Masao Tago

Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis.

PURPOSE To perform an individual patient data (IPD) meta-analysis of randomized controlled trials evaluating stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT) for patients presenting with 1 to 4 brain metastases. METHOD AND MATERIALS Three trials were identified through a literature search, and IPD were obtained. Outcomes of interest were survival, local failure, and distant brain failure. The treatment effect was estimated after adjustments for age, recursive partitioning analysis (RPA) score, number of brain metastases, and treatment arm. RESULTS A total of 364 of the pooled 389 patients met eligibility criteria, of whom 51% were treated with SRS alone and 49% were treated with SRS plus WBRT. For survival, age was a significant effect modifier (P=.04) favoring SRS alone in patients ≤50 years of age, and no significant differences were observed in older patients. Hazard ratios (HRs) for patients 35, 40, 45, and 50 years of age were 0.46 (95% confidence interval [CI] = 0.24-0.90), 0.52 (95% CI = 0.29-0.92), 0.58 (95% CI = 0.35-0.95), and 0.64 (95% CI = 0.42-0.99), respectively. Patients with a single metastasis had significantly better survival than those who had 2 to 4 metastases. For distant brain failure, age was a significant effect modifier (P=.043), with similar rates in the 2 arms for patients ≤50 of age; otherwise, the risk was reduced with WBRT for patients >50 years of age. Patients with a single metastasis also had a significantly lower risk of distant brain failure than patients who had 2 to 4 metastases. Local control significantly favored additional WBRT in all age groups. CONCLUSIONS For patients ≤50 years of age, SRS alone favored survival, in addition, the initial omission of WBRT did not impact distant brain relapse rates. SRS alone may be the preferred treatment for this age group.

Megavoltage CT-assisted stereotactic radiosurgery for thoracic tumors: original research in the treatment of thoracic neoplasms.

PURPOSE The aim of the study was to evaluate the efficacy of stereotactic radiosurgery (SRS) for thoracic tumors with megavoltage computed tomography (MVCT) from the point of view of symptom palliation as well as local control. METHODS AND MATERIALS MVCT-assisted positioning verification and real-time monitoring for a multileaf collimator (MLC) were used to enhance the accuracy of the thoracic SRS. Twenty-two thoracic tumors in 15 patients underwent the present treatment. All but 1 tumor were metastases from various primary malignancies. Eleven patients were symptomatic. The treatment site was the chest wall/pleura in 10 tumors, and the lung in 12 tumors. The median volume of the clinical target was 4.5 cc and the median peripheral dose was 20 Gy, for the lung tumors. For the chest wall/pleura tumors, the median volume of the clinical target was 40 cc and the median peripheral dose was 20 Gy. Conventional fractionated conformal radiation therapy (CRT) followed SRS in 10 tumors. RESULTS Of 21 tumors eligible for evaluation, there were 13 with complete responses, 6 with partial responses, and 2 without response. Duration of local control ranged from 0.6 to 82 months with a median of 8 months, with only one local recurrence seen. Immediate palliation was obtained in most symptomatic patients. Interstitial changes in the lung were limited. Autopsy performed for a patient revealed remarkable histologic effects with minimal injuries to the lung. CONCLUSION The geometric accuracy of MVCT-assisted SRS appeared to enhance the clinical efficacy and safety of treatment to thoracic malignancies.

Exceptionally high incidence of symptomatic grade 2-5 radiation pneumonitis after stereotactic radiation therapy for lung tumors.

BackgroundTo determine the usefulness of dose volume histogram (DVH) factors for predicting the occurrence of radiation pneumonitis (RP) after application of stereotactic radiation therapy (SRT) for lung tumors, DVH factors were measured before irradiation.MethodsFrom May 2004 to April 2006, 25 patients were treated with SRT at the University of Tokyo Hospital. Eighteen patients had primary lung cancer and seven had metastatic lung cancer. SRT was given in 6–7 fields with an isocenter dose of 48 Gy in four fractions over 5–8 days by linear accelerator.ResultsSeven of the 25 patients suffered from RP of symptomatic grade 2–5 according to the NCI-CTC version 3.0. The overall incidence rate of RP grade2 or more was 29% at 18 months after completing SRT and three patients died from RP. RP occurred at significantly increased frequencies in patients with higher conformity index (CI) (p = 0.0394). Mean lung dose (MLD) showed a significant correlation with V5–V20 (irradiated lung volume) (p < 0.001) but showed no correlation with CI. RP did not statistically correlate with MLD. MLD had the strongest correlation with V5.ConclusionEven in SRT, when large volumes of lung parenchyma are irradiated to such high doses as the minimum dose within planning target volume, the incidence of lung toxicity can become high.

