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Biomedical subjects

H Brem

Publications and source records attributed to H Brem.

At least 55 records · Page 3Linked to original sources
PubMed1998

Local delivery of chemotherapy prolongs survival in experimental brain metastases from breast carcinoma.

OBJECTIVE: Despite improved systemic control of metastatic breast cancer, the incidence of brain metastases from breast carcinoma continues to rise, in part because most systemically administered agents have poor central nervous system penetration. Therefore, as a method of optimizing drug delivery into the central nervous system, we studied the safety and efficacy of chemotherapy delivered locally via biodegradable polymers in a mouse model of breast carcinoma metastases to the brain. METHODS: The chemotherapeutic agents carmustine (BCNU), carboplatin, and camptothecin were incorporated into controlled release polymers and tested individually against intracranial challenges of EMT-6 breast tumor in BALB/c female mice. For each drug, four groups were tested: Group 1, empty polymer (no drug); Group 2, external beam radiotherapy (XRT) alone; Group 3, local chemotherapy from biodegradable polymer alone; and Group 4, local chemotherapy and XRT together. Polymers were implanted 5 days after intracranial tumor inoculation; XRT was administered on Days 7 through 9 (300 cGy/d). RESULTS: BCNU polymer alone (n = 10; median survival time, >200 d; P < 0.0001) and BCNU and XRT together (n = 10; median survival time, 41 d; P = 0.02) significantly improved survival in mice with intracranial EMT-6 breast cancer in comparison with control animals (n = 20; median survival time, 17 d). Carboplatin and camptothecin, either with or without XRT, and XRT alone did not have any significant effect on survival. CONCLUSION: Local delivery of BCNU with biodegradable polymers can significantly prolong survival in a murine model of intracranial metastatic breast cancer. Surgical resection and placement of BCNU polymers into the resection cavity may decrease the incidence of local recurrence of breast cancer metastases with minimal morbidity.

Animals↗
PubMed1998

The New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium: Organization, Objectives, and Activities.

BACKGROUND: Despite advances in neuro-imaging, neurosurgery, radiation therapy, and chemotherapy, limited progress has been made in the treatment of patients with high-grade astrocytomas. The National Cancer Institute has attempted to speed advances in this field by funding CNS consortia to conduct innovative clinical trials in this patient population since 1994. METHODS: The NABTT CNS Consortium is composed of a consortium headquarters and nine member institutions with outstanding multidisciplinary expertise, clinical and laboratory research capabilities, and access to large numbers of patients with brain tumors. RESULTS: The objectives of the NABTT Consortium are to improve the therapeutic outcome for adults with primary brain tumors, to conduct basic science and clinical research, and to improve the care and quality of life of adults with primary brain tumors. NABTT's clinical studies have discovered important drug interactions between anticonvulsant and antineoplastic agents, defined the activity of paclitaxel and 9-aminocamptothecin in glioblastoma multiforme, tested a novel dose escalation strategy for brain tumor trials, and established new protocol "classes" to expedite and standardize clinical research in this field. CONCLUSIONS: Significant progress in the care of patients with primary brain tumors is likely to result from the highly focused and multidisciplinary efforts of the NIH-funded CNS consortia.

Journal Article↗
PubMed1998

Implantable Slow-Release Chemotherapeutic Polymers for the Treatment of Malignant Brain Tumors.

BACKGROUND: Despite significant advances in neurosurgery, radiation therapy, and chemotherapy, the prognosis for patients with malignant brain tumors remains dismal. In an effort to improve control of local disease, we have developed a biodegradable, controlled-release polymer that is implanted directly at the tumor site. METHODS: The preclinical and clinical development of the polymeric delivery of chemotherapeutic agents for treatment of patients with malignant gliomas is reviewed. RESULTS: Carmustine (BCNU)-impregnated biodegradable polymer is the first new therapy approved by the FDA for patients with gliomas in 23 years. This delivery system provides high local concentration of drug with minimal systemic toxicity and obviates the need for drug to cross the blood-brain barrier. Randomized, multi-institutional, double-blinded, placebo-controlled studies have shown improved survival in patients treated for gliomas both at initial presentation and at recurrence. Several clinical principles have emerged from the use of this polymer system, and further applications are currently being investigated. CONCLUSIONS: Local delivery of therapeutic agents via biodegradable polymers may play an increasing role in patients with brain tumors.

