Central nervous system cancers.

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.

Late Effects of Craniospinal Irradiation Using Electron Spinal Fields for Pediatric Patients With Cancer.

PURPOSE: For children, craniospinal irradiation (CSI) with photons is associated with significant toxic effects. The use of electrons for spinal fields is hypothesized to spare anterior structures but the long-term effects remain uncertain. We studied late effects of CSI using electrons for spinal radiation therapy (RT). METHODS AND MATERIALS: Records of 84 consecutive patients treated with CSI using electrons for the spine at a single institution between 1983 and 2014 were reviewed. Median age at RT was 5 (range, 1-14) years. The most common histologies were medulloblastoma/primitive neuroectodermal tumor (59%) and ependymoma (8%). The median prescribed dose to the entire spine was 30 Gy (range, 6-45). A subset of 48 (57%) patients aged 2 to 14 at RT with clinical follow-up for ≥5 years was analyzed for late effects. Height z scores adjusted for age before and after CSI were assessed using stature-for-age charts and compared with a t test. RESULTS: At median follow-up of 19 years (range, 0-38 years), the median survival was 22 years (95% confidence interval, 12-28 years) after RT, with 47 patients (56%) alive at last follow-up. On subset analysis for late effects, 19 (40%) patients developed hypothyroidism and 5 (10%) developed secondary malignancies. Other complications reported were esophageal stricture and periaortic hemorrhage in 1 and restrictive pulmonary disease in 1 patient. Median height z score before treatment was -0.4 (36th percentile; interquartile range, -1.0 to 0.0) and at last follow-up was -2.2 (first percentile; interquartile range, -3.1 to -1.6; P < .001). Of 44 patients with spinal curvature assessments, 15 (34%) had scoliosis with median Cobb angle 15° (range, 10°-35°) and 1 (2%) required surgery. CONCLUSIONS: Frequent musculoskeletal toxic effects and predominantly decreased height were seen with long-term follow-up. Scoliosis and hypothyroidism were each seen in at least one-third of long-term survivors. However, clinically evident esophageal, pulmonary, and cardiac toxic effects were infrequent.

Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.

BACKGROUND: It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction. METHODS: Patients with one to three newly diagnosed brain metastases were randomly assigned using a standard permutated block algorithm with random block sizes to SRS plus WBRT or SRS alone from Jan 2, 2001, to Sept 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histology. The randomisation sequence was masked until assignation, at which point both clinicians and patients were made aware of the treatment allocation. The primary endpoint was neurocognitive function: objectively measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test-Revised (HVLT-R) total recall at 4 months. An independent data monitoring committee monitored the trial using Bayesian statistical methods. Analysis was by intention-to-treat. This trial is registered at www.ClinicalTrials.gov, number NCT00548756. FINDINGS: After 58 patients were recruited (n=30 in the SRS alone group, n=28 in the SRS plus WBRT group), the trial was stopped by the data monitoring committee according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function (mean posterior probability of decline 52%) at 4 months than patients assigned to receive SRS alone (mean posterior probability of decline 24%). At 4 months there were four deaths (13%) in the group that received SRS alone, and eight deaths (29%) in the group that received SRS plus WBRT. 73% of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p=0.0003). In the SRS plus WBRT group, one case of grade 3 toxicity (seizures, motor neuropathy, depressed level of consciousness) was attributed to radiation treatment. In the group that received SRS, one case of grade 3 toxicity (aphasia) was attributed to radiation treatment. Two cases of grade 4 toxicity in the group that received SRS alone were diagnosed as radiation necrosis. INTERPRETATION: Patients treated with SRS plus WBRT were at a greater risk of a significant decline in learning and memory function by 4 months compared with the group that received SRS alone. Initial treatment with a combination of SRS and close clinical monitoring is recommended as the preferred treatment strategy to better preserve learning and memory in patients with newly diagnosed brain metastases.

Evaluation of peritumoral edema in the delineation of radiotherapy clinical target volumes for glioblastoma.

