Hypofractionated high-dose irradiation for the treatment of malignant astrocytomas using simultaneous integrated boost technique by IMRT.

PURPOSE: We evaluated the clinical significance of hypofractionated high-dose irradiation using simultaneous integrated boost technique with intensity-modulated radiation therapy (IMRT) for the treatment of malignant astrocytomas (MAs). METHODS AND MATERIALS: Twenty-five patients with MAs were treated by IMRT. Three layered planning target volumes (PTVs) were contoured. PTV-1 was the area of enhanced lesion with 5-mm margin; PTV-2 was the area with 15-mm margin surrounding the PTV-1; PTV-3 was the area of perifocal edema. Irradiation was performed in 8 fractions, and only the dose for PTV-1 was escalated from 48 Gy to 68 Gy while maintaining the dose for PTV-2 (40 Gy) and PTV-3 (32 Gy). The clinical outcome of IMRT was compared with 60 MA patients treated by conventional external beam irradiation (EBI). RESULTS: The progression-free survival of patients in the IMRT group was significantly longer than that in the EBI group (p < 0.0001). No distant failure was observed in both groups. In the IMRT group, dissemination was the most frequent cause of death (70%). The overall survival of patients in the IMRT group was better than that in the EBI group (p = 0.043). CONCLUSIONS: Our regimen of IMRT contributed to the control of both the regional and infiltrating tumors, resulting in better survival of patients.

Inhibition of metastatic brain tumor growth by intramuscular administration of the endostatin gene.

The cancer patients suffering from brain metastases are basically incurable. The conventional tumoricidal strategies frequently cause severe side effects instead of life prolongation of such patients. On the other hand, antiangiogenic therapy seems to be a promising strategy to avoid such unfavorable effects. In the present study, we experimentally investigated tumor dormancy effect of the excessively produced endostatin, a potent angiostatic factor, by intramuscular administration of the endostatin gene against primary cancer and metastatic brain tumor. For this purpose, we established a model system in which FM3A P-15 cells, a high metastatic mouse breast cancer cell line, were inoculated simultaneously into the brain as an artificially metastatic brain tumor (herein referred as "metastatic brain tumor") and the mammary pad as a primary cancer (referred as "primary breast cancer"), and utilized a non-viral system to deliver an expression plasmid encoding a secretable form of mouse endostatin into muscle tissues. The plasmid vector formulated with the synthetic polymer, polyvinylpyrrolidone, was administrated at 3 and 10 days after the inoculation of FM3A P-15 cells. A significant increase in the serum level of endostatin was achieved at 7 days after second administration of the plasmid vector (p=0.0066). Consequently, the growth of metastatic brain tumor was significantly retarded (p=0.0455), while no significant change in the weight of primary breast cancer was observed (p=0.1531). Intratumoral microvessel density in metastatic brain tumor but not in primary cancer as revealed by Factor VIII immunohistochemistry was significantly decreased in the endostatin gene-administrated group (p=0.0027). In conclusion, the present study demonstrates the potential efficacy of intramuscular delivery of antiangiogenic gene for treatment of metastatic brain tumor.

Gamma knife radiosurgery for metastatic brain tumors from lung cancer: a comparison between small cell and non-small cell carcinoma.

OBJECT: The purpose of this retrospective study was to evaluate the effectiveness of gamma knife radiosurgery (GKS) for the treatment of metastatic brain tumors from lung cancer, with particular reference to small cell lung carcinoma (SCLC) compared with non-SCLC (NSCLC). METHODS: Two hundred forty-five consecutive patients meeting the following five criteria were evaluated in this study: 1) no prior brain tumor treatment; 2) 25 or fewer lesions; 3) a maximum of three tumors with a diameter of 20 mm or larger; 4) no surgically inaccessible tumor 30 mm or greater in diameter; and 5) more than 3 months of life expectancy. According to the same treatment protocol, large tumors (> or = 30 mm) were surgically removed and the other small lesions (< 30 mm) were treated with GKS. New lesions were treated with repeated GKS. Chemotherapy was administered, according to the primary physician's protocol, as aggressively as possible. Progression-free, overall, neurological, qualitative, and new lesion-free survival were calculated with the Kaplan-Meier method and were compared in the SCLC and NSCLC groups by using the log-rank test. The poor prognostic factors for each type of survival were also analyzed with the Cox proportional hazard model. CONCLUSIONS: Tumor control rate at 1 year was 94.5% in the SCLC group and 98% in the NSCLC group. The median survival time was 9.1 months in the SCLC group and 8.6 months in the NSCLC group. The 1-year survival rates in the SCLC group were 86.5% for neurological survival and 68.9% for qualitative survival; those in the NSCLC group were 87.9% for neurological and 78.9% for qualitative survival. The estimated median interval to emergence of a new lesion was 6.9 months in the SCLC group and 9.8 months in the NSCLC group. There was no significant difference between the two groups for any type of survival; this finding was verified by multivariate analysis. The results of this study suggest that GKS appears to be as effective in treating brain metastases from SCLC as for those from NSCLC.

Extraosseous accumulation of bone scanning agents in malignant brain tumors: comparison to semi-quantitative evaluation with 99mTc SPECT/201Tl SPECT and histological findings.