High-Dose Conformal Radiotherapy Influenced the Pattern of Failure But Did Not Improve Survival in Glioblastoma Multiforme

BACKGROUND AND PURPOSE Although glioblastoma multiforme is clearly radiation-resistant, there is evidence of a dose-dependent response relationship. The purpose of the study was to evaluate the impact of higher dose by rotational multileaf collimator (MLC) conformal radiation therapy. MATERIALS AND METHODS From 1984 to 1995, 38 consecutive cases with intracranial glioblastoma multiforme were treated using the rotational MLC conformal therapy. There were 25 men and 13 women with a median age of 47 years (12-73 years, mean 46.5 years). Median Karnofsky performance score was 80 (30-100, mean 78.2). Median tumor volume was 64 cc (8-800 cc, mean 110.3 cc). All underwent surgical intervention (only biopsy in 1, partial resection in 13, subtotal resection in 21, and gross total resection in 3). Radiation dose to was 60 to 80 Gy (median 68.5 Gy, mean 68.3 Gy) in 21 patients treated before 1990 and 90 Gy in the 17 patients thereafter. Biweekly i.v. chemotherapy was also administered for both arms. RESULTS The 1-year, 2-year, 5-year, and 10-year overall survival rates were 75%, 42%, 20%, and 15%, respectively. Univariate analysis showed the initial tumor volume, residual tumor volume, and Karnofsky performance score were statistically significant factors for survival. Only the residual tumor volume was statistically significant by multivariate analysis. The 5-year survival rate of patients with residual tumors of 5 cc or less in volume was as good as 37%. Survival of the 90-Gy Group appeared inferior to that of the Low-Dose Group, though no statistical difference was seen (the 3-year survival was 40% vs. 22%). Local failure was observed in 16 of the 19 recurrences in the Low-Dose Group, whereas it was observed in only 4 of the 13 recurrences in the 90-Gy Group. The difference in pattern of failure was statistically significant. Two patients of the High-Dose Group developed radiation necrosis and one died of it. CONCLUSIONS The high-dose conformal radiotherapy did not improve survival in the disease, but did change the pattern of failure.

