Image-guided robotic stereotactic body radiotherapy for benign spinal tumors: theUniversity of California San Francisco preliminary experience.

We evaluate our preliminary experience using the Cyberknife Radiosurgery System in treating benign spinal tumors. A retrospective review of 16 consecutively treated patients, comprising 19 benign spinal tumors, was performed. Histologic types included neurofibroma [11], chordoma [4], hemangioma [2], and meningioma [2]. Three patients had Neurofibromatosis Type 1 (NF1). Only one tumor, recurrent chordoma, had been previously irradiated, and as such not considered in the local failure analysis. Local failure, for the remaining 18 tumors, was based clinically on symptom progression and/or tumor enlargement based on imaging. Indications for spine stereotactic body radiotherapy (SBRT) consisted of either adjuvant to subtotal resection (5/19), primary treatment alone (12/19), boost following external beam radiotherapy (1/19), and salvage following previous radiation (1/19). Median tumor follow-up is 25 months (2-37), and one patient (with NF1) died at 12 months from a stroke. The median total dose, number of fractions, and prescription isodose was 21 Gy (10-30 Gy), 3 fx (1-5 fx), 80% (42-87%). The median tumor volume was 7.6 cc (0.2-274.1 cc). The median V100 (volume V receiving 100% of the prescribed dose) and maximum tumor dose was 95% (77-100%) and 26.7 Gy (15.4-59.7 Gy), respectively. Three tumors progressed at 2, 4, and 36 months post-SR (n=18). Two tumors were neurofibromas (both in NF1 patients), and the third was an intramedullary hemangioblastoma. Based on imaging, two tumors had MRI documented progression, three had regressed, and 13 were unchanged (n=18). With short follow-up, local control following Cyberknife spine SBRT for benign spinal tumors appear acceptable.

Differentiation of glioblastoma multiforme and single brain metastasis by peak height and percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging.

BACKGROUND AND PURPOSE: Glioblastoma multiforme (GBM) and single brain metastasis (MET) are the 2 most common malignant brain tumors that can appear similar on anatomic imaging but require vastly different treatment strategy. The purpose of our study was to determine whether the peak height and the percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MR imaging could differentiate GBM and MET. MATERIALS AND METHODS: Forty-three patients with histopathologic diagnosis of GBM (n=27) or MET (n=16) underwent DSC perfusion MR imaging in addition to anatomic MR imaging before surgery. Regions of interest were drawn around the nonenhancing peritumoral T2 lesion (PTL) and the contrast-enhancing lesion (CEL). T2* signal intensity-time curves acquired during the first pass of gadolinium contrast material were converted to the changes in relaxation rate to yield T2* relaxivity (Delta R2*) curve. The peak height of maximal signal intensity drop and the percentage of signal intensity recovery at the end of first pass were measured for each voxel in the PTL and CEL regions of the tumor. RESULTS: The average peak height for the PTL was significantly higher (P=.04) in GBM than in MET. The average percentage of signal intensity recovery was significantly reduced in PTL (78.4% versus 82.8%; P=.02) and in CEL (62.5% versus 80.9%, P<.01) regions of MET compared with those regions in the GBM group. CONCLUSIONS: The findings of our study show that the peak height and the percentage of signal intensity recovery derived from the Delta R2* curve of DSC perfusion MR imaging can differentiate GBM and MET.

Dose conformity of gamma knife radiosurgery and risk factors for complications.

