Dennis E. Bullard

Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma

BACKGROUND Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results. METHODS We included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy. RESULTS A total of 251 eligible patients were enrolled from 1998 through 2002. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%. A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival. CONCLUSIONS In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375.).

Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial : Clinical article

OBJECT In 1998, the Radiation Therapy Oncology Group initiated a Phase II study of observation for adults < 40 years old with cerebral low-grade glioma who underwent a neurosurgeon-determined gross-total resection (GTR). METHODS Patient eligibility criteria included the presence of a World Health Organization Grade II astrocytoma, oligodendroglioma, or mixed oligoastrocytoma confirmed histologically; age 18-39 years; Karnofsky Performance Scale score > or = 60; Neurologic Function Scale score < or = 3; supratentorial tumor location; neurosurgeon-determined GTR; and pre- and postoperative MR imaging with contrast enhancement available for central review by the principal investigator. Patients were observed following GTR and underwent MR imaging every 6 months. Prognostic factors analyzed for their contribution to patient overall survival, progression-free survival (PFS), and tumor recurrence included age, sex, Karnofsky Performance Scale score, Neurologic Function Scale score, histological type, contrast enhancement on preoperative MR imaging, preoperative tumor diameter, residual disease based on postoperative MR imaging, and baseline Mini-Mental State Examination score. RESULTS Between 1998 and 2002, 111 eligible patients were entered into the study. In these 111 patients, the overall survival rates at 2 and 5 years were 99 and 93%, respectively. The PFS rates in these 111 patients at 2 and 5 years were 82 and 48%, respectively. Three prognostic factors predicted significantly poorer PFS in univariate and multivariate analyses: 1) preoperative tumor diameter > or = 4 cm; 2) astrocytoma/oligoastrocytoma histological type; and 3) residual tumor > or = 1 cm according to MR imaging. Review of the postoperative MR imaging results revealed that 59% of patients had < 1 cm residual disease (with a subsequent 26% recurrence rate), 32% had 1-2 cm residual disease (with a subsequent 68% recurrence rate), and 9% had > 2 cm residual disease (with a subsequent 89% recurrence rate). CONCLUSIONS These data suggest that young adult patients with low-grade glioma who undergo a neurosurgeon-determined GTR have a > 50% risk of tumor progression 5-years postoperatively, warranting close follow-up and consideration for adjuvant treatment.

Growth and Chemotherapeutic Response in Athymic Mice of Tumors Arising from Human Glioma-derived Cell Lines

Fifteen permanent cell lines derived from human gliomas were subcutaneously transplanted into athymic nude mice (nu/nu genotype, NIH Swiss and BALB/c backgrounds). Four were tumorigenic. Three of the four (D-54 MG, U-118 MG, and U-251 MG) produced progressively growing, solid, noncystic tumors. Subcutaneous volume measurement of these tumors, which correlated directly with tumor weight, was a reliable method for monitoring growth. All three cell lines which produced progressively growing subcutaneous tumors were also tumorigenic when cells were inoculated intracerebrally. These grew as well-circumscribed, intraparenchymal brain tumors. After initial implantation, each of the progressively growing, solid, subcutaneous tumors was histologically similar to the permanent cell lines from which it was derived. Tumors could be reliably passed, and stabilization of latency periods and growth rates developed. Tumors became morphologically less distinct in later passages, though some individual features remained. Mice bearing subcutaneous tumors from each of these cell lines were treated with a single ip dose of 25 mg/kg BCNU and compared to controls receiving only drug vehicle. A significant, but different, amount of reduction in tumor mass occurred among each of the three tumor lines. This model allows cell lines derived from human gliomas to be grown in animal hosts, thereby providing a potential means for evaluating growth parameters and chemotherapeutic responsiveness of tumors derived from individual human gliomas or cell lines.

Chromosomal evolution in malignant human gliomas starts with specific and usually numerical deviations

Our previous karyotypic studies of malignant human gliomas have demonstrated that their most consistent early or primary gross changes include gains of #7, losses of #10, #22, and the gonosomes, and the presence of double minutes. Karyotypes of 15 additional malignant human gliomas reported here have confirmed these observations and, by enlarging our series, we can now show that in addition to double minutes, certain other gross structural abnormalities also are clearly associated with the early evolution of this type of tumor. The most prevalent deviations are deletions and translocations involving 9p. Other chromosomes commonly involved in rearrangements are #1, #6, and #13, and less frequently #7, #11, and #16.

