Tumor Resection Cavity Research Articles

Dosimetry study of a phase II multiple-dose intracavitary administration of 131I-TM601 in adult patients with recurrent high-grade glioma

e13006 Background: Postoperative radiotherapy for glioma has been shown to improve survival with increased radiation doses. Dose escalation of external beam radiotherapy or brachytherapy is limited by normal brain radionecrosis. Radiolabeled targeting molecules can deliver localized radiation to tumor and reduce normal brain radionecrosis. TM601, or synthetic Chlorotoxin, is a peptide derived from scorpion venom that specifically binds to tumor cells. Here we report dosimetry results of an imaging sub-study of a phase II trial, in which weekly doses of 131I-TM601 were infused into surgically created tumor resection cavities for 3 or 6 weeks. Methods: Five out of 76 patients treated in a phase II trial were imaged after receiving 1, 3, or 6 doses of 40 mCi/0.8 mg 131I-TM601 intracavitarily. For each imaging study, 5 sequential SPECT images (1–168 hour) were registered with MRI to determine the 131I-TM601 radiation dose to the 2-cm tumor cavity margin. Five sequential body scans were also acquired to determine 131I-TM601 radiation dose to extra-cranial organs. Results: 131I-TM601 is a rapidly penetrating and clearing radiolabeled peptide. The median residual activity in the cavity at 7 days post injection was 8.4%. Median radiation dose to the cavity margin was 121 cGy/mCi and ranged 52- 338 cGy/mCi in 5 subjects. The median coefficient of variation (intra-patient inter-fraction) for the 2-cm margin dose was 14.7% and ranged 7.1–18.9%. Median tumor cavity volume was 11.4 mL, and ranged 5.2 - 35.5 mL. There was no observed correlation between the 2-cm margin dose and the cavity volume. Median radiation dose to thyroid, kidneys, red marrow, and body was 8.3, 1.3, 0.4, and 0.6 cGy/mCi, respectively. Conclusions: Radiation dose ratio for 2-cm cavity margin-to-normal tissues was quite high. While intra-patient reproducibility was relatively good, cumulative effect of the residual activity was only meaningful within a week. These results support the multi-dose fractionation scheme for 131I-TM601 to minimize normal tissue toxicity, including radiation necrosis, and extend continuous irradiation to clinical or sub-clinical residual tumor cells after surgery. [Table: see text]

Phase Ib Trial of Mutant Herpes Simplex Virus G207 Inoculated Pre-and Post-tumor Resection for Recurrent GBM

We have previously demonstrated safety of G207, a doubly mutated (deletion of both gamma(1)34.5 loci, insertional inactivation of U(L)39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky score >or=70, and ability to resect the tumor without ventricular system breach. Patients received two doses of G207 totaling 1.15 x 10(9) plaque-forming units with 13% of this total injected via a catheter placed stereotactically in the tumor. Two or five days later, tumor was resected en bloc with catheter in place. The balance of G207 dose was injected into brain surrounding the resection cavity. Six patients with recurrent glioblastoma multiforme were enrolled. Two days after the second G207 inoculation, one patient experienced transient fever, delirium, and hemiparesis, which entirely resolved on high-dose dexamethasone. No patient developed HSV encephalitis or required treatment with acyclovir. Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.

How to overcome the limitations to determine the resection margin of pituitary tumours with low-field intra-operative MRI during trans-sphenoidal surgery: usefulness of Gadolinium-soaked cotton pledgets