PURPOSE: To quantitatively evaluate dose conformity achieved using Gamma Knife radiosurgery, compare results with those reported in the literature, and evaluate risk factors for complications. METHODS AND MATERIALS: All lesions treated at our institution with Gamma Knife radiosurgery from May 1993 (when volume criteria were routinely recorded) through December 1998 were reviewed. Lesions were excluded from analysis for reasons listed below. Conformity index (the ratio of prescription volume to target volume) was calculated for all evaluable lesions and for lesions comparable to those reported in the literature on conformity of linac radiosurgery. Univariate Cox regression models were used to test for associations between treatment parameters and toxicity. RESULTS: Of 1612 targets treated in 874 patients, 274 were excluded, most commonly for unavailability of individual prescription volume data because two or more lesions were included within the same dose matrix (176 lesions), intentional partial coverage for staged treatment of large arteriovenous malformations (AVMs) (33 lesions), and missing target volume data (26 lesions). The median conformity indices were 1.67 for all 1338 evaluable lesions and 1.40-1.43 for lesions comparable to two linac radiosurgery series that reported conformity indices of 1.8 and 2.7, respectively. Among all 651 patients evaluable for complications, there were one Grade 5, eight Grade 4, and 27 Grade 3 complications. Increased risk of toxicity was associated with larger target volume, maximum lesion diameter, prescription volume, or volume of nontarget tissue within the prescription volume. CONCLUSIONS: Gamma Knife radiosurgery achieves much more conformal dose distributions than those reported for conventional linac radiosurgery and somewhat more conformal dose distributions than sophisticated linac radiosurgery techniques. Larger target, nontarget, or prescription volumes are associated with increased risk of toxicity.

Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome.

OBJECT: The goal of this study was to perform a critical review of literature pertinent to low-grade gliomas of the cerebral hemisphere in adults and, on the basis of this review, to evaluate systematically the prognostic effect of extent of resection on survival and to determine if treatment-related guidelines could be established for patients in whom these tumors have been newly diagnosed. Quality of evidence for current treatment options, guidelines, and standards as well as methodological limitations were evaluated. METHODS: Several prognostic factors thought to affect outcome in patients with low-grade gliomas include the patient's age and neurological status, tumor volume and histological characteristics, and treatment-related variables such as timing of surgical intervention, extent of resection, postoperative tumor volume, and radiation therapy. Patient age and the histological characteristics of the lesion are generally accepted prognostic factors. Among treatment-related factors, timing and extent of resection are controversial because of the lack of randomized controlled trials addressing these issues and the difficulty in obtaining information from available studies that have methodological limitations. All English-language studies on low-grade gliomas published between January 1970 and April 2000 were reviewed. Thirty studies that included statistical analyses were further evaluated with regard to the prognostic effect of extent of resection. Of these 30 studies, those that included pediatric patients, unless adults were analyzed separately, were excluded from further study because of the favorable outcome associated with the pediatric age group. Also excluded were studies including pilocytic and gemistocytic astrocytomas, because the natural histories of these histological subtypes are significantly different from that of low-grade gliomas. Series in which there were small numbers of patients (< 75) were also excluded. Results for oligodendrogliomas are reported separately. Currently, for patients with low-grade glial tumors located in the cerebral hemisphere, the only management standard based on high-quality evidence is tissue diagnosis. All other treatment methods are practice options supported by evidence that is inconclusive or conflicting. The majority of published series that the authors identified had design-related limitations including a small study size, a small number of events (that is, deaths for survival studies), inclusion of pediatric patients, and/or inclusion of various histological types of tumors with different natural histories. Of the 30 series addressing the issue of timing and extent of surgery, almost all had additional design limitations. Methods used to determine the extent of resection were subjective and qualitative in almost all studies. Only five of the 30 series met the authors' criteria, and these studies are discussed in detail. CONCLUSIONS: Management of low-grade gliomas is controversial and practice parameters are ill defined. This is caused by limited knowledge regarding the natural history of these tumors and the lack of high-quality evidence supporting various treatment options. Although a prospective randomized study seems unlikely, both retrospective matched studies and prospective observational trials will improve the clinician's ability to understand the importance of various prognostic factors.

Genetic subgroups of anaplastic astrocytomas correlate with patient age and survival.

