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 1year, 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.Brain metastases are a frequent complication of systemic malignancy. Up to 30% of cancer patients will develop brain metastases, totaling more than 100,000 patients per year in the United States (1, 2). The incidence of brain metastases is likely to increase in the future for several reasons. With the advent of highly effective biological and other targeted therapies in addition to advances in chemotherapy and hormonal therapies, systemic control of metastatic cancer is improving. Because many chemotherapeutic agents do not penetrate into the central nervous system (CNS) well, the brain serves as a sanctuary for metastatic tumor foci. In addition, as a result of prolonged survival, otherwise undetected CNS disease may become more clinically significant. Several recent studies in breast cancer and melanoma have noted an increase in the incidence of CNS involvement with more effective systemic control (3 -9). Contrary to the traditional thinking that most patients with brain metastases die of systemic disease, several authors have noted that a substantial proportion of these patients died from CNS progression in the setting of systemic control (8, 9). Thus, as options for systemic control improve, long-term control of CNS disease may be an increasingly important determinant of survival and quality of life.Currently, treatments for patients with brain metastases are based primarily on the number (and, to a lesser degree, size) of the brain metastases, the extent of systemic disease, and the patient's performance status. The presence of non-CNS metastases, a p...
A prospective pilot study was performed in order to assess the safety of treating recurrent malignant gliomas (MGs) with locally infused autologous tumor infiltrating lymphocytes (TILs) and recombinant interleukin-2 (rIL-2). Six patients were entered between June 27, 1994 and June 2, 1995 and followed until July 1, 1998. At surgery an Ommaya reservoir was placed for later infusion of TILs and rIL-2. Following surgery, autologous TILs were expanded in vitro in the presence of rIL-2 and infused on treatment days 1 and 14, with concurrent rIL-2 infusions performed three times each week for one month. Following completion of immunotherapy all patients were offered chemotherapy. Phenotypic analysis demonstrated TILs to be T-lymphocytes (87-99% CD3+). Of these, 4 of 6 cases (67%) phenotyped as cytotoxic/suppressor T-lymphocytes (CD8+) and 2 of 6 cases (33%) phenotyped as helper/inducer T-lymphocytes (CD4+). TILs demonstrated limited selective cytotoxicity, with dose dependent cytotoxicity against autologous tumor, allogenic tumor and long term MG cell lines. There were no significant (Grade 3 or 4) complications. One patient developed transient low grade fevers, and 2 developed asymptomatic hydrocephalus. All patients developed transient and asymptomatic cerebral swelling, noted on the immediate post-treatment imaging studies. At three and six month follow-up, 3 patients responded with partial response, 2 demonstrated stable disease and 1 patient progressed. At long term follow-up, 1 patient had a complete response (45 month follow-up), 2 had a partial response (48 and 47 month follow-up) and 3 patients expired as a result of progressive disease (at 12, 12 and 18 months following immunotherapy). A relationship between subsequent chemotherapy or extent of resection to outcome was not apparent but could not be excluded. This pilot study demonstrated that locally infused autologous TILs and rIL-2 could be delivered without serious toxicity. Further studies are indicated to determine the safety and long term efficacy of TIL immunotherapy.
Photodynamic therapy (PDT) using purified hematoporphyrin derivative and stereotactic intratumorally implanted optical laser fiber(s) was used to treat patients with recurrent malignant gliomas and metastatic melanoma of the brain. Tumor response to PDT was evaluated by recording changes in the volume and pattern of tumor enhancement between computed tomographic and magnetic resonance imaging scans done before and after PDT, metabolic changes in tumor tissue by31 P magnetic resonance spectroscopy, and patient outcome. Toxicity of PDT to brain was evaluated on the basis of changes in the patients' neurological examinations and correlated with changes in brain adjacent to tumor seen on postoperative imaging studies. Dramatic tumor responses to PDT were seen in all gliomas, but no response of tumor to treatment was seen with melanoma. Transient signs and symptoms of increased peritumoral cerebral edema caused by PDT were seen in all patients. Two patients suffered permanent neurological sequelae, monocular blindness and a partial visual field defect, as a result of treatment. Two patients with recurrent anaplastic astrocytomas remain in remission at 45 and 35 weeks after PDT. We conclude that intratumoral photoradiation therapy of hematoporphyrin derivative-photosensitized malignant gliomas effectively produces necrosis of the solid component of malignant gliomas: however, intratumoral photoradiation may not reach the portion of tumor that invades normal brain.
Photodynamic therapy (PDT) using purified hematoporphyrin derivative and stereotactic intratumorally implanted optical laser fiber(s) was used to treat patients with recurrent malignant gliomas and metastatic melanoma of the brain. Tumor response to PDT was evaluated by recording changes in the volume and pattern of tumor enhancement between computed tomographic and magnetic resonance imaging scans done before and after PDT, metabolic changes in tumor tissue by 31P magnetic resonance spectroscopy, and patient outcome. Toxicity of PDT to brain was evaluated on the basis of changes in the patients' neurological examinations and correlated with changes in brain adjacent to tumor seen on postoperative imaging studies. Dramatic tumor responses to PDT were seen in all gliomas, but no response of tumor to treatment was seen with melanoma. Transient signs and symptoms of increased peritumoral cerebral edema caused by PDT were seen in all patients. Two patients suffered permanent neurological sequelae, monocular blindness and a partial visual field defect, as a result of treatment. Two patients with recurrent anaplastic astrocytomas remain in remission at 45 and 35 weeks after PDT. We conclude that intratumoral photoradiation therapy of hematoporphyrin derivative-photosensitized malignant gliomas effectively produces necrosis of the solid component of malignant gliomas; however, intratumoral photoradiation may not reach the portion of tumor that invades normal brain.
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