Journal Article↗
PubMed1997

Short course radiotherapy is an appropriate option for most malignant glioma patients.

PURPOSE: To determine whether a shortened course of radiotherapy (RT) is an appropriate treatment option for malignant glioma patients. METHODS AND MATERIALS: Prognostic groups published by the Radiation Therapy Oncology Group (RTOG) are used to compare results for a short radiotherapy regimen with results of aggressive protocol treatment. The study group includes 219 patients treated during 1975-1993 with 51 Gy in 17 fractions. Patients were retrospectively assigned to six prognostic groups previously identified in a recursive partitioning analysis of the RTOG. The prognostic groups are based on age, histology, performance status, mental status, neurologic function, resection extent, length of symptoms, and RT dose. RESULTS: The six RTOG prognostic groupings were significantly predictive of outcome for patients treated with this shortened regimen (log-rank, p < 0.001). The median survival for our patients by RTOG groups 1-6 were 68, 57, 22, 13, 8, and 5 months, respectively. Two-year survival results were 64, 67, 45, 8, 3, and 3%. The median and two-year survival results for each prognostic grouping were similar to the results achieved by aggressive treatment on RTOG malignant glioma trials for selected patients. Treatment toxicity was uncommon. CONCLUSION: This shortened regimen is an appropriate treatment option for most malignant glioma patients (RTOG groups 4-6), resulting in similar survival as standard regimens with reduced patient effort and cost. Although acute side effects are acceptable and the risk of brain necrosis is low, we do not recommend this treatment to the minority of patients who have a substantial long term survival probability (RTOG groups 1-3) because long term neurocognitive assessment is lacking.

Brain Neoplasms↗
PubMed1997

Optimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumors.

Two approaches for improving the interstitial administration of carmustine (BCNU) using 3.8% loaded poly(carboxyphenoxypropane-sebacic acid), an implantable biodegradable anhydride which significantly prolongs survival in patients with recurrent malignant gliomas, were evaluated. First, increasing the ratio of carboxyphenoxypropane (CPP) to sebacic acid (SA) in the polymer increases its hydrolytic stability, thus prolonging its half-life in vivo, and extending the period of drug release. A second approach is to increase the dose of drug loaded into the polymer. This study evaluated the relative merits of these two approaches by comparing release kinetics, safety, and efficacy of escalating BCNU does in polymers with 20:80 and 50:50 ratios of CPP to SA. At the highest dose tested, the 50:50 polymer released BCNU 2.5 times as long in vitro as the 20:80 polymer. Both formulations were nontoxic in rat brains for all BCNU doses tested except 32%. The 20:80 and 50:50 polymers were equally effective in the rat intracranial 9L-glioma model. A dose-response relationship for BCNU was observed (hazard ratio 0.8354 for each mg/kg increase, P < 0.001). The two highest loading doses of BCNU improved survival 40-fold (P < 0.001). The 20% BCNU-loaded 20:80 polymer achieved the best balance of toxicity and antitumor efficacy, yielding a 75% long-term survival rate. Further evaluation of this polymer in monkeys suggests that it might be used with acceptable toxicity. This study establishes that a dose-escalation strategy for improving BCNU controlled-release polymers is more effective than adjusting the ratio of CPP to SA to prolong drug release.

Animals↗
PubMed1997

Implantable biodegradable polymers for IUdR radiosensitization of experimental human malignant glioma.

