Toshihiko Iuchi

Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma

BACKGROUND Brain metastases (BM) are a common in patients with lung cancer. Although whole-brain radiation therapy (WBRT) is the standard therapy, it may have a risk of decline in cognitive function of patients. In this study, we evaluated the efficacy of gefitinib alone without radiation therapy for the treatment of patients with BM from lung adenocarcinoma. MATERIALS AND METHODS Eligible patients had BM from lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Gefitinib was given at 250 mg orally once a day until tumor progression or unacceptable toxicity. RESULTS Forty-one patients were enrolled. The response rate was 87.8%. No patient experienced grade ≥4 toxicity. The median progression-free survival time was 14.5 months (95% CI, 10.2-18.3 months), and the median overall survival time was 21.9 months (95% CI, 18.5-30.3 months). In compared with L858R, exon 19 deletion was associated with better outcome of patients after treatment with gefitinib in both progression-free (p = 0.003) and overall survival (p = 0.025). CONCLUSION Favorable response of BM to gefitinib even without irradiation was demonstrated. Exon 19 deletion was both a predictive and prognostic marker of patients with BM treated by gefitinib.

Gamma knife treatment for multiple metastatic brain tumors compared with whole-brain radiation therapy.

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.

Diagnostic value of thallium-201 chloride single-photon emission computerized tomography in differentiating tumor recurrence from radiation injury after gamma knife surgery for metastatic brain tumors.

OBJECT The authors assessed the diagnostic value of 201Tl Cl single-photon emission computerized tomography (SPECT), performed after gamma knife surgery (GKS) for metastatic brain tumors in differentiating tumor recurrence from radiation injury. METHODS Of 6503 metastatic brain tumors treated with GKS, 201Tl SPECT was required in 72 to differentiate between tumor recurrence and radiation injury. When the Tl index was greater than 5, the lesion was diagnosed as a tumor recurrence. When the index was < 3.0 it was called radiation injury. In cases with a Tl index between 3 and 5, 201Tl SPECT was repeated once per month until the Tl index was greater than 5 or less than 3. If the Tl index fluctuated between 3 and 5 for 2 months, the lesion was diagnosed as radiation injury. The final diagnosis was based on histological examination or clinical course. The sensitivity of the method was 91%; thus 201Tl SPECT is effective for differentiating between tumor recurrence and radiation injury in metastatic brain tumors treated with GKS. Caution is necessary, however, for the following reasons: 1) simple interinstitutional comparisons of Tl indices are not possible because measurement methods are institute specific; 2) steroid administration decreases the Tl index to a variable degree; and 3) a severe radiation injury lesion, as is often seen after repeated GKS or very high dose GKS, may have a Tl index greater than 5. CONCLUSIONS Used with critical insight 201Tl Cl SPECT can be useful in distinguishing between tumor regrowth and radiation necrosis in patients with cerebral metastases.

MRI Prediction of Fibrous Pituitary Adenomas

Summary The transsphenoidal approach is a less invasive and safer procedure for removing pituitary adenomas. However, this procedure becomes extremely difficult when the tumour consistency is fibrous as encountered in about 10% of pituitary adenomas. In this study, we investigated predicting factors of tumour consistency in magnetic resonance images (MRIs). MRIs of two groups, twenty-one soft and five firm (fibrous) adenomas, were retrospectively evaluated and compared in respect of tumour consistency. To compare the two groups objectively, tumour densities on MRI films and percentage of collagen content on operative specimens were expressed as numerical data using NIH-imageTM. The relationships between collagen content and T1-weighted images, T2-weighted images, grade of enhancement effect, and heterogeneity of enhancement were investigated. Signal intensities on T1-weighted images were not correlated with tumour consistency, whereas those on T2-weighted images were significantly correlated with the percentage of collagen content. Adenomas, showing lower signal intensities on T2-weighted images, contained more collagen. On enhanced images, homogeneously enhanced adenomas tended to include more collagen, even though the grade of enhancement effect showed only weak correlation with the tumour hardness. MRIs give us useful information on tumour consistency. Adenomas may be firm and fibrous if they show low signal intensities on T2-weighted images and homogeneous enhancement. To remove such tumours, a long sized and small-calibred ultrasonic aspirators applicable to transsphenoidal approach must be prepared and multi-staged operations may be more than likely needed.