Stereotactic radiosurgery for pituitary adenoma invading the cavernous sinus

The purpose of this paper was to note a potential source of error in magnetic resonance (MR) imaging. Magnetic resonance images were acquired for stereotactic planning for GKS of a vestibular schwannoma in a female patient. The images were acquired using three-dimensional sequence, which has been shown to produce minimal distortion effects. The images were transferred to the planning workstation, but the coronal images were rejected. By examination of the raw data and reconstruction of sagittal images through the localizer side plate, it was clearly seen that the image of the square localizer system was grossly distorted. The patient was returned to the MR imager for further studies and a metal clasp on her brassiere was identified as the cause of the distortion.A-60-year-old man with medically intractable left-sided maxillary division trigeminal neuralgia had severe cardiac disease, was dependent on an internal defibrillator and could not undergo magnetic resonance imaging. The patient was successfully treated using computerized tomography (CT) cisternography and gamma knife radiosurgery. The patient was pain free 2 months after GKS. Contrast cisternography with CT scanning is an excellent alternative imaging modality for the treatment of patients with intractable trigeminal neuralgia who are unable to undergo MR imaging.The authors describe acute deterioration in facial and acoustic neuropathies following radiosurgery for acoustic neuromas. In May 1995, a 26-year-old man, who had no evidence of neurofibromatosis Type 2, was treated with gamma knife radiosurgery (GKS; maximum dose 20 Gy and margin dose 14 Gy) for a right-sided intracanalicular acoustic tumor. Two days after the treatment, he developed headache, vomiting, right-sided facial weakness, tinnitus, and right hearing loss. There was a deterioration of facial nerve function and hearing function from pretreatment values. The facial function worsened from House-Brackmann Grade 1 to 3. Hearing deteriorated from Grade 1 to 5. Magnetic resonance (MR) images, obtained at the same time revealed an obvious decrease in contrast enhancement of the tumor without any change in tumor size or peritumoral edema. Facial nerve function improved gradually and increased to House-Brackmann Grade 2 by 8 months post-GKS. The tumor has been unchanged in size for 5 years, and facial nerve function has also been maintained at Grade 2 with unchanged deafness. This is the first detailed report of immediate facial neuropathy after GKS for acoustic neuroma and MR imaging revealing early possibly toxic changes. Potential explanations for this phenomenon are presented.In clinical follow-up studies after radiosurgery, imaging modalities such as computerized tomography (CT) and magnetic resonance (MR) imaging are used. Accurate determination of the residual lesion volume is necessary for realistic assessment of the effects of treatment. Usually, the diameters rather than the volume of the lesion are measured. To determine the lesion volume without using stereotactically defined images, the software program VOLUMESERIES has been developed. VOLUMESERIES is a personal computer-based image analysis tool. Acquired DICOM CT scans and MR image series can be visualized. The region of interest is contoured with the help of the mouse, and then the system calculates the volume of the contoured region and the total volume is given in cubic centimeters. The defined volume is also displayed in reconstructed sagittal and coronal slices. In addition, distance measurements can be performed to measure tumor extent. The accuracy of VOLUMESERIES was checked against stereotactically defined images in the Leksell GammaPlan treatment planning program. A discrepancy in target volumes of approximately 8% was observed between the two methods. This discrepancy is of lesser interest because the method is used to determine the course of the target volume over time, rather than the absolute volume. Moreover, it could be shown that the method was more sensitive than the tumor diameter measurements currently in use. VOLUMESERIES appears to be a valuable tool for assessing residual lesion volume on follow-up images after gamma knife radiosurgery while avoiding the need for stereotactic definition.This study was conducted to evaluate the geometric distortion of angiographic images created from a commonly used digital x-ray imaging system and the performance of a commercially available distortion-correction computer program. A 12 x 12 x 12-cm wood phantom was constructed. Lead shots, 2 mm in diameter, were attached to the surfaces of the phantom. The phantom was then placed inside the angiographic localizer. Cut films (frontal and lateral analog films) of the phantom were obtained. The films were analyzed using GammaPlan target series 4.12. The same procedure was repeated with a digital x-ray imaging system equipped with a computer program to correct the geometric distortion. The distortion of the two sets of digital images was evaluated using the coordinates of the lead shots from the cut films as references. The coordinates of all lead shots obtained from digital images and corrected by the computer program coincided within 0.5 mm of those obtained from cut films. The average difference is 0.28 mm with a standard deviation of 0.01 mm. On the other hand, the coordinates obtained from digital images with and without correction can differ by as much as 3.4 mm. The average difference is 1.53 mm, with a standard deviation of 0.67 mm. The investigated computer program can reduce the geometric distortion of digital images from a commonly used x-ray imaging system to less than 0.5 mm. Therefore, they are suitable for the localization of arteriovenous malformations and other vascular targets in gamma knife radiosurgery.

Results of radiosurgery for brain stem arteriovenous malformations.

OBJECTIVE To assess the treatment results of radiosurgery for brain stem arteriovenous malformations (AVMs) and to seek optimal dose and treatment volume prescription for these lesions. METHODS The clinical and radiological data of 30 consecutive patients with brain stem AVM treated with gamma knife radiosurgery were retrospectively reviewed with a mean follow up period of 52.2 months. There were 26 patients with previous haemorrhages and 21 with neurological deficit. Seventeen AVMs were located in the midbrain, 11 in the pons, and two in the medulla oblongata. All of the lesions were small with the intra-axial component occupying less than one third of the area of brain stem parenchyma on axial section of multiplaner MRI or CT. The mean diameter of the nidus was 1.26 cm, and the nidus volume within the brain stem parenchyma ranged from 0.1 to 2.0 cm3. The mean radiation dose to the AVM margin was 18.4 Gy. RESULTS The actuarial 3 year obliteration rate was 52.2%; 69.4% in cases treated with standard doses (minimum target dose, 18–20Gy), and 14.3% in cases treated with low doses (<18 Gy) (p<0.05). Two patients sustained symptomatic radiation injury, but there was no permanent neurological deficit caused by radiosurgery. Five patients had haemorrhage from the AVM after irradiation, including four fatal cases, resulting in a 4.0% annual rate of post-treatment bleeding. CONCLUSIONS Radiosurgery is a viable treatment modality for patients with small deep parenchymal brain stem AVMs. A standard radiosurgical dose is safe and effective when directed to a small treatment volume. However, latent interval haemorrhage remains a significant problem until the nidus is obliterated completely.