PURPOSE: The potential of halogenated pyrimidines for the radiosensitization of human malignant gliomas remains unrealized. To assess the role of local delivery for radiosensitization, we tested a synthetic, implantable biodegradable polymer for the controlled release of 5-iodo-2'-deoxyuridine (IUdR) both in vitro and in vivo and the resultant radiosensitization of human malignant glioma xenografts in vivo. MATERIALS AND METHODS: In vitro: To measure release, increasing (10%, 30%, 50%) proportions (weight/weight) of IUdR in the polyanhydride [(poly(bis(p-carboxyphenoxy)-propane) (PCPP): sebacic acid (SA) (PCPP : SA ratio 20:80)] polymer discs were incubated (1 ml phosphate-buffered saline, 37 degrees C). The supernatant fractions were serially assayed using high performance liquid chromatography. To measure modulation of release, polymer discs were co-loaded with 20 microCi 5-125-iodo-2'-deoxyuridine (125-IUdR) and increasing (10%, 30%, or 50%) proportions of D-glucose. To test radiosensitization, cells (U251 human malignant glioma) were sequentially exposed to increasing (0 or 10 microM) concentrations of IUdR and increasing (0, 2.5, 5.0, or 10 Gy) doses of acute radiation. In vivo. To measure release, PCPP : SA polymer discs having 200 microCi 125-IUdR were surgically placed in U251 xenografts (0.1-0.2 cc) growing in the flanks of nude mice. The flanks were reproducibly positioned over a collimated scintillation detector and counted. To measure radiosensitization, PCPP : SA polymer discs having 0% (empty) or 50% IUdR were placed in the tumor or contralateral flank. After five days, the tumors were acutely irradiated (500 cGy x 2 daily fractions). RESULTS: In vitro: Intact IUdR was released from the PCPP : SA polymer discs in proportion to the percentage loading. After 4 days the cumulative percentages of loaded IUdR that were released were 43.7 +/- 0.1, 70.0 +/- 0.2, and 90.2 +/- 0.2 (p < 0.001 ANOVA) for the 10, 30, and 50% loadings. With 0, 10, 30, or 50% D-glucose co-loading, the cumulative release of 125-IUdR from PCPP : SA polymers was 21, 70, 92, or 97% (p < 0.001), respectively, measured 26 days after incubation. IUdR radiosensitized U251 cells in vitro. Cell survival (log10) was -2.02 +/- 0.02 and -3.68 +/- 0.11 (p < 0.001) after the 10 Gy treatment and no (control) or 10 microM IUdR exposures, respectively. In vivo: 125-IUdR Release: The average counts (log10 cpm +/- SEM) (hours after implant) were 5.2 +/- 0.05 (0.5), 4.3 +/- 0.07 (17), 3.9 +/- 0.08 (64), and 2.8 +/- 0.06 (284). Radiosensitization: After intratumoral implantation of empty polymer or intratumoral 50% IUdR polymer, or implantation of 50% IUdR polymers contralateral to tumors the average growth delays of tumors to 4 times the initial volumes were 15.4 +/- 1.8, 20.1 + 0.1, and 20.3 + 3.6 (mean + SEM) days, respectively (p = 0.488 one-way ANOVA). After empty polymer and radiation treatments, no tumors regressed and the growth delay was 31.1 + 2.1 (p = 0.046 vs. empty polymer alone) days. After implantation of 50% IUdR polymers either contralateral to the tumors or inside the tumors, followed by radiation, tumors regressed; growth delays to return to the initial average volumes of 14.0 + 3.6 or 24.2 + 0.2 (p < 0.01) days, respectively. CONCLUSIONS: Synthetic, implantable biodegradable polymers hold promise for the controlled release and local delivery of IUdR for radiosensitization of gliomas.

Animals↗
PubMed1997

Facial nerve injury in acoustic neuroma (vestibular schwannoma) surgery: etiology and prevention.

Facial nerve injury associated with acoustic neuroma surgery has declined in incidence but remains a clinical concern. A retrospective analysis of 611 patients surgically treated for acoustic neuroma between 1973 and 1994 was undertaken to understand patterns of facial nerve injury more clearly and to identify factors that influence facial nerve outcome. Anatomical preservation of the facial nerve was achieved in 596 patients (97.5%). In the immediate postoperative period, 62.1% of patients displayed normal or near-normal facial nerve function (House-Brackmann Grade 1 or 2). This number rose to 85.3% of patients at 6 months after surgery and by 1 year, 89.7% of patients who had undergone acoustic neuroma surgery demonstrated normal or near-normal facial nerve function. The surgical approach appeared to have no effect on the incidence of facial nerve injury. Poor facial nerve outcome (House-Brackmann Grade 5 or 6) was seen in 1.58% of patients treated via the suboccipital approach and in 2.6% of patients treated via the translabyrinthine approach. When facial nerve outcome was examined with respect to tumor size, there clearly was an increased incidence of facial nerve palsy seen in the immediate postoperative period in cases of larger tumors: 60.8% of patients with tumors smaller than 2.5 cm had normal facial nerve function, whereas only 37.5% of patients with tumors larger than 4 cm had normal function. This difference was less pronounced, however, 6 months after surgery, when 92.1% of patients with tumors smaller than 2.5 cm had normal or near normal facial function, versus 75% of patients with tumors larger than 4 cm. The etiology of facial nerve injury is discussed with emphasis on the pathophysiology of facial nerve palsy. In addition, on the basis of the authors' experience with these complex tumors, techniques of preventing facial nerve injury are discussed.