Phase 2 Trial of Hypofractionated High-Dose Intensity Modulated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Newly Diagnosed Glioblastoma

PURPOSE/OBJECTIVES To assess the effect and toxicity of hypofractionated high-dose intensity modulated radiation therapy (IMRT) with concurrent and adjuvant temozolomide (TMZ) in 46 patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS All patients underwent postsurgical hypofractionated high-dose IMRT. Three layered planning target volumes (PTVs) were contoured. PTV1 was the surgical cavity and residual tumor on T1-weighted magnetic resonance images with 5-mm margins, PTV2 was the area with 15-mm margins surrounding the PTV1, and PTV3 was the high-intensity area on fluid-attenuated inversion recovery images. Irradiation was performed in 8 fractions at total doses of 68, 40, and 32 Gy for PTV1, PTV2, and PTV3, respectively. Concurrent TMZ was given at 75 mg/m(2)/day for 42 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m(2)/day for 5 days every 28 days. Overall and progression-free survivals were evaluated. RESULTS No acute IMRT-related toxicity was observed. The dominant posttreatment failure pattern was dissemination. During a median follow-up time of 16.3 months (range, 4.3-80.8 months) for all patients and 23.7 months (range, 12.4-80.8 months) for living patients, the median overall survival was 20.0 months after treatment. Radiation necrosis was diagnosed in 20 patients and was observed not only in the high-dose field but also in the subventricular zone (SVZ). Necrosis in the SVZ was significantly correlated with prolonged survival (hazard ratio, 4.08; P=.007) but caused deterioration in the performance status of long-term survivors. CONCLUSIONS Hypofractionated high-dose IMRT with concurrent and adjuvant TMZ altered the dominant failure pattern from localized to disseminated and prolonged the survival of patients with GBM. Necrosis in the SVZ was associated with better patient survival, but the benefit of radiation to this area remains controversial.

Gamma knife surgery for brain metastases: indications for and limitations of a local treatment protocol

SummaryObjective. The purpose of this retrospective study was to evaluate results of a local treatment protocol using gamma knife surgery (GKS) for brain metastases without upfront whole brain radiation therapy (WBRT).Methods. Results for 521 consecutive patients satisfying the following 3 criteria were analysed: 1) a maximum of 3 tumours with a diameter of 25 mm or more; 2) no prior WBRT; 3) no surgically in accessible large (>30 mm) tumours. Large tumours were surgically removed and all smaller lesions were treated by GKS without up front WBRT. New lesions, detected with follow-up MRI, were appropriately treated with repeat GKS. Overall survival (OS), neurological survival (NS), qualitative survival (QS) and new lesion-free survival (NLFS) curves were calculated and the prognostic values of covariates were obtained. OS and NS were compared according to tumour number.Results. In total, 1023 separate sessions were required to treat 4562 lesions. The primary organs were lung in 369 patients, gastro-intestinal tract in 70, breast in 33, urinary tract in 24, and others/unknown in 25. The median OS period was 9.0 months. On multivariate analysis, the significant prognostic factors for OS were found to be extracranial disease (risk factor: active), Karnofsky performance status (KPS) score (<70) and gender (male). NS and QS at one year were 85.6% and 73.0%, respectively. The only significantly poor prognostic factor for NS was carcinomatous meningitis. NLFS at 6 months was 68.9%. For both OS and NS, the differences between a few (≤3) and many (4–10) brain lesions were not significant (OS: p=0.3128, NS: p=0.5509). Patients with numerous (>10) tumours had a significantly poorer prognosis than those with ≤10.Conclusion. Our protocol, aggressively applying GKS, provides excellent results in selected patients with ≤10 brain lesions and no carcinomatous meningitis.

Identification of the small interstitial deletion at chromosome band 1p34–p35 and its association with poor outcome in oligodendroglial tumors

To narrow down the putative tumor‐suppressor gene locus and to assess the predictability of clinical courses by genomic alterations, we analyzed 46 oligodendroglial tumors for loss of heterozygosity (LOH) in the distal region of the short arm of chromosome 1. LOH at 1p was found in 43 tumors (93.5%), including all 28 oligodendrogliomas, all eight oligo‐astrocytomas, six of eight anaplastic oligodendrogliomas, and in one of two anaplastic oligo‐astrocytomas. Thirty‐seven tumors showed LOH patterns consistent with a large terminal deletion, whereas six tumors showed LOH suggesting interstitial deletions. Our data also showed two small regions of overlap at 1p34–p35 (∼5.7 Mb) and at 1p36.1–p36.2 (∼12 Mb). Among the six tumors with interstitial deletion, the proximal region was deleted in five tumors, whereas the distal region was deleted in only half of them. Overall, 91% of tumors showed deletion including this proximal region. To examine the clinical significance of the LOH pattern, the samples were classified into three groups: tumors without 1p LOH (Group 1, n = 3), tumors with an interstitial deletion (Group 2, n = 6), and tumors with a large terminal deletion (Group 3, n = 37). Both overall and progression‐free survival of patients in Group 2 was extremely poor compared with those included in Group 3 (P = 0.0006 and P = 0.003, respectively). As to the clinical response to chemotherapy, nimustine prevented tumor recurrence in Group 3 (P = 0.034) but not in Group 2. Our results demonstrate that a putative tumor‐suppressor gene(s) in oligodendroglial tumors is localized at 1p34–p35 and that small interstitial deletions, in contrast to large terminal deletions, are strongly predictive of both chemoresistance and aggressive characteristics of these tumors.

