Faculty Bibliography

We investigated how frequently the imaging procedure we use immediately prior to radiosurgery--triple-dose gadolinium-enhanced MR performed with the patient immobilized in a nonrelocatable head frame and 1-mm-thick MPRAGE (magnetization-prepared rapid gradient echo) images (SRS3xGado)-identifies previously unrecognized cerebral metastases in patients initially imaged by conventional MR with single-dose gadolinium (1xGado). Between July 1998 and July 2000, the diagnoses established for 47 patients who underwent radio-surgical procedures for treatment of cerebral metastases at The Gamma Knife Center of New York University were based initially on the 1xGado protocol. In July 1998, we began using SRS3xGado as our routine imaging protocol in preparation for targeting lesions for radio-surgery, using triple-dose gadolinium and acquisition of contiguous 1-mm Tl-weighted axial images. Because our SRS3xGado scans sometimes unexpectedly revealed additional metastases, we sought to learn how frequently the initial 1xGado scans would underestimate the number of metastases. We therefore reviewed the number of brain metastases identified on the SRS3xGado studies and compared the results to the number found by the 1xGado protocol, which had initially identified the brain metastases. Additional metastases, ranging from 1 to 23 lesions per patient, were identified on the SRS3xGado scan in 23 of 47 patients (49%). In 57% of the 23 patients, only one additional lesion was identified. The mean time interval between the 1xGado and the SRS3xGado scans was 20.6 days (range, 4-83 days), and the number of additional lesions detected and the time interval between two scans were negatively correlated (-0.11). The number of lesions detected on the SRS3xGado was associated only with the number of lesions on the 1xGado and not with any other patient or tumor pretreatment characteristics such as age, gender, largest tumor volume on the 1xGado, or number of days between the 1xGado and the SRS3xGado or prior surgery. The identification of additional lesions with SRS3xGado MR may have implications for patients who are treated with stereotactic radiosurgery alone (without whole-brain irradiation) with single-dose gadolinium imaging, in that unidentified lesions may go untreated. As a result of these findings we continue to use and advocate SRS3xGado scans for radiosurgery

BACKGROUND: Brainstem gliomas often respond to radiotherapy but long term disease control is exceptional. The concomitant administration of a chemotherapy agent with radiosensitizing properties such as carboplatin may increase the efficacy of radiotherapy. METHODS: A dose escalation schedule of carboplatin was devised to determine the maximum tolerated dose (MTD) of intravenous carboplatin when given on a twice-weekly schedule during a course of hyperfractionated, involved field radiotherapy (100 centigrays [cGy] twice daily to 7200 cGy). The starting dose was 20 mg/m(2) and the dose was increased by 15 mg/m(2) after every 3 patients provided no Grade 3 or 4 (according to the National Institutes of Health Common Toxicity Criteria) toxicity occurred. Magnetic resonance imaging (MRI) scans (brain and spine) were obtained before treatment and at the time of disease progression. Clinical entry criteria included an MRI scan demonstrating a diffuse intrinsic pontine tumor and a typical 2-3-month history of evolving cranial neuropathies and a gait disorder. Biopsy-confirmed evidence of a high grade glioma was required for nonpontine brain stem tumors. RESULTS: A total of 34 patients were enrolled. The median age of the patients was 7.8 years (range, 3.6-15.4 years) and the median prodrome duration was 1.5 months (range, 0.25-36 months). The MTD was 110 mg/m(2) or a total cumulative dose of 1540 mg/m(2) over 7 weeks. The dose-limiting toxicity was hematologic. The median progression free survival was 8 months (range, 0-104+ months) and the overall survival was 12 months (range, 5-104+ months). At last follow-up there were 5 long term survivors (15%) who remained in continuous remission after a mean follow-up period of 79 months (range, 46-104 months). Fifteen of the 29 patients (52%) with recurrence and or disease progression developed leptomeningeal/intraaxial tumor spread beyond the local radiation field. CONCLUSIONS: The cumulative MTD for carboplatin is 1540 mg/m(2) when administered concomitantly with involved field, hyperfractionated radiotherapy in a twice-weekly schedule for 7 weeks. Subsequent Phase II and III clinical trials can be conducted safely at this level.