Astrocytomas are brain tumors with variable responses to radiation and chemotherapy. Tumor grade and patient age are important prognostic factors but do not account for the variability in clinical outcome. We hypothesized that genetic subgroups play a role in the outcome of grade III astrocytomas and studied 80 grade III astrocytomas by comparative genomic hybridization. Some chromosomal aberrations (+7p/q, -9p, -10q, -13q, +19q) were related to aberrations that are frequent in grade IV astrocytoma, whereas others (+10p, -11q, +11p, -Xq) were more frequent in grade III astrocytoma. +7p, +19 and -4q were more frequent in tumors from older patients while -11p was more frequent in tumors from younger patients. Finally, gains of 7p and 7q were associated with shorter patient survival, independent of age. Our results indicate that genetic events underlie the well-known effects of age on survival in grade III astrocytoma and demonstrate the importance of molecular classification in astrocytic tumors.

A hypoxia-regulated adeno-associated virus vector for cancer-specific gene therapy.

The presence of hypoxic cells in human brain tumors is an important factor leading to resistance to radiation therapy. However, this physiological difference between normal tissues and tumors also provides the potential for designing cancer-specific gene therapy. We compared the increase of gene expression under anoxia (<0.01% oxygen) produced by 3, 6, and 9 copies of hypoxia-responsive elements (HRE) from the erythropoietin gene (Epo), which are activated through the transcriptional complex hypoxia-inducible factor 1 (HIF-1). Under anoxic conditions, nine copies of HRE (9XHRE) yielded 27- to 37-fold of increased gene expression in U-251 MG and U-87 MG human brain tumor cell lines. Under the less hypoxic conditions of 0.3% and 1% oxygen, gene activation by 9XHRE increased expression 11- to 18-fold in these cell lines. To generate a recombinant adeno-associated virus (rAAV) in which the transgene can be regulated by hypoxia, we inserted the DNA fragment containing 9XHRE and the LacZ reporter gene into an AAV vector. Under anoxic conditions, this vector produced 79- to 110-fold increase in gene expression. We believe this hypoxia-regulated rAAV vector will provide a useful delivery vehicle for cancer-specific gene therapy.

Relationship between pattern of enhancement and local control of brain metastases after radiosurgery.

PURPOSE: A desired goal in the radiosurgery (RS) of brain metastases is improved local control. Our earlier retrospective review identified pattern of enhancement on day-of-treatment imaging as a prognostic indicator for freedom from progression (FFP) after RS in 219 brain metastases. The current study was performed to corroborate this preliminary finding. METHODS AND MATERIALS: Records and imaging studies of patients treated with RS from 1991 to 1997 were reviewed. Each metastasis was categorized as homogeneously-, heterogeneously-, or ring-enhancing. Kaplan-Meier FFP was calculated from the date of RS to the first imaging showing tumor progression. Univariate and multivariate analyses were performed using Cox proportional hazard models stratified by primary site and type of RS (alone, as a boost, or for recurrence). RESULTS: Of 682 lesions in 258 patients, 518 lesions in 193 patients were evaluable. Pattern of enhancement was homogeneous in 59%, heterogeneous in 32%, and ring-like in 8% of lesions. One-year FFP probabilities for homogeneously-, heterogeneously-, and ring-enhancing lesions were 90% (95% confidence interval, 84-93%), 76% (64-84%), and 57% (35-74%), respectively. The p-value for pattern of enhancement from the stratified multivariate analysis was 0.019 adjusting for RS dose and treatment period (1991-1994 vs. 1995-1997). Similar results were achieved adjusting for tumor volume instead of RS dose. CONCLUSION: Pattern of enhancement is confirmed as a significant prognostic factor for FFP of brain metastases treated with RS, independent of dose and volume. A possible explanation is radioresistance of hypoxic tumor cells associated with necrotic regions, suggesting future investigations with radiosensitizers, hypoxic cell sensitizers, or strategies to improve tumor oxygenation.

Radiosurgery for brain metastases from primary lung carcinoma.