Control of epilepsy associated with cerebral arteriovenous malformations after radiosurgery

OBJECTIVE To investigate the effect of radiosurgery for symptomatic epilepsy associated with cerebral arteriovenous malformations (AVMs). METHODS Thirty five patients with unruptured epileptogenic AVMs were studied with a mean follow up of 43.0 months. The duration of epilepsy before radiosurgery ranged from 2 months to 21 years (mean 2.8 years). Fifteen patients showed partial seizures; eight of these had associated secondary generalisation. The remaining 20 patients showed only generalised seizures without preceding focal seizures. RESULTS At the final follow up examination, 28 patients remained seizure free, whereas seizures continued in seven. Variables significantly associated with continuity of seizures after radiosurgery were the number of seizures before therapy (p<0.01) and duration of epilepsy (p<0.05). According to Engel’s classification, the 10 patients with intractable seizures before treatment included five with grade I, four with grade III, and one with grade IV. The frequency of seizures began to decrease several months after radiosurgery; much shorter than the time required for morphological change in the AVMs. CONCLUSIONS Radiosurgery seems to be beneficial for seizure control in patients with unruptured epileptogenic AVM.

Stereotactic Radiosurgery With or Without Whole-Brain Radiotherapy for Brain Metastases: Secondary Analysis of the JROSG 99-1 Randomized Clinical Trial

IMPORTANCE It remains uncertain whether treatment with stereotactic radiosurgery (SRS) alone can be safely applied to all patient populations with 1 to 4 brain metastases (BMs) exhibiting heterogeneous prognoses. OBJECTIVE To investigate the feasibility of SRS alone for patients with different prognoses determined by the diagnosis-specific Graded Prognostic Assessment (DS-GPA). DESIGN, SETTING, AND PARTICIPANTS A secondary analysis (performed in September 2014) of the Japanese Radiation Oncology Study Group (JROSG) 99-1, a phase 3 randomized trial, comparing SRS alone and whole-brain radiotherapy (WBRT) + SRS conducted in 1999 to 2003. Among a total of 132 patients, 88 with non-small-cell lung cancer (NSCLC) and 1 to 4 BMs were included and poststratified by DS-GPA scores to avoid potential bias from BMs from different primary cancer types. The median follow-up time was 8.05 months. INTERVENTIONS The WBRT schedule was 30 Gy in 10 fractions over 2 to 2.5 weeks. The mean SRS dose was 21.9 Gy in SRS alone and 16.6 Gy in WBRT + SRS. MAIN OUTCOMES AND MEASURES The primary end point was overall survival (OS), and the secondary end points included brain tumor recurrence (BTR), salvage treatment, and radiation toxic effects. RESULTS Forty-seven patients had a favorable prognosis, with DS-GPA scores of 2.5 to 4.0 (26 SRS-alone and 21 WBRT + SRS [DS-GPA 2.5-4.0 group]), and 41 had an unfavorable prognosis, with DS-GPA scores of 0.5 to 2.0 (19 SRS-alone and 22 WBRT + SRS [DS-GPA 0.5-2.0 group]). Significantly better OS was observed in the DS-GPA 2.5-4.0 group in WBRT + SRS vs the SRS alone, with a median survival time of 16.7 (95% CI, 7.5-72.9) months vs 10.6 (95% CI, 7.7-15.5) months (P = .04) (hazard ratio [HR], 1.92; 95% CI, 1.01-3.78). However, no such difference was observed in the DS-GPA 0.5-2.0 group (HR, 1.05; 95% CI, 0.55-1.99) (P = .86). This benefit could be explained by the differing BTR rates, in that the prevention against BTR by WBRT had a more significant impact in the DS-GPA 2.5-4.0 group (HR, 8.31; 95% CI, 3.05-29.13) (P < .001) vs the DS-GPA 0.5-2.0 group (HR, 3.57; 95% CI, 1.02-16.49) (P = .04). CONCLUSIONS AND RELEVANCE Despite the current trend of using SRS alone, the important role of WBRT for patients with BMs from NSCLC with a favorable prognosis should be considered. Our findings should be validated through appropriately designed prospective studies. TRIAL REGISTRATION umin.ac.jp/ctr Identifier: C000000412.