PURPOSE: The 3-year survival rate of pediatric patients with infiltrating brain stem gliomas (BSG) is < 10%. Treatment involves local field radiation, and local failure has been the hallmark of recurrence. With therapeutic advances and improved radiographic monitoring, perceived and actual patterns of failure may change. We report patterns of recurrence in a group of patients with close follow-up, treated on an institutional protocol incorporating hyperfractionated involved-field radiation therapy and concomitant carboplatin, who have been uniformly staged and treated and have undergone MRI surveillance. METHODS AND MATERIALS: From 1990-1995, 18 pediatric patients with BSG were treated on a Phase I-II trial of concurrent carboplatin and hyperfractionated radiotherapy. Eight had surgical procedures to document histology. Nine had hydrocephalus prior to death. All had pretreatment brain and spine MRIs, with and without gadolinium, that showed no other evidence of disease. Treatment consisted of 72.00 Gy involved-field hyperfractionated radiation therapy and dose-escalating concomitant carboplatin. RESULTS: Fifteen children have had progression of disease (median PFS = 9 months); and 13 have died (median OS = 14 months). Fourteen of the 15 children with progression had local failures, 8 of whom had evidence of noncontiguous spinal (4) or intracranial (7) disease documented by MRI or autopsy. One child with local control developed an intracranial metastasis. None had clinical manifestations of leptomeningeal disease. CONCLUSION: Leptomeningeal dissemination occurred within 1 month of local progression in nearly 30% of our patients and, overall, occurred in 50% prior to death. This high incidence may reflect close MRI surveillance or a changing pattern of recurrence. Because the majority of leptomeningeal disease occurs in the setting of local progression, treatment efforts must be directed primarily toward local control. However, management of leptomeningeal dissemination at recurrence is of increasing concern

PURPOSE/OBJECTIVE: Radiation of the entire shaft of a long bone affected by multiple myeloma (MM) is often advocated to prevent recurrent disease in the bone remote from the symptomatic site. Our standard of care has been to irradiate only the symptomatic area. We investigated the pattern of recurrence in patients treated in this manner. METHODS AND MATERIALS: 163 patient with MM were treated between 1971 and 1994. Twenty-seven patients received treatment to a long bone with 41 sites irradiated (17 humeri, 22 femurs, 1 radius, 1 ulna). The most common long bone treated was the femur. All patients were treated with megavoltage therapy. The symptomatic lesion, plus a margin of 1-2 cm was treated with no attempt to treat the entire shaft. Mean radiation dose was 27.82 Gy (range 6.00-44.80 Gy). The length of the field was measured in centimeters and expressed as both an absolute (AL) and relative (RL) length (i.e., percentage of total length of bone). RESULTS: The mean total AL and RL for femur fields was 18 cm and 42%, respectively. For the humerus, the AL and RL were 20 cm and 68%, respectively. Only four patients developed progressive disease in the same bone but outside the previously irradiated field. In three of the four patients the RL was between 20 and 30%. The dose of radiation given to these patients was 12.50, 21.00, 30.00, and 35.00 Gy. In all of these four cases, treatment of progressive disease in adjacent sites provided effective palliation of symptoms. CONCLUSION: Radiation therapy to the symptomatic portion of a long bone affected by MM is effective for palliation. Symptomatic recurrence out of the irradiated field is uncommon and can be effectively treated. Potential benefits of this approach include irradiation of less normal marrow and elimination of use of pairs of fields or extended distance treatment to cover the entire femur

PURPOSE: Ependymoma is an uncommon intracerebral tumor in adults. Since the site of origin frequently prevents complete surgical removal, adjunctive radiotherapy is used to destroy residual disease. We present our experience in treating 10 adults with intracranial ependymoma. METHODS: Five men and 5 women were treated in the past 16 years. The median age was 38 (range 24-69). All had contrast enhanced CT or MRI showing the extent of the tumor. One patient had total excision while the remainder had subtotal removal. Radiation therapy was delivered to the tumor bed with a 1-2 cm margin of normal tissue generally at 180-200 centiGray (cGy) per treatment once a day. Total dose ranged from 5400 to 7200 cGy. Two patients received experimental treatment with 100 cGy delivered twice a day for total of 6800 and 7200 cGy respectively. Four patients received initial treatment to a large field with a subsequent boost to the tumor bed. One patient received his entire course of treatment via this large field. RESULTS: With a median follow-up of 64 months, 7 patients are alive and free of disease while 2 died of intercurrent disease, without evidence of tumor, at 7 and 9 years following treatment. Another patient died 1 1/2 years after treatment of unknown causes. CONCLUSION: We conclude that postoperative radiotherapy is effective in preventing regrowth of intracranial ependymoma following subtotal resection in adults. Treatment fields should cover the initial tumor bed with a 1-2 cm margin to avoid long term radiation damage