Proliferation, Vascular Endothelial Growth Factor Expression and Cavernous Sinus Invasion in Growth Hormone Secreting Pituitary Adenomas

Summary Surgical cure of growth hormone producing pituitary adenomas (GHomas) becomes difficult when they invade the cavernous sinus (CS). Tumour proliferative activity and angiogenesis are thought to be required for tumour growth and invasion, and vascular endothelial growth factor (VEGF) activates neovascularization around tumours. In this study, the mechanism and clinical significance of CS invasion is analysed. In 25 surgically treated GHomas, the extent of CS invasion was classified as high (Knosps grade 3 and 4), and low (grade 0, 1 and 2) MR grades, and the MR grades were compared with tumour proliferative potential (Ki-67 expression), angiogenetic demand (VEGF expression), volume of adenomas and serum hormone levels. The Ki-67 index of high MR grade adenomas (1.17±0.62%) was significantly higher than that of low MR grade adenomas (0.55±0.42%, p=0.027), whereas VEGF expression showed no significant correlation with MR grades (p>0.999). Tumour volume also showed a significant correlation with MR grade (p=0.002). VEGF expression was not correlated with serum hormone level and volume, but was correlated with tumour proliferative potential. Proliferative potential and tumour volume were two independent factors related to CS invasion. Although VEGF expression was not a direct factor related to CS invasion, it may indirectly play a role in activation of tumour aggressiveness, which is required in CS invasion. Our results show that high MR grade adenomas have higher proliferative ability. In order to improve the surgical outcome, pre-operative medical debulking is indicated, particularly, in such adenomas.

Detection of epithelial growth factor receptor mutations in cerebrospinal fluid from patients with lung adenocarcinoma suspected of neoplastic meningitis.

Background: Neoplastic meningitis (NM) is a devastating neurological complication of cancer that needs to be diagnosed in the early stages of disease. Polymerase chain reaction detection of epithelial growth factor receptor (EGFR) mutations in cerebrospinal fluid (CSF), which are predictive markers for EGFR tyrosine kinase inhibitor therapy in lung cancer, might be important to diagnose and to treat NM in patients with lung cancer. In this study, we attempted to detect EGFR mutations in CSF and to compare EGFR status between CSF and primary or metastatic lesions in patients with lung adenocarcinoma suspected of NM. Methods: Twenty-nine patients with lung adenocarcinoma suspected of having NM underwent lumbar puncture. EGFR status of CSF was analyzed by direct DNA sequencing. EGFR mutations of primary or metastatic lesions (lymph nodes and bones) were analyzed in 20 cases. Results: EGFR mutations were detected in CSF of 13 (45%) of 29 patients. In 5 (31%) of 16 patients with negative CSF cytology, EGFR mutations were detected. In four patients, EGFR mutations were shown in CSF, but not in primary or metastatic lesions. Conversely, in two patients, EGFR mutations were shown in primary or metastatic lesions, but not in CSF despite positive CSF cytology. Conclusions: EGFR mutations, suggesting the existence of malignant cells, were detected in CSF, even in patients with non-small cell lung cancer with negative cytological results. EGFR mutations in CSF do not always reflect the same status as in primary or metastatic lesions.

Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: a phase II prospective, randomised study

Objective Phenytoin (PHT) is routinely used for seizure prophylaxis in patients with brain tumours during and after craniotomy, despite incomplete evidence. We performed a prospective, randomised study to investigate the significance of prophylactic use of levetiracetam (LEV), in comparison with PHT, for patients with supratentorial tumours in the perioperative period. Methods Patients were randomised to receive LEV, 500 mg/body every 12 h until postoperative day 7, or PHT, 15–18 mg/kg fosphenytoin followed by 125 mg PHT every 12 h until postoperative day 7. The primary end point was the occurrence of seizures, and secondary end points included the occurrence of haematological and non-haematological adverse events. Results One hundred and forty-six patients were randomised to receive LEV (n=73) or PHT (n=73). The incidence of seizures was significantly less in the LEV group (1.4%) compared with the PHT group (15.1%, p=0.005), suggesting benefit of LEV over PHT. The observed OR for being seizure free in the LEV prophylaxis group relative to the PHT group was 12.77 (95% CI 2.39 to 236.71, p=0.001). In a subgroup analysis of patients who did not have seizures before craniotomy, similar results were demonstrated: the incidence of seizures was 1.9% (LEV) and 13.8% (PHT, p=0.034), and OR was 8.16 (95% CI 1.42 to 154.19, p=0.015). LEV was completed in all cases, although PHT was withdrawn in five patients owing to liver dysfunction (1), skin eruption (2) and atrial fibrillation (2). Conclusions Prophylactic use of LEV in the perioperative period is recommended because it is safe and significantly reduces the incidence of seizures in this period. Trial registration number UMIN13971.