Adolescent↗
PubMed1996

Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models.

Local chemotherapy with biodegradable polymers prolongs survival with minimal morbidity in patients with intracranial high-grade gliomas. However, use of local chemotherapy for metastatic brain tumors has not been defined. We studied the safety and the efficacy of locally delivered chemotherapy with and without concurrent radiation therapy in treating tumors that frequently metastasize to the brain. The chemotherapeutic agents 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), carboplatin, and camptothecin were incorporated into controlled-release polymers and tested individually against intracranial challenges with one of four tumors (lung carcinoma, renal cell carcinoma, colon carcinoma, and melanoma). For each combination of drug and tumor type, four groups were tested: (a) empty polymer (no drug); (b) external beam radiotherapy (XRT) alone; (c) local chemotherapy from biodegradable polymer alone; and (d) local chemotherapy and XRT together. Polymers were implanted 5 days after tumor inoculation; XRT was given on days 7-9 (300 cGy/day). BCNU and XRT together were effective against all four tumors. BCNU polymer alone significantly prolonged survival in mice with intracranial melanoma or renal cell carcinoma. Carboplatin alone was effective against both melanoma and colon carcinoma and in combination with XRT against colon and renal cell carcinomas. Camptothecin was effective only with XRT against melanoma. These studies demonstrate that local delivery of chemotherapy with concurrent radiation therapy is safe and can significantly prolong survival in models of common intracranial metastatic tumors. Concurrent use of local chemotherapy with standard XRT appears to be more effective than either treatment alone. Local chemotherapy may also be of benefit to patients who have previously received maximal cranial irradiation but suffer an intracranial recurrence.

Animals↗
PubMed1996

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

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.

Animals↗
PubMed1996

Morphological characterization of polyanhydride biodegradable implant gliadel during in vitro and in vivo erosion using scanning electron microscopy.

PURPOSE: The objectives of the current study are to characterize the distribution of the chemotherapeutic agent carmustine (BCNU) in spray dried polyanhydride microspheres and to describe the morphological changes that occur during the in vitro and in vivo erosion of the polyanhydride implant--GLIADEL, which consists of BCNU distributed in the copolymer matrix of poly(carboxyphenoxy propane:sebacic acid) in a 20:80 molar ratio (p(CPP:SA, 20:80)). METHODS: Scanning electron microscopy (SEM) was used to visualize the morphological changes of the polymer during the manufacturing process and in vitro and in vivo erosion. RESULTS: This study revealed that BCNU was homogeneously distributed within spray dried polyanhydride microspheres with no phase separation. The porosity of the wafer fabricated from spray dried polyanhydride microspheres gradually increased during erosion. During the initial period following wafer implantation in the brains of rats, erosion was mainly confined to the surface layer of the wafer with the majority of the wafer remaining intact. The eroding front gradually advanced from the surface to the interior of the wafer in a layerwise fashion, creating pores and connecting channel. Eventually both the interior and exterior of the wafers were eroded and the same porous structure was seen throughout the whole wafer. CONCLUSIONS: This study provides the first visual observation of the morphological changes of the GLIADEL(R) wafer during erosion of the polyanhydride matrix and release of the drug substance BCNU. The observations in this study support the conclusion that BCNU release from a polyanhydride wafer is controlled both by diffusion of the drug and erosion of the polymer matrix.

Anhydrides↗
PubMed1996

Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain.

