrane-active antisickling agents, and gene manipulation - are described.

Gefitinib in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): The Expanded Access Protocol Experience at the University of Pennsylvania

Gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE) is an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with favorable toxicity and antitumor activity in pretreated patients with non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the toxicity and efficacy of gefitinib in patients with advanced NSCLC treated at our institution as part of an expanded access protocol; 112 patients with advanced NSCLC were entered. All patients had failed at least one previous chemotherapy regimen, or were not suitable for any systemic chemotherapy because of poor performance status (PS), or were ineligible for other clinical trials. Therapy consisted of gefitinib 250 mg orally once daily; 10.5% (95% CI 5.3–17.9%) of patients achieved partial/minimal response (PR/MR) and 29.5% (95% CI 21.0–39.2%) had stable disease (SD), resulting in a disease control rate (PR/MR + SD) of 40% (95% CI 31–50%). The median duration of treatment for all patients was 12 weeks (range 2–116 weeks) and for patients achieving disease control 28 weeks (range 8–116). Nine patients received gefitinib for more than 1 year. Median survival was 30 weeks. Symptoms were improved in 36% of evaluable patients, and 64% of patients who achieved disease control experienced improvement of their disease related symptoms. Adverse events were generally mild and consisted mostly of skin rash (48%) and diarrhea (38%). A statistically significant association was observed between disease control and skin rash (p = < 0.001), nonsmoking status (p = 0.048), and symptom improvement (p = 0.001). The disease control rate was not statistically associated with histology, PS, gender, or number of prior treatments. In addition, longer survival was significantly associated with skin rash (p = < 0.001) and symptom improvement (p = < 0.001). Gefitinib demonstrated relevant clinical activity and a favorable toxicity profile in pretreated patients with advanced NSCLC. The development of toxicity was associated with a favorable response. In addition, a history of never having smoked seems to predict a higher efficacy of gefitinib.

The Effect of Enzyme-Inducing Antiseizure Drugs on the Pharmacokinetics and Tolerability of Procarbazine Hydrochloride

Purpose: Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum tolerated dose and pharmacokinetics of PCB are affected by the concurrent use of enzyme-inducing antiseizure drugs (EIASD). Experimental Design: Adults with recurrent high-grade glioma were divided into cohorts who were (+) and were not (−) taking EIASDs. PCB was given orally for 5 consecutive days each month. Six patients were evaluated at each dose level beginning with 200 mg/m2/d and escalated using the modified continual reassessment method. Toxicity and response were assessed. Pharmacokinetic studies were done with a new electrospray ionization mass spectrometry assay. Results: Forty-nine patients were evaluated. The maximum tolerated dose was 393 mg/m2/d for the +EIASD group and the highest dose evaluated in −EIASD patients was 334 mg/m2/d. Myelosuppression was the primary dose-limiting toxicity. Significant hepatic dysfunction occurred in three patients in the +EIASD cohort. Four partial responses (8%) and no complete responses were observed. PCB exhibited linear pharmacokinetics with no significant differences between the two cohorts. A marked increase in peak PCB levels was noted on day 5 relative to day 1, which was not attributable to drug accumulation. Conclusions: This study suggests that (a) EIASD use does not significantly affect the pharmacokinetics of PCB; (b) changes in the peak plasma concentration of PCB, consistent with decreased apparent oral clearance due to autoinhibition of hepatic metabolism, occur with daily dosing; and (c) severe hepatic dysfunction may accompany this administration schedule.

Sequential computerized tomography and positron emission tomography studies in a patient with malignant glioma.

Computerized tomography (CT) and positron emission tomography (PET) using fluorine-18-deoxyglucose were performed in a patient with malignant glioma over a one-year period. Postoperatively and during radiation therapy, there was slight improvement in metabolic activity in the hemisphere ipsilateral to the tumor. After radiation therapy and during chemotherapy, there was a rapid and then gradual decline in whole brain metabolic rate by 39%. This might have been explained by radiation effect on brain. The tumor area was metabolically similar to the adjacent brain until one year after diagnosis, when an area of abnormal increased activity was noted. Even though CT scans showed minimal evidence of tumour growth, a large glioblastoma multiforme was found at autopsy at the site of the increased activity. Radiation leukoencephalopathy was also observed at autopsy. It is concluded that PET studies may offer new information regarding the metabolic effects of anti-tumor therapy, and may demonstrate regrowth of tumor prior to CT.