Matthew G. Ewend

Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

PURPOSE One third of women with advanced human epidermal growth factor receptor 2 (HER-2)-positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2-positive brain metastases. PATIENTS AND METHODS Patients had HER-2-positive breast cancer, progressive brain metastases, prior trastuzumab treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included objective response in non-CNS sites, time to progression, overall survival, and toxicity. RESULTS Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%). CONCLUSION The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2-positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.

Spinal cord stimulation for chronic, intractable pain: Superiority of “multi-channel” devices

&NA; Spinal cord stimulation has evolved over the past 20 years into an easily implemented technique, with low morbidity, for the treatment of intractable, chronic pain in properly selected patients. We report our experience with a series of 62 patients implanted between 1983 and 1987, with percutaneous and laminectomy electrodes, and with single‐ and “multi‐channel” (programmable, multi‐contact) devices. Fifty had chronic, intractable low back and leg pain (“failed back surgery syndrome,” lumbar arachnoid fibrosis), five had spinal cord injuries, and seven “peripheral” pathology or stump pain. Statistical analysis of these and other patient characteristics and technical factors was undertaken to identify predictors of outcome. All patients were interviewed by a disinterested third party at a mean of 2.14 years following implantation. A majority of patients reported at least 50% sustained relief of pain and indicated that they would go through the procedure again for the same result. There was corresponding improvement in ability to perform various everyday activities, and decrease in use of analgesics. Ten of 40 failed back patients who were disabled before the procedure returned to work postoperatively. Superposition of stimulation paresthesias upon a patients topography of pain was found to be a statistically significant predictor of successful relief of pain, by linear regression methods. Univariate and multivariate analysis of patient characteristics and technical factors as predictors of outcome demonstrated significant advantages for female patients, and for patients implanted with “multi‐channel” devices. With these devices, electrode geometries with central cathode(s) flanked by rostral and caudal anode(s) were favored disproportionately. Technical improvements in implanted spinal cord stimulation devices, in particular the development of multi‐contact percutaneous electrode arrays and supporting programmable electronics, have significantly improved clinical results.

The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: Phase I trial

The results of a multi-institutional phase I trial evaluating the safety of surgically implanted biodegradable 1,3-bis(chloro-ethyl)-1-nitrosourea (BCNU) impregnated polymer as theinitial therapy for malignant brain tumors are reported. This is the first study of locally delivered BCNU and standard external beam radiation therapy (XRT) given concurrently.Twenty-two patients were treated at three hospitals. The entry criteria were: single unilateral tumor focus larger than 1 cm3; age over 18 years; Karnofsky Performance Score (KPS) of at least 60 h; and an intra-operative diagnosis of malignant glioma.Twenty-one of twenty-two patients had glioblastoma multiforme. After surgery, seven or eight BCNU-loaded polyanhydride polymer discs (7.7 mg BCNU each) were placed in the resection cavity. Postoperatively, all patients received standard radiation therapy; none received additional chemotherapy in the first 6 months.Neurotoxicity, systemic toxicity, and survival were assessed. No perioperative mortality was seen. Neurotoxicity was equivalent to that occurring in other series of patients undergoing craniotomy and XRT without local chemotherapy. Systematically, no significant bone marrow suppression occurred, and there were no wound infections. Median survival in this group of older patients (mean age=60) was 42 weeks, 8 patients survived 1 year, and 4 patients survived more than 18 months.Interstitial chemotherapy with BCNU-polymer with subsequent radiation therapy appears to be safe as an initial therapy. Several long-term survivors in this group of older patients with predominantly glioblastoma suggests efficacy in some patients. Dose escalation and efficacy trials are planned to further evaluate interstitial chemotherapy for the initial treatment of malignant gliomas.

Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse

The ability to predict metastatic potential could be of great clinical importance, however, it is uncertain if predicting metastasis to specific vital organs is feasible. As a first step in evaluating metastatic predictions, we analyzed multiple primary tumors and metastasis pairs and determined that >90% of 298 gene expression signatures were found to be similarly expressed between matched pairs of tumors and metastases; therefore, primary tumors may be a good predictor of metastatic propensity. Next, using a dataset of >1,000 human breast tumor gene expression microarrays we determined that HER2-enriched subtype tumors aggressively spread to the liver, while basal-like and claudin-low subtypes colonize the brain and lung. Correspondingly, brain and lung metastasis signatures, along with embryonic stem cell, tumor initiating cell, and hypoxia signatures, were also strongly expressed in the basal-like and claudin-low tumors. Interestingly, low “Differentiation Scores,” or high expression of the aforementioned signatures, further predicted for brain and lung metastases. In total, these data identify that depending upon the organ of relapse, a combination of gene expression signatures most accurately predicts metastatic behavior.

Cerebral blood volume measurements and proton MR spectroscopy in grading of oligodendroglial tumors.

OBJECTIVE The purpose of this study was to determine whether perfusion-weighted imaging (PWI) and proton MR spectroscopy (MRS) are useful in differentiating high- and low-grade oligodendroglial tumors. MATERIALS AND METHODS PWI and MRS studies of 22 patients with histologically proven oligodendroglioma or oligoastrocytoma (13 low-grade and nine anaplastic tumors) were retrospectively reviewed. PWI of 14 subjects was performed with a dynamic contrast-enhanced susceptibility-weighted echo-planar technique. Intratumoral relative cerebral blood volume ratio was calculated and normalized to the same value in contralateral normal-appearing white matter. Multivoxel MRS was performed with a point-resolved spectroscopy sequence at a TE of 135 milliseconds in 20 patients and with the addition of a TE of 30 seconds in 17 patients. MRS data were expressed as intratumoral metabolite ratios (choline to creatine [Cho/Cr], choline to N-acetyl aspartate, N-acetyl aspartate to creatine, and myoinositol to creatine). RESULTS Relative cerebral blood volume ratios were significantly different (p = 0.004) between low-grade (1.61 +/- 1.20) and high-grade tumors (5.45 +/- 1.96). The optimal relative cerebral blood volume ratio cutoff value in identification of anaplastic oligodendroglial tumors was 2.14. Analysis of MRS data showed significantly higher Cho/Cr ratios (p = 0.002) in high-grade than in low-grade tumors. A Cho/Cr ratio cutoff value of 2.33 had the highest accuracy in identification of high-grade tumors. CONCLUSION Relative cerebral blood volume measurement and MRS are helpful in differentiating low-grade from anaplastic oligodendroglial tumors.

The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases

Brain metastases (BM) arising from triple‐negative breast cancer (TNBC) portend a poor prognosis. TNBC is more common in premenopausal and African‐American (AA) patients; both of these characteristics also confer a poor prognosis. In a single‐institution cohort study, the authors attempted to determine whether the inferior outcome noted with TNBC brain metastases is more reflective of a higher risk population or the subtype itself.

Potentiation of chemotherapeutic agents following antagonism of nuclear factor kappa B in human gliomas

Future success using chemotherapy against human gliomas may result from exploiting unique molecular vulnerabilities of these tumors. Chemotherapy frequently results in DNA damage. When such damage is sensed by the cell, programmed cell death, or apoptosis, may be initiated. However, chemotherapy-induced DNA damage may activate nuclear factor kappa B (NF-κB) and block apoptosis. We inhibited NF-κB using a gene therapy approach to determine whether this would render human glioma cells more susceptible to chemotherapy. U87 and U251 glioma cell lines were infected with either treatment adenovirus containing the gene for a mutant non-degradable form of IκBα, which is an inhibitor of NF-κB nuclear translocation, or empty control virus. Following viral infection, cells were treated either with BCNU, carboplatin, tumor necrosis factor alpha (TNF-α), or SN-38.Chemotherapy resulted in a marked increase in active intranuclear NF-κB. This response was greatly decreased by insertion of the mutant repressor gene. Similarly, a significant increase in cell killing by all chemotherapy age was demonstrated following infection with treatment virus. Expression of the mutant repressor gene also resulted in increased apoptosis by TUNEL assay following chemotherapy.Numerous genes are responsible for glioma chemoresistance. DNA damage by chemotherapy may induce the antiapoptotic factor NF-κB and prevent programmed cell death. Insertion of a mutant inhibitor of NF-κB strips cells of this antiapoptotic defense and renders them more susceptible to killing by chemotherapy via increased apoptosis.