PURPOSE: Brain metastases are a common problem in patients with lung cancer. This retrospective review was performed to describe the efficacy and toxicity of stereotactic radiosurgery for brain metastases from lung carcinoma and to evaluate prognostic factors for survival. PATIENTS AND METHODS: A retrospective review was performed of 113 patients with the diagnosis of lung carcinoma who underwent radiosurgery with or without whole-brain radiotherapy for management of newly diagnosed or recurrent, single, or multiple brain metastases from 1991 through 1998 at the University of California, San Francisco. Freedom from progression and survival were measured from the date of radiosurgery and estimated using the Kaplan-Meier method. Prognostic factors were evaluated with the log-rank test and Cox proportional hazards models. RESULTS: The median patient age at the time of radiosurgery was 59 years (range, 37-82 years), and the median Karnofsky performance score was 90 (range, 50-100). The median survival time from radiosurgery was 12.0 months overall, 13.9 months for 41 patients treated with radiosurgery alone initially, 14.5 months for 19 patients treated with radiosurgery and whole-brain radiotherapy initially, and 10.0 months for 53 patients with recurrent brain metastases. Among newly diagnosed patients, multivariate analysis showed that improved survival was associated with absence of extracranial metastases and fewer brain metastases. Among patients with recurrent brain metastases, improved survival was associated with higher Karnofsky performance score, control of the primary tumor, and fewer metastases. Measured by lesion, 1-year local freedom from progression probabilities were 81% for radiosurgery alone, 86% for radiosurgery and whole-brain radiotherapy, and 65% for radiosurgery performed after recurrence. In patients with newly diagnosed brain metastases, there was a significantly greater risk of developing subsequent brain metastases and of worse overall brain freedom from progression after radiosurgery alone versus radiosurgery and whole-brain radiotherapy. One-year brain freedom from progression probabilities were 13% without salvage therapy and 62% with salvage therapy in the 41 patients treated initially with radiosurgery alone, versus 67% without salvage therapy and 89% with salvage therapy in the 19 patients treated initially with radiosurgery plus whole-brain radiotherapy. DISCUSSION: Radiosurgery is an effective therapy for selected patients with newly diagnosed or recurrent brain metastases from lung carcinoma. Initial whole-brain radiotherapy with radiosurgery appears to improve brain control but not survival. Prospective, randomized trials are needed to further investigate the role of radiosurgery with and without whole-brain radiotherapy for brain metastases.

Protease pretreatment increases the efficacy of adenovirus-mediated gene therapy for the treatment of an experimental glioblastoma model.

Effective virus-mediated gene therapy for cancer will be facilitated by procedures that enhance the low level of gene transfer mediated by replication-deficient, recombinant viral vectors. We found recently that protease pretreatment of solid tumors is a useful strategy for enhancing virus-mediated gene transduction in vivo. In this study, we examined the potential of protease pretreatment to improve the efficacy of a gene therapy strategy for prodrug activation that depends on infection with a recombinant adenovirus encoding herpes simplex virus thymidine kinase (Ad-HSV-tk). Trypsin or a dissolved mixture of collagenase/dispase was inoculated into xenografts derived from the human glioblastoma multiforme-derived cell lines, U87 or U251. Ad-HSV-tk was administered 24 h after protease pretreatment, and animals were then treated for 10 days with ganciclovir (GCV). We found that protease pretreatment increased the efficacy of adenovirus mediated HSV-tk/GCV gene therapy in these experimental tumor models. Mice receiving Ad-HSV-tk/GCV after protease pretreatment demonstrated a significantly greater regression of tumors compared with those treated with Ad-HSV-tk/GCV alone. No adverse effects of protease pretreatment were observed. No signs of metastasis were seen either by histological inspection of lymph nodes or by a PCR-based analysis of selected mouse tissues to detect human tumor cells. Our findings indicate that protease pretreatment may be a useful strategy to enhance the efficacy of virus-mediated cancer gene therapy.