PURPOSE: To evaluate the spatial relationship between peritumoral edema and recurrence pattern in patients with glioblastoma (GBM). METHODS AND MATERIALS: Forty-eight primary GBM patients received three-dimensional conformal radiotherapy that did not intentionally include peritumoral edema within the clinical target volume between July 2000 and June 2001. All 48 patients have subsequently recurred, and their original treatment planning parameters were used for this study. New theoretical radiation treatment plans were created for the same 48 patients, based on Radiation Therapy Oncology Group (RTOG) target delineation guidelines that specify inclusion of peritumoral edema. Target volume and recurrent tumor coverage, as well as percent volume of normal brain irradiated, were assessed for both methods of target delineation using dose-volume histograms. RESULTS: A comparison between the location of recurrent tumor and peritumoral edema volumes from all 48 cases failed to show correlation by linear regression modeling (r(2) = 0.0007; p = 0.3). For patients with edema >75 cm(3), the percent volume of brain irradiated to 46 Gy was significantly greater in treatment plans that intentionally included peritumoral edema compared with those that did not (38% vs. 31%; p = 0.003). The pattern of failure was identical between the two sets of plans (40 central, 3 in-field, 3 marginal, and 2 distant recurrence). CONCLUSION: Clinical target volume delineation based on a 2-cm margin rather than on peritumoral edema did not seem to alter the central pattern of failure for patients with GBM. For patients with peritumoral edema >75 cm(3), using a constant 2-cm margin resulted in a smaller median percent volume of brain being irradiated to 30 Gy, 46 Gy, and 50 Gy compared with corresponding theoretical RTOG plans that deliberately included peritumoral edema.

Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure.

OBJECT: The authors report data concerning the safety, effectiveness, and patterns of failure obtained in a Phase I/II study of stereotactic body radiotherapy (SBRT) for spinal metastatic tumors. METHODS: Sixty-three cancer patients underwent near-simultaneous computed tomography-guided SBRT. Spinal magnetic resonance imaging was conducted at baseline and at each follow-up visit. The National Cancer Institute Common Toxicity Criteria 2.0 assessments were used to evaluate toxicity. RESULTS: The median tumor volume of 74 spinal metastatic lesions was 37.4 cm3 (range 1.6-358 cm3). No neuropathy or myelopathy was observed during a median follow-up period of 21.3 months (range 0.9-49.6 months). The actuarial 1-year tumor progression-free incidence was 84% for all tumors. Pattern-of-failure analysis showed two primary mechanisms of failure: 1) recurrence in the bone adjacent to the site of previous treatment, and 2) recurrence in the epidural space adjacent to the spinal cord. Grade 3 or 4 toxicities were limited to acute Grade 3 nausea, vomiting, and diarrhea (one case); Grade 3 dysphagia and trismus (one case); and Grade 3 noncardiac chest pain (one case). There was no subacute or late Grade 3 or 4 toxicity. CONCLUSIONS: Analysis of the data obtained in the present study supports the safety and effectiveness of SBRT in cases of spinal metastatic cancer. The authors consider it prudent to routinely treat the pedicles and posterior elements using a wide bone margin posterior to the diseased vertebrae because of the possible direct extension into these structures. For patients without a history of radiotherapy, more liberal spinal cord dose constraints than those used in this study could be applied to help reduce failures in the epidural space.

Phase II Radiation Therapy Oncology Group trial of conventional radiation therapy followed by treatment with recombinant interferon-beta for supratentorial glioblastoma: results of RTOG 9710.