Interstitial delivery of carboplatin via biodegradable Polymers is effective against experimental glioma in the rat

Abstract Purpose: Carboplatin has shown promise experimentally as an antineoplastic agent against both primary central nervous system (CNS) tumors and several solid tumors that frequently metastasize to the brain. Unfortunately, carboplatin is limited in its clinical use for tumors in the CNS by systemic toxicity and poor penetration through the blood–brain barrier. Recent advances in polymer technology have made feasible the intracranial implantation of a biodegradable polymer capable of local sustained delivery of chemotherapy for brain neoplasms. This study assessed the toxicity and efficacy of carboplatin delivered from intracranial sustained release polymers in the treatment of experimental gliomas in rodents. Methods: Two biodegradable anhydride polymer systems were tested: a copolymer of 1,3-bis-(p-carboxyphenoxy propane) and sebacic acid, and a copolymer of fatty acid dimer and sebacic acid. The polymers were loaded with carboplatin and dose escalation studies evaluating toxicity were performed by implanting carboplatin-loaded polymers into the brains of rats. Next, efficacy was tested. F-98 glioma cells were injected intracranially into rats, and 5 days later polymers containing the highest tolerated doses were implanted at the site of tumor growth. The survival of animals receiving carboplatin-loaded polymer was compared with that of animals receiving intraperitoneal doses of the same agent. Results: Carboplatin-polymer was well tolerated at doses up to 5% loading in both polymer systems. Locally delivered carboplatin effectively prolonged survival of rats with F98 gliomas. Maximal treatment effect was seen with 5% loading of either polymer, with median survival increased threefold over control (P<0.004). Systemic carboplatin also significantly prolonged survival, but the best intracranial polymer dose was significantly more effective than the best systemic dose tested. Conclusions: Carboplatin can be safely delivered intracranially by biodegradable sustained-release polymers. This treatment improves survival in rodents with experimental gliomas, with locally delivered carboplatin being more effective than systemic carboplatin.

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

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.

Systemic and local paracrine cytokine therapies using transduced tumor cells are synergistic in treating intracranial tumors.

Development of an effective immunotherapeutic approach for treatment of CNS tumors must take into account the unique anatomic and immunologic features of the brain. We explored the antitumor immune response in the brain elicited by nonreplicating melanoma cells genetically engineered to produce either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) in a paracrine fashion. Using a new model of intracranial melanoma in C57BL/6 mice, the cytokine-producing cells were given either as a subcutaneous vaccine to induce systemic antitumor immunity or as a direct injection into the brain as local immunotherapy. We found that GM-CSF-transduced cells, as a subcutaneous vaccine but not as an intracranial injection, afforded some protection from intracranial challenge with the wild-type tumor. In contrast, direct intracranial injection of tumor cells secreting IL-2 was protective whereas flank vaccination with IL-2 transductants was not. Combination therapy with both the subcutaneous GM-CSF-transductants as a vaccine and local administration of IL-2-transductants in the brain achieved a synergistic response. These findings provide a basis for the application of paracrine cytokine delivery to brain cancer therapy both as a systemic vaccine and via local administration. The demonstration of synergy between paracrine cytokine therapies holds promise as a novel therapy for brain tumors.