Chromosomal abnormalities subdivide ependymal tumors into clinically relevant groups.

Ependymoma occurs most frequently within the central nervous system of children and young adults. We determined relative chromosomal copy-number aberrations in 44 ependymomas using comparative genomic hybridization. The study included 24 intracranial and 20 spinal cord tumors from pediatric and adult patients. Frequent chromosomal aberrations in intracranial tumors were gain of 1q and losses on 6q, 9, and 13. Gain of 1q and loss on 9 were preferentially associated with histological grade 3 tumors. On the other hand, gain on chromosome 7 was recognized almost exclusively in spinal cord tumors, and was associated with various other chromosomal aberrations including frequent loss of 22q. We conclude that cytogenetic analysis of ependymomas may help to classify these tumors and provide leads concerning their initiation and progression. The relationship of these aberrations to patient outcome needs to be addressed.

Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients.

Glioblastoma multiforme (GBM) carries a dismal prognosis. However, a range of survival times exists, and parameters that define prognostic groups may help to optimize treatment. To identify such prognostic groups, we analyzed tumor tissue from 110 cases of newly diagnosed GBM from two clinical protocols. Similar to other studies, we found no association of epidermal growth factor receptor (EGFR) overexpression (as assessed by immunohistochemistry), p53 immunopositivity, or p53 mutation with survival in the entire sample. However, EGFR overexpression showed trends toward worse prognosis in patients younger than the median age, but better prognosis in patients older than the median age. This interaction of EGFR with age group was statistically significant and led us to focus our further analyses on the younger patients. In this group, a statistically significant association of EGFR overexpression with worse survival was identified in the p53-negative but not p53-positive tumors. We found a similar result after screening these cases for mutations in p53: EGFR overexpression was negatively associated with survival only in the p53 wild-type cases. To confirm this unexpected result, this finding was reproduced in a validation sample of an additional 42 tumors from younger patients on the same two clinical protocols. This complex relationship between EGFR and p53 in younger patients remained in a multivariate analysis that incorporated additional prognostic variables. The results suggest that analysis of prognostic markers in GBM is complex, and maximal information may require analysis of subgroups based on age and the status of specific markers such as p53. In addition, they suggest a specific group of patients on which to focus promising therapies targeting EGFR.

Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme.

PURPOSE: To report the results of a prospective Phase III trial for patients with newly diagnosed glioblastoma multiforme (GBM), treated with either accelerated hyperfractionated irradiation with or without difluromethylornithine (DFMO) or standard fractionated irradiation with or without DFMO. METHODS AND MATERIALS: Adult patients with newly diagnosed GBM were registered and randomized following surgery to one of 4 treatment arms: Arm A, accelerated hyperfractionation alone using 2 fractions a day of 1.6 Gy to a total dose of 70.4 Gy in 44 fractions; Arm B, accelerated hyperfractionation as above plus DFMO 1.8 gm/m2 by mouth every 8 h beginning one week before radiation until the last fraction was given; Arm C, single-fraction irradiation of 1.8 Gy/day to 59.4 Gy; Arm D, single-fraction irradiation as in Arm C plus DFMO given as in Arm B. Patients were followed for progression-free survival (PFS) and overall survival (OS), as well as for toxicity. Eligibility required histologically proven GBM, age > or =18, Karnofsky performance status (KPS) > or =60, and no prior chemotherapy or radiotherapy. Adjuvant chemotherapy was not used in this protocol. RESULTS: A total of 231 eligible patients were enrolled. There were 95 men and 136 women with a median age of 57 years, and median KPS of 90. Extent of resection was total in 23, subtotal in 152, and biopsy only in 56 patients. The 4 arms were balanced with respect to age, KPS, and extent of resection. Times to event measurements are from date of diagnosis. Median OS and PFS were 40 and 19 weeks for Arm A; 42 and 22 weeks for Arm B; 37 and 16 weeks for Arm C; and 44 and 19 weeks for Arm D (p = 0.48 for survival; p = 0.32 for PFS). Comparison of the 2 arms treated with DFMO to the 2 arms without DFMO revealed no difference in OS (37 weeks vs. 42 weeks, p = 0.12) or PFS and thus no benefit to the use of DFMO. Comparison of the 2 standard fractionation arms to the 2 accelerated hyperfractionation arms also resulted in no difference in OS (42 weeks vs. 41 weeks, p = 0.75) or PFS, showing no benefit to accelerated hyperfractionated irradiation. CONCLUSION: In this prospective Phase III study, no survival or PFS benefit was seen with accelerated hyperfractionated irradiation to 70.4 Gy, nor was any benefit seen with DFMO as a radiosensitizer. Standard fractionated irradiation to 59.4 Gy remains the treatment of choice for newly diagnosed patients with glioblastoma multiforme.