PURPOSE: The aim of this study was to determine whether recombinant human interferon beta-1a (rhIFN-beta), when given after radiation therapy, improves survival in glioblastoma. METHODS AND MATERIALS: After surgery, 109 patients with newly diagnosed supratentorial glioblastoma were enrolled and treated with radiation therapy (60 Gy). A total of 55 patients remained stable after radiation and were treated with rhIFN-beta (6 MU/day i.m., 3 times/week). Outcomes were compared with the Radiation Therapy Oncology Group glioma historical database. RESULTS: RhIFN-beta was well tolerated, with 1 Grade 4 toxicity and 8 other patients experiencing Grade 3 toxicity. Median survival time (MST) of the 55 rhIFN-beta-treated patients was 13.4 months. MST for the 34 rhIFN-beta-treated in RPA Classes III and IV was 16.9 vs. 12.4 months for historical controls (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 0.89-1.81). There was also a trend toward improved survival across all RPA Classes comparing the 55 rhIFN-beta treated patients and 1,658 historical controls (HR = 1.24, 95% CI = 0.94-1.63). The high rate of early failures (54/109) after radiation and before initiation of rhIFN-beta was likely caused by stricter interpretation of early radiographic changes in the current study. Matched-pair and intent-to-treat analyses performed to try to address this bias showed no difference in survival between study patients and controls. CONCLUSION: RhIFN-beta given after conventional radiation therapy was well tolerated, with a trend toward survival benefit in patients who remained stable after radiation therapy. These data suggest that rhIFN-beta warrants further evaluation in additional studies, possibly in combination with current temozolomide-based regimens.

Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques?

PURPOSE: To calculate treatment plans and compare the dose distributions and dose-volume histograms (DVHs) for photon three-dimensional conformal radiation therapy (3D-CRT), electron therapy, intensity-modulated radiation therapy (IMRT), and standard (nonintensity modulated) proton therapy in three pediatric disease sites. METHODS AND MATERIALS: The tumor volumes from 8 patients (3 retinoblastomas, 2 medulloblastomas, and 3 pelvic sarcomas) were studied retrospectively to compare DVHs from proton therapy with 3D-CRT, electron therapy, and IMRT. In retinoblastoma, several planning techniques were analyzed: A single electron appositional beam was compared with a single 3D-CRT lateral beam, a 3D-CRT anterior beam paired with a lateral beam, IMRT, and protons. In medulloblastoma, three posterior fossa irradiation techniques were analyzed: 3D-CRT, IMRT, and protons. Craniospinal irradiation (which consisted of composite plans of both the posterior fossa and craniospinal components) was also evaluated, primarily comparing spinal irradiation using 3D-CRT electrons, 3D-CRT photons, and protons. Lastly, in pelvic sarcoma, 3D-CRT, IMRT, and proton plans were assessed. RESULTS: In retinoblastoma, protons resulted in the best target coverage combined with the most orbital bone sparing (10% was the mean orbital bone volume irradiated at > or =5 Gy for protons vs. 25% for 3D-CRT electrons, 69% for IMRT, 41% for a single 3D lateral beam, 51% for a 3D anterolateral beam with a lens block, and 65% for a 3D anterolateral beam without a lens block). A single appositional electron field was the next best technique followed by other planning approaches. In medulloblastoma, for posterior fossa and craniospinal irradiation, protons resulted in the least dose to the cochlea (for only posterior fossa irradiation at > or =20 Gy, 34% was the mean cochlear volume irradiated for protons, 87% for IMRT, 89% for 3D-CRT) and hypothalamus-pituitary axis (for only posterior fossa irradiation at > or =10 Gy, 21% was the mean hypothalamus-pituitary volume irradiated for protons, 81% for IMRT, 91% for 3D-CRT); additional dose reductions to the optic chiasm, eyes, vertebrae, mandible, thyroid, lung, kidneys, heart, and liver were seen. Intensity-modulated radiotherapy appeared to be the second best technique for posterior fossa irradiation. For spinal irradiation 3D-CRT electrons were better than 3D-CRT photons in sparing dose to the thyroid, heart, lung, kidney, and liver. With pelvic sarcoma, protons were superior in eliminating any dose to the ovaries (0% of mean ovarian volume was irradiated at > or =2 Gy with protons) and to some extent, the pelvic bones and vertebrae. Intensity-modulated radiotherapy did show more bladder dose reduction than the other techniques in pelvic sarcoma irradiation. CONCLUSIONS: In the diseases studied, using various techniques of 3D-CRT, electrons, IMRT, and protons, protons are most optimal in treating retinoblastomas, medulloblastomas (posterior fossa and craniospinal), and pelvic sarcomas. Protons delivered superior target dose coverage and sparing of normal structures. As dose-volume parameters are expected to correlate with acute and late toxicity, proton therapy should receive serious consideration as the preferred technique for the treatment of pediatric tumors.