PURPOSE: There is limited information about the outcome of AIDS patients with primary central nervous system lymphoma treated with definitive irradiation. The purpose of this study was to determine factors associated with increased survival in such patients. METHODS: An analysis was performed of 163 patients with AIDS who were evaluated at nine urban hospitals. These patients were treated for primary central nervous system lymphoma after the establishment of a tissue diagnosis or on a presumptive basis after failing empiric treatment for toxoplasmosis. All patients were treated between 1983 and 1995 with radiotherapy (median dose-fractionation scheme = 3 Gy x 10) and steroids (> 90% dexamethasone). Because multiple fractionation schemes were used, prescriptions were converted to biologically effective dose according to the formula Gy10 = Total Dose x (1 + fractional dose/alpha-beta), using an alpha-beta of 10. RESULTS: Longer median survival times were associated with high Karnofsky performance status (KPS > or = 70 vs < or = 60: 181 vs 77 days), young age (< 35 vs > 35: 162 vs 61 days), and high total definitive irradiation doses (> 39 Gy10 vs < 39 Gy10: 162 vs 40 days). Tissue diagnosis, gender, race, number of lesions (solitary vs multiple), and the presence of other cancers did not influence outcome. In multivariate analysis, young age, high Karnofsky performance status, and the delivery of higher biologically effective doses of irradiation retained independent significance relative to the endpoint of survival. CONCLUSIONS: Even at urban tertiary medical centers, few AIDS patients with intracranial lesions undergo biopsies to establish a precise tissue diagnosis. Survival following definitive irradiation is strongly related to two pretreatment factors (young age, high performance status) and one treatment factor (total biologically effective dose of cranial radiotherapy). These variables should be considered in selecting patients for definitive irradiation and in designing future studies

PURPOSE: Seven percent of patients with high grade gliomas enrolled in RTOG 83-02 had mixed astrocytoma/oligodenroglial elements on central pathology review. It has often been assumed that the most aggressive histologic component of a tumor determines biologic behavior; however in this trial, the survival of patients who had mixed glioblastomas/oligodenrogliomas was significantly longer than that of patients with pure glioblastomas (GBM). We therefore evaluated the effect of an oligodendroglial component on the survival of patients who had anaplastic astrocytomas (AAF) treated in the same trial. METHODS AND MATERIALS: One hundred nine patients who had AAF and 24 patients with mixed AAF/oligodendrogliomas (AAF/OL) were enrolled in a Phase I/II trial of randomized dose-escalation hyperfractioned radiotherapy plus BCNU. AAF/OL patients were older and more likely to have had more aggressive surgery than AAF patients. Other pretreatment characteristics were balanced between groups, as was assigned treatment. RESULTS: The median survival time for AAF was 3.0 years versus 7.3 years for AAF/OL (p = 0.019). In a multivariate analysis, adjusting for extent of surgical resection and age, an oligodendroglial component was an independent prognostic factor for survival. CONCLUSION: The results support the concept that AAFs with an oligodendroglial component have a better prognosis than pure AAF tumors, similar to the effect seen among patients with glioblastoma multiforme tumors. This better survival outcome should be taken into consideration in the design and stratification of future trials. Additionally, in contrast to patients with GBMs, patients who have AAF/OL have the potential for prolonged survival; therefore, late sequelae of treatment (both radiation and chemotherapy) must be weighed more heavily in the benefits to risks analysis

PURPOSE: To catalogue the presenting symptoms of patients with AIDS who are presumed to have primary central nervous system lymphoma (PCNSL). To document the palliative efficacy of cranial irradiation (RT) relative to the endpoints of complete and overall response for the respective symptoms. METHODS: An analysis of 163 patients with AIDS-related PCNSL who were evaluated at nine urban hospitals was performed. These patients were treated for PCNSL after the establishment of a tissue diagnosis or on a presumptive basis after failing empiric treatment for toxoplasmosis. All patients were treated between 1983 and 1995 with radiotherapy (median dose-fractionation scheme = 3 Gy x 10) and steroids (>90% dexamethasone). Because multiple fractionation schemes were used, prescriptions were converted to biologically effective doses according to the formula, Gy10 = Total Dose x (1 + fractional dose/alpha-beta); using an alpha-beta value of 10. RESULTS: The overall palliative response rate for the entire group was 53%. In univariate analysis, trends were present associating complete response rates with higher performance status (KPS > or = 70 vs. KPS < or = 60 = 17% vs. 5%), female gender (women vs. men = 29% vs. 8%), and the delivery of higher biologically effective doses (BED) of RT (Gy10 > 39 vs. < or = 39 = 20% vs. 5%). In multivariate analysis of factors predicting complete response, both higher KPS and higher BED retained independent significance. A separate univariate analysis identified high performance status (KPS > or = 70 vs. KPS < or = 60 = 71% vs. 47%), and young age (< or = 35 vs. > 35 = 61% vs. 40%) as factors significantly correlating with the endpoint of the overall response. In multivariate analysis, high performance status and the delivery of higher biologically effective doses of irradiation correlated significantly with higher overall response rates. CONCLUSION: Most AIDS patients who develop symptoms from primary lymphoma of the brain can achieve some palliation from a management program that includes cranial irradiation. Young patients with excellent performance status are most likely to respond to treatment. The delivery of higher biologically effective doses of irradiation also may increase the probability of achieving a palliative response