Faculty Bibliography

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: 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

BACKGROUND: Both systemic and primary central nervous system (CNS) non-Hodgkin's lymphomas (NHL) occur in people with acquired immune deficiency syndrome (AIDS). The radiographic manifestations may be similar to other neoplasms and opportunistic infections that are also found frequently in AIDS. Furthermore, these diseases may coexist with NHL in the AIDS patient. METHODS: To evaluate the use of Tc-99m Lymphoscan (the Fab' fragment of the anti-CD-22 antibody LL-2; Immunomedics, Inc., Morris Plains, NJ) in patients with suspected AIDS lymphoma, we studied 7 patients with 35 sites of suspected disease. Six had CNS lesions suspicious for parenchymal brain lymphoma. Each patient underwent planar and single photon emission computed tomography imaging at 3-5 and 18-24 hours after administration of Lymphoscan. Scintigraphic results were compared with results of conventional diagnostic modalities. RESULTS: Overall, the sensitivity of Lymphoscan was 92% and the specificity was 86%. In brain lesions, there was 100% sensitivity and 100% specificity. Lymphoscan also had 100% sensitivity for sites of lymphomatous lymphadenopathy and for liver involvement. Although less specific in extracranial sites, Lymphoscan was correctly negative in sites of coexisting adenocarcinoma and pneumonia. Two patients had both parenchymal CNS and systemic lymphoma proven by biopsy. CONCLUSIONS: Lymphoscan appears to be a sensitive and specific method for diagnosing CNS lymphoma in AIDS patients. Although slightly less specific in extracranial sites, it may be helpful in differentiating lymphoma from other etiologies in these patients at risk for multiple neoplasms and opportunistic infections

BACKGROUND: Primary hypothyroidism is a common sequela of craniospinal radiotherapy in the treatment of pediatric brain tumors. METHODS: The authors compared the incidence of primary hypothyroidism after hyperfractionated radiotherapy (HFRT) (n = 14 patients) versus conventionally fractionated radiotherapy (CRT) (n = 34 patients) in a group of pediatric patients with medulloblastoma/primitive neuroectodermal tumors (MB/PNET). RESULTS: The mean age at the time of tumor diagnosis was 7.9 years in the HFRT group and 8.4 years in the CRT group. The patients were followed for a mean of 4.6 years (HFRT) and 8.3 years (CRT) after diagnosis. Mean radiation doses to the thyroid were similar in both radiotherapy groups (29 gray [Gy] [HFRT] vs. 24 Gy [CRT]). Approximately 14% of the HFRT and 62% of the CRT patients developed primary hypothyroidism within a similar period after irradiation (3.2 years [HFRT] vs. 3.0 years [CRT]). Analysis by cumulative incidence function demonstrated a significant difference in the risk of developing thyroid dysfunction between these two groups of patients (P = 0.02). CONCLUSIONS: The current study findings suggest that the use of HFRT in the treatment of pediatric patients with MB/PNET is associated with a lower risk of these patients developing primary hypothyroidism

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

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

We assessed the effect of cranial irradiation on hypothalamic-pituitary (HP)-adrenal function in 17 patients (12 females, 5 males) treated with cranial/ craniospinal irradiation for acute leukemia (2 patients) or tumors distant from the hypothalamus and pituitary (8 medulloblastoma, 3 astrocytoma, 3 rhabdomyosarcoma, 1 ependymoma). Estimated doses of radiation (RT) to the HP region ranged from 18 to 72 Gy. Thirteen of seventeen patients were also treated with chemotherapy. Patients were a median of 3.75 years of age (1.5-19 years) at diagnosis and were studied at a median of 5 years (0.1-20 years) after RT. Patients received corticotropin-releasing factor (oCRF, 1 microgram/kg i.v.), and sampling for cortisol and ACTH levels was performed at -15, 0, 15, 30, 60, 90 and 120 min. The-5- and 0-min levels were combined for a standardized baseline value (Base). Cortisol levels at 0, Base, 30 and 120 min, as well as the peak cortisol response, were significantly lower in the patients. Twelve of seventeen patients' peak cortisol levels fell below the normal range. The patients' mean integrated values for cortisol (area under the curve) were not, however, different from controls. The ACTH responses to oCRF did not differ between patients and controls. No relationship was observed between ACTH or cortisol responses and the time elapsed from treatment or dose of HP RT. Further, in 10 of 12 patients, 0-min dehydroepiandrosterone sulfate levels were lower than the expected normal mean levels for age, sex and pubertal status, and in 4 of these 10 patients the values were below the normal range. These data suggest that some patients treated with HP RT may be at risk for adrenal insufficiency