Case-control study of stereotactic radiosurgery for recurrent glioblastoma multiforme.

OBJECT: The role of stereotactic radiosurgery (SRS) for recurrent glioblastoma multiforme (GBM) was evaluated in a case-control study. METHODS: All patients who underwent SRS for recurrent GBM before March 2003 formed the case group. A control group of patients who did not undergo SRS was created from an institutional database, and each case was matched for known prognostic factors in GBM. The medical and neuroimaging records of all the patients were reviewed, and survival and treatment outcomes were recorded. The case and control groups were well matched with regard to demographics and pre-SRS interventions. In the control group, the date on which magnetic resonance imaging identified a recurrent lesion that would have been eligible for SRS was deemed the "SRS" date. The number of surgeries performed in the control group was statistically higher than that in the case group. The median duration of overall survival from diagnosis was 26 months in the case group and 23 months in the control group. From the date of SRS or "SRS", the median duration of survival was 11 months in the case group and 10 months in the control group, a difference that was not statistically significant. CONCLUSIONS: It appears that a subgroup of patients with GBMs has a higher than expected median survival duration despite the initial prognostic factors. In patients with localized recurrences, survival may be prolonged by applying aggressive local disease management by using either SRS or resection to equal advantage.

Intractable vomiting from glioblastoma metastatic to the fourth ventricle: three case studies.

Dissemination of malignant glioma to the fourth ventricle with metastatic deposits and intractable vomiting is rare. Leptomeningeal extension of malignant glioma is an uncommon condition that has been reported in patients with end-stage disease and is usually unresponsive to any treatment modality. We describe 3 patients with progressing recurrent glioblastoma multiforme in whom leptomeningeal invasion manifested itself as intractable vomiting due to tumor metastases in the floor of the fourth ventricle. All patients received additional radiation therapy focused to the posterior fossa, with complete resolution of vomiting occurring within 10 days after irradiation. The remission of symptoms in these patients persisted until their death 3-4 months after the repeat radiation therapy. These reports indicate that additional focused radiation should be considered because of its significant therapeutic effect in alleviating intractable nausea and vomiting in patients with glioma metastasized to the posterior fossa.

The prognostic value of neurologic function in astrocytic spinal cord glioma.

To assess the prognostic value of neurologic function (NF) in patients with astrocytic spinal cord glioma, we conducted a retrospective study of 25 patients who were treated at our institution between January 1970 and December 1999. The median age was 40 years, and the median follow-up was 54 months. Nineteen patients had a biopsy, 5 had a subtotal resection, and 1 had a gross total resection. Twenty-two patients received postoperative radiotherapy to a median dose of 45 Gy. NF ratings of 1 and 2 were considered favorable, and 3 and 4 were considered unfavorable, based on a scale of 1 to 4. Dual neuropathologic review confirmed the tumor to be low, intermediate, or high grade, based on the WHO grades I-II, III, or IV, respectively. Actuarial rates of local control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed. Our study results revealed that an improved 5-year OS rate was associated with favorable NF at diagnosis (73% vs. 22% for patients with unfavorable NF; P = 0.04) and favorable NF before radiation therapy (89% vs. 28% for patients with unfavorable NF; P = 0.049). There was a significant difference in OS based on tumor grade ( P < 0.001) and age (risk ratio, 1.04; P = 0.027). PFS and LC were significantly better for young patients and those with lower tumor grade ( P < 0.05). A multivariate analysis of age, NF at diagnosis, and postoperative NF for all patients showed postoperative NF and age to be independent prognostic factors for OS. We conclude that favorable NF may be associated with improved outcome in patients with astrocytic spinal cord glioma.

An evaluation of radiation exposure from portal films taken during definitive course of pediatric radiotherapy.