Intra-operative MRI (iMRI) is used as an immediate intra-operative quality control, allowing surgeons to extend resections in situations involving residual tumour remnants. Despite these advantages, low-field iMRI has some limitations with regards to image quality and artefacts. The aim of this study is to report our experience with bone wax and Gadolinium-soaked cotton pledgets in obtaining precise tumour resection margins using low-field iMRI. The study group included 63 consecutive patients who underwent endonasal trans-sphenoidal surgery with use of intra-operative low-field iMRI (0.15 T, PoleStar N20, Medtronic Navigation, Louisville, CO, U.S.A.). The indications for intra-operative MRI use included a suprasellar or retrosellar extension (n = 23), cavernous sinus invasion (n = 21), a tumour located in the vicinity of critical anatomic structures (such as the internal carotid artery, n = 10), recurrent or revision procedures (n = 5), and pre-operative imaging revealing unusual anatomy (n = 4). Overall, among the 51 patients with intended complete tumour removal, iMRI revealed definite tumour remnants or suspicious findings in 13 patients (25.5%), leading to an extended resection and allowing completion of the resection in 10 patients. There was an increased rate of complete tumour removal from 74.5% (38 out of 51) to 94.1% (48 out of 51). The iMRI scan for complete tumour removal was more efficient in the group receiving Gadolinium-soaked cotton pledgets (85.2-100%) than in the group receiving bone wax or the conventional method (62.5-87.5%). The results of iMRI and the estimation by the surgeon concerning the extent of resection revealed a discrepancy in five patients (15.6%) in the Gadolinium-soaked cotton pledgets application group, and in 14 (45.2%) of the bone wax application group. More valuable information for determining the resection margin can be obtained with the use of contrast-soaked cottonoid packing in the tumour resection cavity during iMRI scanning. We believe that the use of this simple method reduces the false-positive results and also overcomes the disadvantages of low-field iMRI.

Tumor-specific targeting of intravenous 131I-chlorotoxin (131I-TM-601) in patients with metastatic melanoma

20003 Background: Previous clinical trials of 131I-chlorotoxin in patients with recurrent glioblastoma multiforme administered this targeted peptide locally into a tumor resection cavity. In this t...

Treatment of Single Brain Metastasis with Resection, Intracavity Carmustine Polymer Wafers, and Radiation Therapy Is Safe and Provides Excellent Local Control

To define the safety and efficacy of carmustine polymer wafers when added to a regimen of surgery and external beam radiotherapy for treatment of a single brain metastasis. Adult patients underwent craniotomy for a single brain metastasis, and carmustine polymer wafers were placed in the tumor resection cavity. Patients then received whole-brain radiotherapy and were followed for patterns of recurrence in the central nervous system, toxicity, and survival. We enrolled 25 patients with solitary brain metastases from lung (13 patients), melanoma (4 patients), breast (3 patients), and renal carcinoma (3 patients). Two patients had severe adverse events thought to be related to wafer placement, one with seizures alone, and one with seizures and subsequent respiratory compromise. Both responded to medical therapy. There were no wound infections. The local recurrence rate was surprisingly low (0%). Four patients (16%) relapsed elsewhere in the brain, and two patients (8%) relapsed in the spinal cord. Median survival was 33 weeks; 33% of patients survived 1 year, and 25% survived 2 years. The addition of local chemotherapy delivered via carmustine polymer wafers to a regimen of surgical resection and external beam radiotherapy was well tolerated by patients undergoing surgery for a single brain metastasis. There were no local recurrences, suggesting that this treatment further reduced the risk of local relapse.

Gamma knife surgery for glioblastoma multiforme

Despite the implementation of increasingly aggressive surgery, chemotherapy, and fractionated radiotherapy for the treatment of glioblastoma multiforme (GBM), most therapeutic regimens have resulted in only modest improvements in patient survival. Gamma knife surgery (GKS) has become an indispensable tool in the primary and adjuvant management of many intracranial pathologies, including meningiomas, pituitary tumors, and arteriovenous malformations. Although it would seem that radiosurgical techniques, which produce steep radiation dose fall-off around the target, would not be well suited to treat these infiltrative lesions, a limited number of institutional series suggest that GKS might provide a survival benefit when used as part of the comprehensive management of GBM. This may largely be attributed to the observation that tumors typically recur within a 2-cm margin of the tumor resection cavity. Despite these encouraging results, enthusiasm for radiosurgery as a primary treatment for GBM is significantly tempered by the failure of the only randomized trial that has been conducted to yield any benefit for patients with GBM who were treated with radiosurgery. In this paper, the authors review the pathophysiological mechanisms of GKS and its applications for GBM management.