High-dose conformal radiotherapy for supratentorial malignant glioma: a historical comparison

BACKGROUND Although radiotherapy remains the main postoperative treatment for patients with malignant glioma, modifications to regimens have not improved the poor outlook of patients with this disease. We aimed to investigate whether high-dose conformal radiotherapy improves the survival of patients with supratentorial malignant glioma compared with conventional radiotherapy. METHODS 29 patients with anaplastic astrocytoma and 61 patients with glioblastoma who received high-dose conformal radiotherapy during 1990-2002 were compared with 34 patients with anaplastic astrocytoma and 60 patients with glioblastoma who received conventional 60 Gy radiotherapy during 1979-89. 77 of the 90 patients receiving high-dose radiotherapy were given 80 Gy; the remaining 13 patients, all with glioblastoma, received 90 Gy. Radiotherapy was planned on the basis of images taken before surgery, and doses were delivered in 2 Gy per fraction per day for 5 days a week. Hazard ratios for death were calculated with a Cox model, and were adjusted for age, Karnofsky performance scale, tumour size, and extent of resection. FINDINGS Patients who received high-dose radiotherapy had significantly longer overall survival compared with those who received conventional radiotherapy (adjusted hazard ratio 0.30 [95% CI 0.12-0.76], p=0.011 for anaplastic astrocytoma and 0.49 [0.28-0.87], p=0.014 for glioblastoma). Patients with anaplastic astrocytoma in the high-dose group have not yet reached median survival; median survival in the conventional radiotherapy group was 22.3 months (95% CI 20.6-24.0). 5-year survival was 51.3% (29.2-73.4) for the high-dose group and 14.7% (0.0-30.0) for the conventional group. Median survival in patients with glioblastoma was 16.2 months (12.8-19.6) for the high-dose group and 12.4 months (10.0-14.8) for the conventional group. 2-year survival was 38.4% (23.5-53.3) for the high-dose group and 11.4% (0.0-25.3) for the conventional group. Survival did not differ between those that received 80 Gy radiotherapy and those that received 90 Gy (hazard ratio 0.94 [95% CI 0.42-2.12]). The higher frequency of radiation-induced white matter abnormality in the high-dose group compared with the conventional radiotherapy group did not lead to increased disability. INTERPRETATION High-dose, standard-fractionated radiotherapy shows potential as the main postoperative treatment for patients with supratentorial malignant glioma.

Stereotactic radiosurgery for tentorial dural arteriovenous fistulae draining into the vein of Galen: report of two cases.

OBJECTIVE AND IMPORTANCE Treatment of tentorial dural arteriovenous fistulae (DAVFs) primarily draining into the vein of Galen remains a therapeutic challenge. We present two cases of ruptured galenic DAVFs that were successfully treated with gamma knife radiosurgery. CLINICAL PRESENTATION Patient 1, a 66-year-old woman, experienced a sudden onset of headache and loss of consciousness. Neuroimaging studies revealed intraventricular hemorrhage and a DAVF with aneurysmal dilation of the vein of Galen. The DAVF was supplied by tentorial branches of the right meningohypophyseal artery and bilateral supracerebellar arteries, which drained directly into the vein of Galen. Patient 2, a 64-year-old woman, experienced subarachnoid hemorrhage. Cerebral angiography revealed a galenic DAVF at the falcotentorial junction, which was supplied by bilateral supracerebellar arteries. This patient had an aneurysm at the origin of the left supracerebellar artery. INTERVENTION Both patients were treated with gamma knife radiosurgery. In each case, the fistula was exclusively targeted and a dose of more than 20 Gy was delivered. Complete obliteration of the fistula was confirmed 27 and 29 months after radiosurgery for Patients 1 and 2, respectively, whereas the normal venous structures of the galenic system were preserved. CONCLUSION Gamma knife radiosurgery is an effective treatment modality for DAVFs primarily draining into the vein of Galen. Irradiation doses of more than 20 Gy, strictly limited to the fistulae, seem to be sufficient for successful obliteration of these high-risk vascular lesions, with minimal invasiveness.