PURPOSE: Recently, considerable attention has been directed toward computed tomography radiation doses (estimated 1 to 4 cGy) received by pediatric patients, because of the potential for increasing a pediatric patient's risk for developing a secondary malignancy. However, minimal attention has been given to the radiation exposure outside the treatment field resulting from the use of portal films to visualize surrounding anatomy. The objective of this study was to quantify the radiation dose from portal imaging delivered within and outside the radiation treatment field during a course of radiation therapy. METHODS AND MATERIALS: A retrospective review was conducted of the port film dose for 56 consecutive pediatric patients who underwent definitive radiation therapy between January 2001 and January 2002. Treatment locations were classified as brain, 27 patients; abdomen, 11 patients; extremities, 9 patients; pelvis, 6 patients; and thorax, 3 patients. Using the dose per monitor unit and total number of port films taken, the total port film dose for each patient was calculated. In addition, port film dose was quantified for 5 pediatric patients undergoing intensity modulated radiation therapy. RESULTS: The mean total port dose varied from a maximum of 46 cGy for brain to a minimum of 17 cGy for thorax. The mean total port dose as a percentage of prescribed dose was less than 1.25% for all locations in this study; however, most of the port dose is a result of the open-field dose from the double-exposure technique. CONCLUSIONS: Care should be exercised while exposing port films of pediatric patients to minimize both the number of films and corresponding radiation exposure without compromising the quality of treatment delivery. Specifically, the number of monitor units used to image regions outside the treatment field should be kept to a minimum, because such exposure could lead to an increased risk of development of secondary neoplasms.

Gliomatosis cerebri: improved outcome with radiotherapy.

PURPOSE: Gliomatosis cerebri is a rare, diffuse involvement of the central nervous system by a malignant glioma that permeates the brain extensively without destroying the neural architecture and involves more than two lobes. In this study, we sought to assess the role of radiotherapy (RT) and identify prognostic factors in gliomatosis cerebri. METHODS AND MATERIALS: Thirty patients who received RT at a single institution and had radiographic follow-up were retrospectively reviewed with respect to outcome, radiation parameters, extent of surgery, and chemotherapy. All cases were analyzed histologically and documented. All pathology slides and radiology images were reviewed. RESULTS: The median age at diagnosis was 38.6 years (range 16-68). The median follow-up was 12.8 months (range 3-110). The mean radiation dose was 54.9 Gy, given in a mean of 28 fractions. Radiographic improvement or disease stabilization was achieved in 87% of patients. Clinical improvement was observed in 70%. The median time to progression was 10 months, and it was significantly longer for patients <40 years old (p = 0.0007) and for patients having a tumor histologic subtype other than glioblastoma (p = 0.01). The median overall survival was 18 months and was also longer for patients <40 years (p = 0.0001) and for patients having nonglioblastoma histologic features (p = 0.007). Extensive surgery, administration of chemotherapy, or increased RT volume improved neither overall survival nor the time to disease progression. CONCLUSION: RT is effective against gliomatosis cerebri. Patients who are young and have a nonglioblastoma tumor histologic subtype perform more favorably. In this analysis, no role for chemotherapy, extensive surgery, or whole-brain RT was found.

Acute toxicity and treatment interruption related to electron and photon craniospinal irradiation in pediatric patients treated at the University of Texas M. D. Anderson Cancer Center.

PURPOSE: To determine the incidence of acute toxicity and treatment interruption associated with electron and photon craniospinal irradiation (CSI) in children treated with or without chemotherapy. MATERIALS AND METHODS: A retrospective study involving a computerized search of the radiotherapy database at the University of Texas M. D. Anderson Cancer Center identified a total of 79 eligible patients 6 years), and sequencing of chemotherapy were compared using chi-square tests. RESULTS: The median age of the electron group was lower than that of the photon group (6.7 years and 11.7 years, respectively). The two groups were otherwise well matched in terms of median spinal dose (31.1 vs. 33.3 Gy), fraction size (1.57 vs. 1.63 Gy), and total treatment time (32.4 vs. 30.7 days). Only 2 patients in each group (photon and electron) had a treatment break (>3 days). The mean number of days interrupted was 0.94 (photon) and 1.1 (electron) (p = 0.72). The electron and photon groups were well balanced in terms of receiving pre-CSI chemotherapy (37% vs. 41%, p = 0.776). Chemotherapy given before radiotherapy vs. after or not at all was associated with an increased incidence of Grade 3-4 leukopenia (76% vs. 49%, p = 0.02), thrombocytopenia (90% vs. 10%, p = 0), and neutropenia (50% vs. 15%, p = 0.005). A younger age was associated with Grade 3-4 thrombocytopenia (29% vs. 8.7%, p = 0.034), and decreased hemoglobin (29% vs. 6.5%, p = 0.014). The incidence of leukocyte depression of Grade 3-4 toxicity was 62% in the electron group and 32% in the photon group (p = 0.018). The incidence of Grade 3-4 platelet toxicity was higher with electrons (21%) than with photons (4%), but the difference was of borderline significance (p = 0.053). The difference in Grade 1-2 weight loss was not statistically significant (86% electron vs. 55% photon groups, p = 0.53), and Grade 3-4 weight loss did not occur within the entire study group. Most patients experienced Grade 0-1 radiation dermatitis with either electrons or photons. CONCLUSION: A younger patient age (