Robust nonrigid registration to capture brain shift from intraoperative MRI

We present a new algorithm to register 3-D preoperative magnetic resonance (MR) images to intraoperative MR images of the brain which have undergone brain shift. This algorithm relies on a robust estimation of the deformation from a sparse noisy set of measured displacements. We propose a new framework to compute the displacement field in an iterative process, allowing the solution to gradually move from an approximation formulation (minimizing the sum of a regularization term and a data error term) to an interpolation formulation (least square minimization of the data error term). An outlier rejection step is introduced in this gradual registration process using a weighted least trimmed squares approach, aiming at improving the robustness of the algorithm. We use a patient-specific model discretized with the finite element method in order to ensure a realistic mechanical behavior of the brain tissue. To meet the clinical time constraint, we parallelized the slowest step of the algorithm so that we can perform a full 3-D image registration in 35 s (including the image update time) on a heterogeneous cluster of 15 personal computers. The algorithm has been tested on six cases of brain tumor resection, presenting a brain shift of up to 14 mm. The results show a good ability to recover large displacements, and a limited decrease of accuracy near the tumor resection cavity.

Cerebral edema associated with Gliadel wafers: Two case studies

While the introduction of carmustine wafers (Gliadel wafers) into the tumor resection cavity has been shown to be a beneficial therapy for malignant glioma, it is recognized that clinically significant cerebral edema is a potential adverse effect. Following are two clinical case reports demonstrating profound cerebral edema associated with implantation of Gliadel wafers. As a result, one of these individuals had premature death. A brief literature review is provided to assist in explaining the mechanisms by which clinically significant cerebral edema may develop.

Radiation Safety Considerations In GliaSite 125I Brain Implant Procedures

The traditional approach to treatment of certain malignant brain tumors involves permanent implantation of I seeds sequential to tumor's resection. This approach has recently been changed for patients with unifocal recurrent gliomas. What began during the 1990's as a large clinical trial utilizing GliaSite Radiotherapy System, is currently becoming standard of care. This radiotherapy system consists of an inflatable balloon catheter, 2, 3, or 4 cm diameter, which is surgically placed in the tumor resection cavity; its positioning and the level of conformity within the cavity are verified via MRI imaging with contrast. The balloon is then filled with appropriate volume of I in the liquid form. Radiation treatment prescription dose ranges from 40 to 60 Gy (4,000 to 6,000 rads). This is accomplished by allowing 2.77 to 16.6 GBq (75 to 450 mCi) of I to remain in the balloon for 3-5 d. Numerous technical, dosimetric, and logistical considerations arise when handling large quantities of iodine necessary to perform GliaSite procedures. They require coordination of efforts of several hospital departments and the institution's RSO-in our case, two RSOs, at the University of Colorado Hospital and University of Colorado Health Sciences Center hold separate radioactive materials licenses. Based on our experiences and those of others, we conclude that, with appropriate guidance and care, these procedures can be performed safely without excessive restrictions.

Human/murine chimeric 81C6 F(ab′) 2 fragment: preclinical evaluation of a potential construct for the targeted radiotherapy of malignant glioma

We have obtained encouraging responses in recent Phase I studies evaluating 131I-labeled human/murine chimeric 81C6 anti-tenascin monoclonal antibody (ch81C6) administered into surgically-created tumor resection cavities in brain tumor patients. However, because the blood clearance is slow, hematologic toxicity has been higher than seen with murine 81C6 (mu81C6). In the current study, a series of paired-label experiments were performed in athymic mice bearing subcutaneous D-245 MG human glioma xenografts to compare the biodistribution of the fragment ch81C6 F(ab′) 2 labeled using Iodogen to a) intact ch81C6, b) mu81C6, and c) ch81C6 F(ab′) 2 labeled using N-succinimidyl 3-[ 131I]iodobenzoate. Tumor retention of radioiodine activity for the F(ab′) 2 fragment was comparable to that for intact ch81C6 for the first 24 h and to that for mu81C6 for the first 48 h; as expected, blood and other normal tissue levels declined faster for ch81C6 F(ab′) 2. Radiation dosimetry calculations suggest that 131I-labeled ch81C6 F(ab′) 2 may warrant further evaluation as a targeted radiotherapeutic for the treatment of brain tumors.