PURPOSE: This single-institution Phase III study conducted from 1989 to 1995 evaluates the feasibility of a multimodality protocol combining hyperfractionated craniospinal radiotherapy (HFRT) followed by adjuvant chemotherapy in 23 patients with newly diagnosed primitive neuroectodermal tumors (PNET) arising in the central nervous system. METHODS AND MATERIALS: All 23 patients had a histologically confirmed PNET and were over 3 years of age at diagnosis. The eligibility criteria for PNET patients with cerebellar primaries (medulloblastoma) included either a high T stage (T3b or 4) or high M stage (M1-3). All patients with noncerebellar primaries were eligible regardless of T or M stage. The median age of the 23 patients was 9 years (mean 3-25); 11 were female. The primary tumor arose in the cerebellum in 19. Of these medulloblastoma patients, 15 had high T stages (T3b or T4) with large locally invasive tumors and no evidence of metastases (M0), constituting Group 1. Thirteen (86%) of these patients had gross total resections. Four other medulloblastoma patients had both high T and high M stages, constituting Group 2. Group 3 consisted of four other patients with exocerebellar primaries (two brain, one brain stem, and one cauda equina), three of whom were M3. Hyperfractionated radiotherapy was administered within 4 weeks of surgery. Twice-daily 1-Gy fractions were administered separated by 4-6 h. The total dose to the primary intracranial tumor and other areas of measurable intracranial disease was 72 Gy. The prophylactic craniospinal axis dose was 36 Gy, and boosts of 44-56 Gy were administered to metastatic spinal deposits. Following radiotherapy, monthly courses of multiagent chemotherapy were administered sequentially (cyclophosphamide-vincristine followed by cisplatin-etoposide followed by carboplatin-vincristine) for a total of 9 months. RESULTS: All patients completed radiotherapy as planned. Only three patients lost >10% of their body weight. One patient had clinically apparent radiation-induced esophagitis. The mean white blood count (WBC) nadir was 2.5/dl, and hematologic recovery occurred in all within 4 weeks of completing HFRT without the need of granulocyte-colony-stimulating factor. Two patients refused adjuvant chemotherapy, 3 patients experienced tumor progression during chemotherapy, and 2 of 18 remaining patients could not tolerate the full 9 months owing to hematologic toxicity. Of the 15 patients (93%) in Group 1, 14 remain in continuous remission for a median of 78 months, and none have died. Two of four patients in Group 2 are in continuous remission at 67 and 35 months, and two died at 18 and 30 months. One of the two patients in Group 2 who died refused adjuvant chemotherapy and developed tumor progression in the bone marrow. None of the three patients in Group 3 with evaluable disease (M3) had a complete response to therapy, and eventually all four died of progressive or recurrent disease. CONCLUSION: This multimodality protocol is feasible in the short term, and long-term monitoring of neurocognitive and neuroendocrine effects are in progress. Excellent long-term disease control has been achieved for medulloblastoma patients with high T stages who were M0 at diagnosis (Group 1), the majority of whom had gross total resections. This group has a progression-free survival of 95% after a median period of follow-up of 6.5 years. Alternative treatment strategies must be developed for patients with high M stages, as five of seven patients died of progressive or recurrent disease