Hypofractionated radiotherapy for elderly or younger low-performance status glioblastoma patients: outcome and prognostic factors.

PURPOSE: To evaluate the outcome for elderly or younger poor prognosis glioblastoma patients treated with hypofractionated radiotherapy (HypoRT). METHODS AND MATERIALS: Retrospective review at The University of Texas M. D. Anderson Cancer Center identified 59 glioblastoma patients (median age 65 years) treated with HypoRT between 1988 and 2001 with 50 Gy given at 2.5 Gy/fraction/day in 20 fractions within 4 weeks. Classification was according to the Radiation Therapy Oncology Group recursive partitioning analysis and was Class IV in 11, V in 29, and VI in 19. Surgery consisted of gross total resection (n = 16), subtotal resection (n = 28), and biopsy only (n = 13). Two patients were treated presumptively on the basis of radiographic findings. Chemotherapy was given either as part of the initial treatment (n = 15) or for progression (n = 9). RESULTS: The median survival time for the entire study population was 7 months, and the median progression-free survival was 3.9 months. The median survival time for patients with Class IV, V, and VI was 11, 7, and 5 months, respectively. Concordance was found with Radiation Therapy Oncology Group-established recursive partitioning analysis class survival. Steroid requirements were not increased during RT compared with preoperatively and immediately postoperatively. Late complications of HypoRT were limited to 3 cases of radiation necrosis suggested by MRI, 2 of which were pathologically confirmed. CONCLUSION: HypoRT consisting of 50 Gy in 4 weeks can be used for selected GBM patients to reduce the overall treatment time of conventional RT by 33-39% without apparent increased toxicity or decrement in survival.

Stereotactic radiosurgical treatment in 103 patients for 153 cerebral melanoma metastases.

PURPOSE: To report on the outcome of patients with melanoma brain metastases treated with stereotactic radiosurgery (SRS). PATIENTS AND METHODS: One hundred three patients with 153 intracranial melanoma metastases consecutively underwent Linac-based SRS between November 1991 and October 2001. The Kaplan-Meier method, univariate comparisons with log-rank test, and multivariate analyses with classification and regression tree models were performed. Calculations were based on last imaging date rather than the date of the last visit. RESULTS: Median age was 51 years (range, 18-93 years). Median Karnofsky performance status was 90. Sixty-one patients (59%) had single brain metastasis at presentation. Treatment sequence was SRS alone (61 patients), SRS + whole-brain radiotherapy (WBRT) (12 patients), and salvage SRS after WBRT (30 patients). The median tumor volume was 1.9 cm(3) (range, 0.06-22.3 cm(3)). The median SRS minimum peripheral dose and isodose was 18 Gy (range, 10-24 Gy) and 85% (range, 60%-100%), respectively. The median follow-up was 6 months for all patients and 13 months (range, 2-46 months) for patients alive at the time of analysis. The 1-year local control (LC) for all patients treated with SRS was 49%. Among the patients treated with initial SRS alone, the 1-year LC was better for patients with tumors < or =2 cm(3) than with tumors >2 cm(3): 75.2% vs. 42.3% (p < 0.05). The 1-year distant brain metastasis-free survival incidence was 14.7% for the 73 patients receiving either initial SRS alone or SRS +WBRT. The initial number of brain lesions (single vs. multiple) was the only factor with a significant effect on distant brain metastasis-free survival at 1 year: 23.5% for single metastases and 0% for multiple lesions (p < 0.05). The 1-year overall survival was 25.2%. Stratification by Score Index for Radiosurgery (SIR) revealed a significant effect on survival, which was 29% at 1 year for SIR >6 and 10% for SIR <==6 (relative hazard ratio, 2.1; p < 0.05) in classification and regression-tree multivariate analysis involving age, Karnofsky performance status, primary tumor control, tumor volume, SRS dose, SIR (>6 vs. < or =6), and systemic disease status. CONCLUSIONS: Initial SRS alone was an effective treatment modality for smaller cerebral melanoma metastases, achieving a 75% incidence of 1-year LC for < or =2 cm(3) single brain metastases and should be considered in patients with SIR >6. The role of WBRT in melanoma brain metastases cannot be addressed, owing to retrospective bias toward administering this treatment to patients with more aggressive disease. A prospective study is needed to assess the role of WBRT in patients with melanoma brain metastasis.