The effects of hydrogen peroxide on brain and brain tumors

Background Hydrogen peroxide (HP) is routinely used during neurosurgical procedures to augment hemostasis after intracranial tissue resection. Elsewhere in the body, HP is used to kill resection margin tumor cells; in vitro studies support these clinical uses. The effects of HP on brain and brain tumors have not been evaluated. In this study, the in vitro and in vivo effects of HP on both rat and human brain parenchyma and brain tumors were examined. Methods Antitumor activity of varied concentrations of HP (0–30%) on cultured primary and metastatic brain tumors ( n = 13) was compared with the effects of various concentrations of ethanol (0–50%). Studies were performed in rats to characterize HP-induced tissue changes that occurred when HP-soaked pledgets were placed on the arachnoid surface and along resection margins ( n = 5). Additionally, the effect of HP on human brain along tumor resection cavities was investigated ( n = 10). Results While HP demonstrated concentration-dependent tumoricidal effects in vitro, similar to results achieved with ethanol, HP caused significant injury to arachnoid and stroma with neuronal and glial injury to a depth of 1 mm in rats. Three percent HP-soaked pledgets placed in resection cavities of excised brain tumors induced similar injury in human brain. Conclusion HP irreversibly damages mesothelial and neural tissue. Although HP appears to have tumoricidal effects in vitro, it should be used with caution in humans because of risks of collateral injury to surrounding normal brain. HP may prove most beneficial for discrete lesions, such as pituitary tumors and metastases.

Immune response induced by retrovirus-mediated HSV-tk/GCV pharmacogene therapy in patients with glioblastoma multiforme.

This study was conducted to investigate immunological components of somatic gene therapy for primary glioblastoma multiforme (GBM) in adults. It involved 13 patients treated by surgical resection of tumor with subsequent radiation therapy. Seven of them received additional herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) gene therapy by direct intracerebral injection of retrovirus (RV) vector producing cells (VPC) during tumor surgery and subsequent systemic administration of GCV. Peripheral blood for FACS immunophenotyping, isolation of peripheral mononuclear cells (PMNC), and serum ELISA assays for IL-12 and soluble Fas ligand (sFasL) was collected daily during the first 4 post-operative weeks. Tumor specimens were obtained at primary or recurrent surgery and at autopsy. Tumors from gene therapy patients showed varying degrees of peritumoral necrosis around the former tumor resection cavity. Numbers of tumor-infiltrating lymphocytes found weeks after gene therapy were not significantly increased compared with primary tumors. Mitotic tumor cells were sparse close to the VPC injection sites, but abundant in brain areas somewhat distant from these sites. Serum ELISA revealed significantly increased sFasL and IL-12 levels in the gene therapy group compared with controls. Immunophenotyping of PMNC did not show a significant activation of T cells or NK cells during gene therapy. Interferon gamma secretion was evaluated by ELISPOT assays employing PMNC cocultivated with autologous tumor cells. It demonstrated an antitumor immune response in the gene therapy group, but not in the control group. These findings support the concept of in vivo induction of a systemic immune response by local intracerebral HSV-tk/GCV pharmacogene therapy for primary human GBM.