Relationship of in Vitro Morphologic and Growth Characteristics of Established Human Glioma-derived Cell Lines to Their Tumorigenicity in Athymic Nude Mice

Fifteen permanent cell lines derived from human gliomas which are individually distinct by immunologic and biochemical criteria were evaluated to determine if morphologic or cell biologic parameters distinguished the 4 lines which were tumorigenic in athymic nude mice. By subjective morphologic appraisal, the 4 tumorigenic lines were considered “malignant” or “borderline,” but 4 of the nontumorigenic lines were also classified in this way. By objective criteria, these 15 lines varied markedly in percentage of piled-up cells, chromatin pattern, pleomorphism, nuclear to cytoplasmic ratio, number of bizarre multinucleate giant cells, presence of abnormal mitotic figures, percentage of colony formation in soft agar, saturation density, population doubling time, and absolute plating efficiency. Among these criteria, percentage of colony formation in soft agar had the highest correlation coefficiency with tumorigenicity, and when this parameter was held constant the only additional characteristic which correlated significantly (p < .05) was the number of bizarre multinucleate giant cells. When the 11 non-tumorigenic lines were ranked by these 2 criteria, 1 non-tumorigenic line (U-251 MGsp) had > .95 predicted probability of tumorigenicity. Although further tumorigenicity testing may increase the number of tumorigenic lines, the lines with few “malignant” characteristics may correspond to the population resembling cells of low grade astrocytomas seen within glioblastomas. The histologic pleomorphism of human gliomas is reflected in their morphologic and cell biologic diversity in culture.

Ependymomas: A clinicopathologic study

Since 1924, when ependymomas were first classified as a distinctive glial neoplasm by Bailey, much has been published concerning these tumors, but there are important points of interest that are still not clear. In order to study more fully the clinical and pathologic characteristics of the ependymoma, we identified 62 patients with histologically proven neoplasms. Twenty-two were supratentorial, 21 were infratentorial, and 19 were intramedullary spinal cord tumors. These groups had mean ages of 17, 7, and 41 years, respectively, at the time of first symptoms. The presenting and accompanying symptoms were related to location and included headaches, nausea, visual changes, hemiparesis, and neck, back, and radicular pain. Neurological signs included papilledema, nystagmus, gait disturbance, cranial nerve palsies, altered mental status, paraparesis, and sensory dysfunction. Radiologic modalities of particular importance included computed tomography and myelography. Surgery and radiation therapy were the primary treatment modalities with median survival times from first symptoms being 92, 36, and 117 months for the above groups, respectively. Based on computer-generated survival curves, several characteristics significantly affected survival. These included tumor site, age, and neuraxis metastases. In patients with supratentorial tumors, cranial nerve palsies, microcystic changes, and mitotic figures were important, while in patients with infratentorial tumors, widened sutures, increased head circumference, age, epithelial features, and subependymal features significantly affected survival. Patients who had complete gross resection of a spinal cord tumor had no recurrences or mortality.

Clinicopathologic correlations in the oligodendroglioma

To determine the prognostic significance of histologic variables in oligodendroglial neoplasms, the presence and degree of 15 such variables were correlated with postoperative survival rates in 71 patients. By univariate analysis, prognostically significant factors, in order of decreasing importance, were mitoses (log), necrosis, nuclear cytologic atypia, vascular hypertrophy, and vascular proliferation. When studied by stepwise regression, necrosis and the number of mitoses contained all of the prognostically useful information. When each of the five variables significant by univariate analysis was tested in the Cox model by adding a variable to the model containing the other four, necrosis was found to be the only independently significant variable. There were significant positive pairwise correlations between each of the five significant histologic variables except for cytologic atypia with necrosis. The only histologic variable with a significant association with older age was the number of mitoses. These results suggest that necrosis and, to a lesser extent, the mitotic count are features that, in the appropriate setting, can be used to identify the “anaplastic” oligodendroglioma.