Phase I clinical evaluation of near-simultaneous computed tomographic image-guided stereotactic body radiotherapy for spinal metastases.

PURPOSE: To evaluate in a Phase I study the safety, feasibility, and patient-positioning accuracy of treating patients with intensity-modulated, near-simultaneous, computed tomographic (CT) image-guided stereotactic body radiotherapy (SBRT). PATIENTS AND METHODS: Fifteen consecutive patients with metastatic spinal disease who met protocol eligibility criteria were entered into a Phase I clinical trial. Each patient received five treatments of intensity-modulated, near-simultaneous CT image-guided SBRT, for a total of 75 treatments with 90 isocenter setups during the course of the study. Patients uniformly received 30 Gy (if possible) of radiotherapy in 5 fractions to the clinical target volume. The total dose was constrained by limiting the spinal cord to a maximum dose of 10 Gy. To verify correct daily patient positioning before each treatment and to determine the daily treatment setup error after radiation delivery, axial CT scans were taken before and immediately after each treatment without moving the patient from the treatment position, for comparison with the planning CT scan. Toxicity was measured using the Common Toxicity Criteria, the Late Effects of Normal Tissue scoring system and a neurologic function scale. Follow-up was conducted 4 weeks after completion of SBRT, and then 2, 3, 6, 9, 12, and every 6 months thereafter. RESULTS: The procedure was technically feasible to perform in all patients. No neurologic toxicity was observed in any patient. The median follow-up time was 9 months (range 6-16). The Clopper-Pearson upper bound on the probability of paralysis with 95% confidence is no greater than 0.181. The positional setup error was determined to be within 1 mm of planning isocenter. CONCLUSIONS: This Phase I study shows that intensity-modulated, near simultaneous, CT image-guided SBRT is a feasible, and highly precise technique for the noninvasive treatment of spinal metastases. Although no paralysis has developed in the 15 patients treated, continued monitoring for spinal cord toxicity is warranted, as larger numbers of patients will be needed to more precisely define the upper bound on the probability of spinal cord myelopathy.

Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: an emerging paradigm for achieving true stereotaxy.