Phase I study of the gliasite radiotherapy system for brachytheray of brain tumor resection cavities

Phase I study of the gliasite radiotherapy system for brachytheray of brain tumor resection cavities

Direct Injection of 90Y MoAbs into Glioma Tumor Resection Cavities Leads to Limited Diffusion of the Radioimmunoconjugates into Normal Brain Parenchyma: A Model to Estimate Absorbed Radiation Dose

Purpose: Previously we have demonstrated that radioimmunoconjugates can be injected into glioma resection cavities to deliver a boost of radiation to the cavity edge with little toxicity to the normal brain. In the mathematical models we have previously published to assist in the development of this strategy we assumed that antibody remains associated with the cavity edge and no diffusion occurs. However, moderate diffusion might be beneficial while, if this were excessive, it would decrease the therapeutic index markedly. Methods and Materials: Selected individuals with relapsed malignant glioma underwent further surgical debulking; 90Y MoAb radioimmunotherapy; and open biopsy to determine the extent to which the conjugate diffuses from the cavity edge. Samples from these patients were taken in radial tracts and the corrected activity in each sample was plotted against distance from the cavity wall to determine appropriate diffusion constants. Results: Our data indicates that diffusion of radioimmunoconjugate from the edge of a glioma resection cavity appears to be an exponential process. The mean R o for each patients data set ranged from 0.48–0.63 (overall mean 0.6) cm. A dosimetric model was developed that translates these measurements into estimates of radiation dose. Applying the clinical data to this model indicates that, in each patient, the peak dose is delivered 0.16–0.18 cm below the cavity margin, and the mean dose at 2 cm deep is 5.3% (4.4–5.8%) of the peak. Conclusion: The model described can be used to translate diffusion constants measured by any method into estimates of absorbed radiation dose. Assuming similar diffusion kinetics, it can also be used to predict the dose deposited if alternative radionuclides are linked to MoAb, although the effect of dose rate should also be considered. In the future, it may be possible to manipulate diffusion by using either different antibodies or antibody fragments for intracavity radioimmunotherapy. Before this can be done, however, further data are needed and a noninvasive approach to measuring diffusion would clearly be optimal.

Monoclonal antibodies in the treatment of central nervous system malignancies.

INTRODUCTION MONOCLONAL ANTIBODIES (Mabs) clearly do not cross the blood-brain when administered systemically. Consequently, their use as targeting agents within the central nervous system (CNS) is limited to situations where they are either given topically or when the barrier is disrupted. In the latter instance, accumulation of isotope is low, approximately 10-~% of the injected dose-gram of tumour [1]. This poor level of uptake is not restricted to CNS malignancies, as similar results have been noted in other solid tumours such as ovarian, colon and small cell lung carcinoma [2]. Improved binding to primary CNS tumours has been shown in animal models by intra-arterial administration of radiolabelled Mabs, but this has not proved to be the case in clinical investigations [3]. Therefore, until this problem has been overcome, Mabs will only have a role in the therapy of CNS tumours when local administration is possible. For primary intracerebral tumours, Mabs have been given by either direct injection into a tumour resection cavity or, when appropriate, instillation into a cystic lesion [4]. Where tumours have spread throughout the cerebrospinal fluid (CSF) pathways, Mabs have been administered into the intrathecal space following either intraventricular or lumbar injection [5]. With respect to the targeted agent, either radioisotope or biological response modifiers (e.g. targeted lymphocyte activated killer cells), have been explored in the CNS compartment [6]. Here we describe the use of targeted radiation therapy, as this has formed the main focus of our studies over the last 6 years.