Pretreatment with protease is a useful experimental strategy for enhancing adenovirus-mediated cancer gene therapy.

A key impediment to the development of effective virus-mediated gene therapy for cancer is the low level of gene transfer that occurs after the administration of recombinant viral vectors. Improving in vivo infection and transduction efficiency is an important goal for gene therapy. The limited distribution of gene delivery is particularly problematic when large vectors such as recombinant adenoviruses and retroviruses are used to mediate transgene delivery to solid tumors. To facilitate the spread of virus, we have investigated the potential of administering proteases prior to the intratumoral inoculation of recombinant replication deficient adenovirus. For these studies, we chose proteases that are active against collagen and the other extracellular matrix proteins found in primary brain tumor tissue, but are not widely expressed in normal brain. Various concentrations of a mixture of collagenase/dispase or trypsin were inoculated into xenografts of human glioblastoma multiforme-derived brain tumor cell lines U87, U251, and SF767. Subsequently, recombinant adenovirus encoding the beta-galactosidase gene was administered and tumor tissue was examined for evidence of virus infection. Both collagenase/dispase and trypsin enhanced virus infection, indicating that protease pretreatment may be a useful strategy for enhancing virus-mediated gene transduction for many in vivo applications.

Efficacy and toxicity of radioimmunotherapy with (90)Y-DOTA-peptide-ChL6 for PC3-tumored mice.

BACKGROUND: Radioimmunotherapy (RIT) is a new therapeutic modality capable of systemic delivery of radionuclides specifically to sites of metastatic cancer. The L6 monoclonal antibody has been shown to target prostate cancer in preclinical studies and, along with chimeric L6 (ChL6), has been used for RIT in breast cancer patients. METHODS: Pharmacokinetics, blood counts, body weight, and antitumor activity of RIT with (90)yttrium-((90)Y)-DOTA-peptide-ChL6 (75-260 microCi) were determined in nude mice bearing human prostate cancer (PC3) xenografts. RESULTS: RIT produced durable, dose-dependent antitumor effects with a 100% response rate using 112 microCi and 150 microCi (the maximum tolerated dose) of (90)Y-DOTA-peptide-ChL6. Myelotoxicity was reversible, dose-limiting, and dose-related. RIT was associated with improved survival (P = 0.05). All 5 mice in the 150-microCi group survived the 84-day study period vs. 1/8 (13%) for untreated, tumored control mice. CONCLUSIONS: (90)Y-DOTA-peptide-ChL6 targets PC3 human prostate cancer xenografts in nude mice and has an antitumor effect. These results provide a basis for future RIT trials for patients with metastatic prostate cancer.

Neovascular targeting with cyclic RGD peptide (cRGDf-ACHA) to enhance delivery of radioimmunotherapy.