PURPOSE: To report treatment setup data from an emerging technique using near-simultaneous computed tomography (CT) image-guided stereotactic radiotherapy for the treatment of spinal and paraspinal tumors. METHODS AND MATERIALS: A targeting system that integrates a CT-on-rails scanner with a linear accelerator (LINAC) was evaluated in the lead-in portion of a Phase I/II protocol for treating patients with paraspinal metastases. Patients were immobilized in supine position by a moldable body cushion vacuum wrapped with a plastic fixation sheet. Planning CT and immediately repeated CT were performed on the LINAC/CT-on-rails unit to assess respiratory-related vertebral body motion. Coplanar intensity-modulated radiotherapy (IMRT) using 7-9 beams was used to deliver 30 Gy in five fractions to the target volume, while limiting the spinal cord dose to <10 Gy. Pretreatment CT scans were fused with the planning CT scans to determine the correct target isocenter by accounting for any translational and roll (axial) rotational discrepancies from the planning CT. (Corrections caused by yaw and pitch rotations have not yet been implemented.) The reproducibility of the treatment isocenter as compared with the planned isocenter was measured with digitally reconstructed radiographs (DRRs), portal film imaging, and immediate post-treatment verification CT scans. Phantom measurements were taken for dose verification for each IMRT plan. RESULTS: Based on a total of 36 CT scans (3 for planning, 3 for respiration study, 15 pretreatment, and 15 post-treatment) from 3 patients, no respiration-associated vertebral body motion was seen. A comparison of the corrected daily anterior-posterior (AP) and lateral (LAT) digital portal images with the planning AP and LAT DRRs confirmed that the isocenter setup accuracy for the 15 treatments was within 1 mm of the planning isocenter. The results from the immediate post-treatment CT scans reconfirmed the findings from the portal images and verified the absence of spinal movement during the treatment. The ion-chamber measurement for the high-dose region was within 2% of the planning dose for three patient treatment plans. Film dose measurement in an IMRT quality assurance phantom demonstrated good agreement from 90% to 30% isodose lines between the planned and measured results. CONCLUSION: Preliminary experience suggests that the near-simultaneous CT image-guided verification technique can be used as a new platform technology for extracranial applications of stereotactic radiotherapy and radiosurgery to spinal and paraspinal tumors.

Radiotherapy after surgery for benign cerebral meningioma.

BACKGROUND AND PURPOSE: To compare the outcome from adjuvant and delayed radiotherapy (RT) after surgery in patients with benign cerebral meningioma. PATIENTS AND METHODS: Between March 1953 and January 2001, 92 patients with benign cerebral meningioma (WHO grade I) were treated with surgery. Forty-eight patients underwent gross total resection (GTR), and 44 patients underwent subtotal resection (STR). Treatments were classified as GTR (n = 48), STR+adjuvant RT (n = 12), STR alone (n = 32). The prognostic factors were assessed as, gender, the Karnofsky performance score (KPS) (> or =90 vs. <90), the extent of surgery, and adjuvant or delayed RT. The endpoints analyzed were progression-free survival (PFS) and overall survival (OS). Overall survival curve of the study population is compared with the age-adjusted expected survival curve for the US population born in 1970. RESULTS: The median follow-up was 7.7 years. The 5-year PFS and OS rates for all patients were 65 and 93%, respectively. The 5-year PFS rates in patients treated with GTR and STR were 77 and 52%, respectively (P = 0.02). Patients treated with STR+adjuvant RT had significantly better PFS (91%) at 5 years than with STR alone (38%) (P = 0.0005). Gender showed no statistically significant impact on either PFS or OS (P > 0.05). However, multivariate analysis showed the KPS to have a statistically significant effect on OS (P = 0.02). The OS rate was the same across all three treatment groups. The age-adjusted expected survival curve for the US population born in 1970 lay within the confidence intervals for the overall survival curve of the study population. CONCLUSIONS: Although OS was not affected, adjuvant RT appeared to significantly reduce tumor progression. However, only a prospective randomized trial can adequately determine whether adjuvant or delayed radiotherapy is the better approach in patients with subtotally resected benign meningioma.

Chromosomal fragility syndrome and family history of radiosensitivity as indicators for radiotherapy dose modification.

Beside a few known radiosensitive syndromes, a patient's reaction to radiotherapy is difficult to predict. In this report we describe the management of a pediatric cancer patient presented with a family history of radiosensitivity and cancer proneness. Laboratory investigations revealed a chromosomal fragility syndrome and an increased cellular radiosensitivity in vitro. AT gene sequencing revealed no mutations. The patient was treated with reduced radiation doses to avoid the presumed increased risks of toxicity to normal tissues. The patient tolerated well the treatment with no significant acute or late radiation sequelae. Five years later, the patient remains both disease and complications free. While an accurate laboratory test for radiosensitivity is still lacking, assessments of chromosomal fragility, cell survival and clinical medicine will continue to be useful for a small number of patients.