Although 201Tl chloride (Tl) SPECT has been used in the differential diagnosis between recurrence of malignant brain tumor and necrosis after treatment, it is not generally recognized as a definite modality to distinguish them. We conducted a preliminary study using Tl SPECT and 99mTc-MDP or 99mTc-HMDP (Tc) SPECT because it has been said that extraosseous accumulation was caused by calcium deposits in necrotic tissues. In our study, for the purposes of clarifying the mechanism of extraosseous uptake and the correlation between extraosseous accumulation of bone-scanning agent and tumor viability in malignant brain tumors, we compared whether Tc uptake was correlated with the histopathological findings and further performed semi-quantitative evaluation between Tc SPECT and Tl SPECT. The correlation coefficients between the ratio of tumor to normal skull count obtained from Tc SPECT (Tc-T/N) and those of tumor to normal brain count (T/N) and to normal scalp count (T/S) both obtained from Tl SPECT were calculated. Using contrast enhanced CT (CE-CT) or contrast enhanced MRI (CE-MRI), 8 of 10 cases showed intensely ring-enhanced tumor with necrotic lesion. Histopathologically, 7 of 8 cases whose tumor had been resected before treatment had necrosis with increased vascularity or bleeding. Of the remaining 2 cases one case, malignant lymphoma had only hypervascularity by biopsy, while the other one was excluded for resection after treatment. Three of these 8 cases whose CE-CT or CE-MRI showed necrotic lesions exhibited Tc and Tl accumulations in the area corresponding to necrosis. In contrast, 2 showed no Tc nor Tl uptake. Tc-T/N had no significant correlation with any of early-, delayed-T/N or T/S. In conclusion, there was no significant correlation between Tc and Tl uptakes by malignant brain tumors in semi-quantitative evaluation.

Extraosseous accumulation of 99mTc phosphonate complexes in primary brain tumor evaluated with SPECT.

Although extraosseous accumulations of 99mTc phosphate complexes are phenomena which can often be seen, no case showing extraosseous accumulation to brain tumor on SPECT has been reported. We report here two cases of primary brain tumor showing extraosseous accumulation of 99mTc phosphate in bone SPECT. 201Tl SPECT also showed increased 201Tl uptake by the tumor. Comparing bone SPECT with 201Tl SPECT, the regions of abnormality of both SPECTs were very similar in the case of glioblastoma, but in the case of malignant lymphoma the region showing intense uptake of 99mTc-MDP was smaller than that on 201Tl SPECT. It was revealed that bone SPECT is more useful in the assessment of extraosseous accumulation to a primary brain tumor than conventional bone scintigraphy.

A rare case of metastatic renal cell carcinoma resembling a nerve sheath tumor of the cauda equina.

We present a rare case of solitary metastasis to the cauda equina from the kidney. The patient was a 68-year-old man with a two-year history of low back pain. His past medical history revealed a renal cell carcinoma diagnosed seven years earlier. His lumbosacral MR imaging showed a well-demarcated, intradural extramedullary mass at the L3 level. He underwent an L2-4 laminectomy. The operative findings of the tumor quite resembled that of a nerve sheath tumor. It did not infiltrate into the subarachnoid space and involved only one spinal nerve. Pathology of the tumor was a metastasis of the renal cell carcinoma. Only 10 cases with such a metastasis to the cauda equina have been reported in the English literature. We added the 11th and reviewed the literature with reference to tumor pathologies, clinical findings and route of metastasis to the cauda equina.

Comparison of intensity modulated radiotherapy and dynamic three-dimensional conformal radiotherapy with regard to dose distribution and sparing of organs at risk.

Dose escalation to the target while sparing the organs at risk near the lesion has been difficult over the last decade. However, recent radiotherapy techniques can deliver more sophisticated doses to the target. This study evaluated whether intensity modulated radiotherapy can deliver more homogeneous and conformal doses to the target than dynamic three-dimensional conformal radiotherapy while sparing organs at risk near the lesion in 13 patients with central nervous system tumors and other tumors around the central nervous system. Dynamic three-dimensional conformal radiotherapy and intensity modulated radiotherapy plans were calculated and dose distributions were compared for all patients with regard to the planning target volume and organs at risk. The plan of intensity modulated radiotherapy was significantly superior to that of dynamic three-dimensional conformal radiotherapy in target dose conformity (p = 0.0006) and organs at risk sparing (p = 0.0257). Intensity modulated radiotherapy could deliver more homogeneous and conformal doses to the target than dynamic three-dimensional conformal radiotherapy with sparing organs at risk near the lesion and may improve local control of radioresistant tumors via dose escalation.

Longterm survival after surgical removal of solitary brain metastasis from osteosarcoma.

The prognosis of osteosarcoma with brain metastasis is very poor. We report a 14-year-old girl with osteosarcoma of the right distal femur who is alive and free of disease 6 years after the craniotomy and irradiation for brain metastasis. This longterm survival is attributed to the absence of active pulmonary metastasis at the onset of brain metastasis and the complete removal of the brain metastasis by craniotomy. Patients without active pulmonary metastasis at the onset of brain metastasis may achieve longterm survival. In such patients, it would be worthwhile to perform craniotomy aggressively.

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 (approximately 5.7 Mb) and at 1p36.1-p36.2 ( approximately 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.