Radioimmunotherapy (RIT) has been hampered by delivery of only a small fraction of the administered dose of radiolabeled MAb to tumor. A strategy for creating and controlling tumor vascular permeability would enable more effective RIT. The alpha v beta 3 integrin receptor is an appealing target for strategies designed to enhance permeability of tumor vessels because it is highly and preferentially expressed in most tumors. In human tumor mouse models, apoptosis of neovascular endothelial cells has been demonstrated after treatment with alpha v beta 3 antagonists. Since this apoptotic effect could transiently increase permeability of tumor blood vessels, radiolabeled antibodies (MAb) circulating during this period would have increased access to extravascular tumor. To determine if this hypothesis was correct, a pharmacokinetic study of an immunospecific MAb given after an alpha v beta 3 antagonist was performed in nude mice bearing human breast cancer xenografts. The alpha v beta 3 antagonist, cyclic RGD pentapeptide (c-RGDf-ACHA; cyclo arginine glycine aspartic acid D-phenylalanine -1 amino cyclohexane carboxylic acid), inhibits alpha v beta 3 binding to its vitronectin ligand at nanomolar levels. Cyclic RGD peptide (250 micrograms i.p.) given 1 hour before 111In-ChL6 MAb resulted in a 40-50% increase in tumor uptake (concentration), when compared to the control tumor uptake, of MAb 24 hours after administration. When cyclic RGD peptide was given as a continuous infusion (17.5 micrograms/hr) for 1 or 24 hours before 111In-ChL6, tumor uptake of 111In-ChL6 was increased less, and, these data were not statistically different from the control data. There were no differences for any of the groups in the groups in the concentrations of 111In-ChL6 in normal organs or blood when compared to the control group. The results suggest that cyclic RGD peptide provided a temporary, selective increase in tumor vascular permeability, that allowed a larger fraction of the 111In-ChL6 to accumulate in the tumor.

A preliminary study of the prognostic value of proton magnetic resonance spectroscopic imaging in gamma knife radiosurgery of recurrent malignant gliomas.

OBJECTIVE: The goal of this study was to investigate the use of proton magnetic resonance spectroscopic imaging as a prognostic indicator in gamma knife radiosurgery of recurrent gliomas. METHODS: Thirty-six patients with recurrent gliomas were studied with proton magnetic resonance spectroscopic imaging at the time of radiosurgery, and with conventional magnetic resonance imaging examinations at regular time intervals until the initiation of a new treatment strategy. Patients were categorized on the basis of their initial spectroscopic results, and their performance was assessed in terms of change in contrast-enhancing volume, time to further treatment, and survival. RESULTS: The trends in the overall population were toward more extensive increase in the percent contrast-enhancing volume, a decreased time to further treatment, and a reduced survival time for patients with more extensive initial metabolic abnormalities. Statistical analysis of the subpopulation of patients with glioblastoma multiforme found a significant increase in relative contrast-enhancing volume (P < 0.01, Wilcoxon signed-rank test), a decrease in time to further treatment (P < 0.01, log-rank test), and a reduction in survival time (P < 0.01, log-rank test) for patients with regions containing tumor-suggestive spectra outside the gamma knife target, compared with patients exhibiting spectral abnormalities restricted to the gamma knife target. Further studies are needed to establish statistical significance for patients with lower-grade lesions and to confirm the results observed in this study. CONCLUSION: The pretreatment spectroscopic results provided information that was predictive of outcome for this patient pool, both in local control (change in contrast-enhancing volume) and global outcome (time to further treatment and survival). This modality may have an important role in improving the selection, planning, and treatment process for glioma patients.

Phase II study of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine chemotherapy with radiotherapy for treating malignant glioma in children.

We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic astrocytoma appeared better than most reports. The combination of TPDCV chemotherapy and radiation therapy for anaplastic ependymomas appears to be active and at least as good as published reports using radiation therapy alone.

67Copper-2-iminothiolane-6-[p-(bromoacetamido)benzyl-TETA-Lym-1 for radioimmunotherapy of non-Hodgkin's lymphoma.