The fallacy of the localized supratentorial malignant glioma

Supratentorial glioblastoma multiforme (GBM) is a lethal malignancy. Subtotal surgical resection and post operative external beam radiotherapy palliate symptoms and prolong survival, but very few patients survive more than 3 years following diagnosis.‘,3,20*32,43,46,48*5’*58,66 Whereas the probability of survival of supratentorial anaplastic astrocytoma (AA) is slightly better, most patients will still succumb to the tumor.58-60*66 The resistance of these neoplasms to conventional therapies has prompted many physicians to undertake new clinical and laboratory investigations. These have included the use of chemotherapy,44 immunotherapy,40 multiple-fraction-perday radiotherapy,2’,34,49 radiotherapy with chemical radiosensitizers,6’ and neutron radiotherapy.45 As interest in the biology and treatment of malignant gliomas has increased, many conceptual verities have been proposed to guide therapeutic investigations, These include the significance of the cellular heterogeneity of AA and GBM,‘2,24 the presence of the blood-brain-barrier (BBB) as a functional obstruction to chemotherapy, and the local nature of these tumors. In this editorial, we focus on the last of these premises. We have selected this issue because of its major implications for any treatment that is directed at a specific portion of the brain rather than the whole brain: BBB disruption, intracarotid drug administration, and brain brachytherapy. Interstitial brachytherapy is used for primary and recurrent GBM and AA. The technique consists of the stereotactic computed tomography (CT) or magnetic resonance imaging (MRI) guided placement of coaxial catheters within and around the tumor. Radioactive sources are after-loaded into the catheters to deliver continuous low-dose rate irradiation. After a specified dose is delivered, the system is removed.22~27~28~39~45 Interstitial hyperthermia generated by implanted microwave antennae may be administered in conjunction with the radiation.52 One of the justifications invoked for brachytherapy is the concept of malignant gliomas as localizedlesions. Allusions to this concept abound in the literature. “Most malignant gliomas are localized to a single area of the brain, central nervous system (CNS) metastases from these tumors are uncommon and systemic metastases are rare.“29 “Since an astrocytoma is almost invariably a nonmetastatizing single mass, ideally it should lend itself best to regional treatment.“** “Because a primary brain tumor is most often a localized disease, hyperthermia, intratumoral chemotherapy, and interstitial irradiation, the stereotactic placement of radioactive sources directly into brain tumors, have been suggested as possible local treatments for brain tumors.“*’

Oligodendroglioma. An analysis of the value of radiation therapy.

The role of radiation therapy in the treatment of supratentorial oligodendrogliomas is controversial. To evaluate the role of radiation therapy, the Duke University Medical Center series was retrospectively analyzed. Clinical history, radiation dosages, and pathologic materials were reviewed. Seventy‐one patients were identified as having histologically proven oligodendroglioma. Analysis of the patient population demonstrated it to be similar in all major parameters to other populations previously reported in the literature. Multivariate statistical analysis of the demographic, clinical and radiographic variables of these patients showed that a poorer prognosis was associated with persons of increased age (P = 0.052) and black persons (P = 0.014), and in those with papilledema (P = 0.07), hemiparesis (P = 0.001), intellectual deficits (P = 0.0002), and necrosis (P = 0.041). All patients had a surgical procedure as first treatment while 18 and three patients, respectively, underwent a second and third surgical procedure. Thirty‐seven patients had a subsequent course of radiotherapy. Univariate and multivariate statistical analysis comparing the patients treated with surgery alone those treated with surgery plus radiotherapy revealed no significant population or prognostic differences between the groups. The median times until clinical deterioration were 39 versus 27 months, the median times until documented tumor recurrence were 27 versus 28 months and the median survival times were 4.5 versus 5.2 years, for nonirradiated versus irradiated patients. These data, from a large and rigidly evaluated population, demonstrated no statistically significant difference in the symptom‐free interval, time until tumor recurrence, or survival between the groups nor did radiation appear beneficial to any subgroup evaluated. The results suggest the need for a prospective clinical trial to evaluate the true role of radiation therapy in the treatment of this tumor.

Central Nervous System Metastases in Malignant Melanoma

In a series of 1341 patients with histologically proven malignant melanoma seen at Duke University Medical Center from 1968 to 1978, 107 patients developed central nervous system (CNS) metastases. These patients were evaluated on the basis of which factors were associated with the development of CNS metastases. Male patients, patients with invasive primary lesions as measured by Clarks system, and patients with primary lesions of the head/neck or oral mucosa had higher incidences of CNS metastasis. Age and race were not significant factors. Clinically, single CNS metastases were seen in 48.8% of the patients; multiple cerebral lesions were seen in 37.2% of the patients. In 22% of the patients there was CNS metastasis alone, in 41% a second organ was involved, and in 20% three organs were involved.