Photodynamic therapy of malignant brain tumours

Experience with intraoperative PDT in 50 patients with malignant supratentorial tumours is reported; in 33 cases the tumour was recurrent. In 45 patients the tumour was a cerebral glioma and in five cases a solitary cerebral metastasis. There were 29 males and 17 females with an age range of 17–73 (mean 48) years. All patients received either haematoporphyrin derivative (HPD) or dihaematoporphyrin ether (DHE) 18–24 h preoperatively. A photoilluminating device, of the authors' design, was coupled to an argon dye pump laser in order to deliver light at 630 nm to a tumour cavity created by radical tumour resection and/or tumour cyst drainage. The total light energy delivered ranged from 440 to 3888 J and the light energy density ranged from 8 to 175 J/cm2. In eight patients a line fibre(s) was used to administer interstitial light as a supplement to the cavitary photoillumination. The additional light dose ranged from 60 to 945 J/cm. There were two postoperative deaths as the consequence of haematoma accumulation in the tumour resection cavity. In three patients neurological function was worse postoperatively and did not recover. Postoperative cerebral oedema was pronounced in some cases and required second craniotomy in two patients (the histology from both showed haemorrhagic necrosis of residual tumour). Four patients developed wound infections; two of these required surgical treatment. Four patients, two of whom were hemiparetic, developed deep vein thrombosis and required anticoagulant therapy. There were no adverse systemic reactions to the administration of either photosensitizer and only three skin photosensitivity reactions. Follow up ranged from 1 to 30 months. In the group of 45 patients with gliomas the death rate per observation year was 0.92 for the interval between PDT and death. For the interval between first diagnosis and death the rate was 0.41 deaths per observation year. The median survival was 8.6 months with a 1 and 2 year actuarial survival rate of 32% and 18%, repectively. In 12 patients a complete or near complete CT scan response was identified post PDT. These patients tended to have a tumour geometry (e.g. cystic) that allowed complete or near complete light distribution to the tumour. The median survival for this group was 17.1 months with a 1 and 2 year actuarial survival of 62% and 38%, respectively. In the 33 cases without a complete response the median survival was 6.5 months with a 1 and 2 year actuarial survival of 22% and 11%, respectively. Photodynamic therapy of malignant brain tumours can be carried out with acceptable risk. Good responses appear to be related to adequate light delivery to the tumour.

Photodynamic therapy of malignant primary brain tumours: clinical effects, post-operative ICP, and light penetration of the brain.

Abstract We are reporting our experience with intraoperative PDT in 32 patients with malignant supratentorial gliomas; in 19 cases the tumour was recurrent. There were 20 males and 12 females with an age range of 17‐73 (mean = 45) yr. The first 8 patients in this series received HpD (Photofrin I) and the next 24 received DHE (Photofrin II). A photo‐illuminating device, of the author's design, was coupled to an argon dye pump laser in order to deliver light at 630 nm to a tumour cavity created by radical tumour resection and/or tumour cyst drainage. The total light energy delivered ranged from 440 to 3888 J and the light energy density ranged from 8 to 68 J cm−2.There were two post‐operative deaths as the consequence of hematoma accumulation in an extensive tumour resection cavity. In two patients neurological function was worse post‐operatively and did not recover. Post‐operative cerebral edema was pronounced in eight cases and required emergency craniotomy in two patients (the histology from both showed hemorrhagic necrosis of residual tumour). We have fashioned continuous post‐operative ICP measurements in the last 15 patients treated with PDT and compared the values to those obtained from cases with malignant gliomas who did not have PDT; the mean ICP was significantly greater in the PDT group. Four patients developed wound infections; two of these required surgical treatment. Four patients, two of whom were hemiparetic, developed deep vein thrombosis and required anticoagulant therapy. There were no adverse systemic reactions to the administration of either photosensitizer and only 3 skin photosensitivity reactions.Follow up has ranged from 1 to 26 months at the time of writing; 38% were still alive; in the interval between PDT and death, the deaths per observation year was 1.11 for the whole group and 1.00 when the two post‐operative deaths are excluded. In the interval between first diagnosis and death the rate was 0.45 deaths per observation year. Photodynamic therapy of malignant brain tumours using surface or cavitary photo‐illumination can be carried out with acceptable risk.In eight patients we determined the penetration depth of light in brain tissue in vivo by reading the detected light flux from a fiber passed radially into the brain towards the centre of the irradiation volume. The optical fiber consisted of a single 400 μ.m, cleaved fiber fixed in a 17‐gauge biopsy needle coupled to a photometer. The light penetration depth ranged from 0.8 to 4.9. The mean PD values in the‘tumour’group and the‘brain’group was 2.9 ± 1.5 and 1.5 ± 0.43, respectively. We attribute this significant difference to the differences in the absorption and scattering properties of brain and tumour.