Copper-67 (67Cu) has ideal properties for radioimmunotherapy. The 62-h half-life is similar to the residence time of antibodies in tumor, and the therapeutic beta emission of 67Cu is comparable to that of 131I. 67Cu, however, has gamma emissions similar to 99mtechnetium that are favorable for imaging. The macrocyclic chelating agent 1,4,7,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA) binds 67Cu tightly and selectively, facilitating linkage to Lym-1, a mouse monoclonal antibody that preferentially targets malignant lymphocytes. The safety, efficacy, and practicality of 67Cu-2-iminothiolane (2IT)-6-[p-(bromoacetamido)benzyl]-TETA (BAT)-Lym-1 was assessed in this Phase I/II clinical trial for patients with non-Hodgkin's lymphoma (NHL) who had failed standard therapy. Up to four doses of 67Cu-2IT-BAT-Lym-1, 25 or 50-60 mCi/m2/dose (0.93 or 1.85-2.22 GBq/m2/dose, respectively) were administered; the lower dosage was used when NHL was detected in the bone marrow. 67Cu-2IT-BAT-Lym-1 provided good imaging of NHL, had favorable radiation dosimetry, and had a response rate of 58% (7 of 12). Hematological toxicity was dose-limiting, but no significant nonhematological toxicity was observed. The ability to image and treat NHL patients with a single radiopharmaceutical with useful physical properties makes 67Cu-labeled monoclonal antibody an option for future clinical trials, as this study showed that 67Cu-2IT-BAT-Lym-1 was safe, effective, and practical.

Factors affecting 131I-Lym-1 pharmacokinetics and radiation dosimetry in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

UNLABELLED: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) when labeled with 131I. Responders had statistically significant prolongation of survival compared with nonresponders. The nonmyeloablative, maximum tolerated dose for each of two doses of 131I-Lym-1 was 3.7 GBq/m2 (total 7.4 GBq/m2 [100 mCi/m2, total 200 mCi/m2]) of body surface area. The purpose of this study was to determine the pharmacokinetics and radiation dosimetry for the initial 131I-Lym-1 therapy dose in patients with NHL and CLL and to compare tumor dosimetry with 131I-Lym-1 dosing and other patient parameters. METHODS: Fifty-one patients with stage 3 or 4 lymphoma were treated with 131I-Lym-1 (0.74-8.04 GBq [20-217 mCi]) in either a maximum tolerated dose (MTD) or low-dose (LD) trial. Total Lym-1 given to each patient was sufficient in all instances to exceed the threshold required for stable pharmacokinetics. Quantitative imaging and physical examination, including caliper and CT measurement of tumor size and analysis of blood, urine and feces, were performed for a period of 7 to 10 d after infusion to assess pharmacokinetics and radiation dosimetry. Clinical records were reviewed to obtain data required for comparative assessments. RESULTS: The concentration (%ID/g) and biologic half-time of 131-Lym-1 in tumor were about twice those in normal tissues, although tumor half-time was similar to that of the thyroid. Pharmacokinetics were similar for patients in the MTD and LD trials, and for NHL and CLL patients in the LD trial, except that the latter group had less tumor concentration of 131I. Mean tumor radiation dose per unit of administered 131I was 1.0 Gy/GBq (3.7 rad/mCi) for patients with NHL whether in MTD or LD trials, about nine times greater than that for body or marrow. Tumor radiation dose was less and liver radiation dose was more in patients with CLL. Otherwise, radiation dosimetry was, on average, remarkably similar among groups of patients and among individual patients. Pharmacokinetics and dosimetry did not appear to be influenced by the amount of 131I or Lym-1 within the ranges administered. Tumor concentration of 131I and radiation dose per gigabecquerel were inversely related to tumor size but did not seem to be related to histologic grade or type, tumor burden or therapeutic response. CONCLUSION: The therapeutic index of 131I-Lym-1 was favorable, although the index for patients with CLL was less than that for patients with NHL. Pharmacokinetics and radiation dosimetry were, on average, remarkably similar among patients and groups of patients in different trials.