PURPOSE: The distribution of [(3)H]BCNU following release from polymer implants in the rat brain was measured and evaluated by using mathematical models. METHODS: [(3)H]BCNU was loaded into p(CPP:SA) pellets, which were subsequently implanted intracerebrally in rats; [(3)H]BCNU was also directly injected into the brains of normal rats and rats with intracranially transplanted 9L gliomas. Concentrations of [(3)H]BCNU on coronal sections of the brain were measured by autoradiography and image processing. For comparison, the kinetics of [(3)H]BCNU release from the p(CPP:SA) polymer discs into phosphate-buffered saline were also measured. RESULTS: High concentrations of BCNU (corresponding to 1 mM) were measured near the polymer for the entire 30-day experiment. The penetration distance, defined as the distance from the polymer surface to the point where the concentration of [(3)H]BCNU in the tissue had dropped to 10 percent of the maximum value, was determined: penetration distance was 5 mm at day 1 and 1 mm at days 3 through 14. Local concentration profiles were compared with a mathematical model for estimation of the modulus phi (2), an indicator of the relative rate of elimination to diffusion in the brain. From day 3 to 14, phi(2) was 7, indicating that BCNU elimination was rapid compared to the rate of diffusive penetration into tissue. The enhanced penetration observed on day 1 appears to be due to convection of extracellular fluid caused by transient, vasogenic edema, which disappears by day 3. CONCLUSIONS: Polymer implants produce very high levels of BCNU in the brain, but BCNU penetration into brain tissue is limited due to rapid elimination.

Animals↗
PubMed1996

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.

Animals↗
PubMed1996

In vivo accuracy testing and clinical experience with the ISG Viewing Wand.

OBJECTIVE: A frameless stereotactic system (the Viewing Wand; Elekta Instruments, Atlanta, GA) has been developed for use with preoperative computed tomography, magnetic resonance imaging, and positron emission tomography as an adjunct for surgical planning and intraoperative navigation. This clinical study was designed to evaluate the safety, efficacy, and accuracy of the Viewing Wand in a variety of intracranial procedures. METHODS: We used this system in 250 patients undergoing a wide range of neurosurgical procedures from July 1990 to July 1994, to assess its clinical usefulness and safety. In a subset of 45 neurosurgical patients studied between March 1993 and March 1994, a battery of objective accuracy measurements was obtained before and during surgery. RESULTS: In this series, there were no instances of adverse outcomes attributable to the use of this system. A comparison of two alternative patient-image registration techniques established that the fiducial-fit method was slightly more accurate than the surface-fit method (geometric means = 2.51 and 3.03 mm, respectively). The clinical accuracy achieved with magnetic resonance imaging was nearly equivalent to that with computed tomography. CONCLUSIONS: On the basis of this clinical series, recommendations are made regarding preoperative scanning parameters, registration techniques, and methods for reestablishing registration if needed during the course of surgery. The primary clinical benefits of the wand in this series were improved intraoperative navigation and surgical safety. For most cases, the wand was also useful in planning the location and size of the scalp incision, craniotomy, or corticotomy, as well as the extent of surgical resection.

Adolescent↗
PubMed1995

Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the rat intracranial 9L gliosarcoma model.

Camptothecin, a naturally occurring inhibitor of the DNA-replicating enzyme topoisomerase I, demonstrated promising anti-tumor activity in pre-clinical testing; however, because of unexpected toxicity and low anti-tumor effects in the initial clinical trials, further testing was discontinued. We hypothesized that local controlled delivery of camptothecin sodium would achieve effective concentrations in brain tumors without the observed systemic side effects, thereby allowing this novel drug to be used to treat patients with malignant gliomas. To test this hypothesis, we evaluated the sensitivity of rat glioma lines and established human glioma lines to camptothecin in vitro. We found that the LD90 for the established rat and human lines was 0.3 to 1.4 microM after a 1 hr exposure and decreased to less than 0.1 microM after continuous exposure for 7 days. We loaded camptothecin into a controlled-release polymer (ethylene-vinyl acetate co-polymer; EVAc) and showed by high-pressure liquid chromatography that controlled release occurred over at least 21 days. We then tested camptothecin against 9L gliosarcoma, implanted into the brain of Fischer 344 rats. Five days after tumor implantation, animals were treated with camptothecin delivered either systemically or locally by release from EVAc. Local controlled delivery by the polymer significantly extended survival: 59% of the treated animals were long-term survivors (> 120 days) compared to 0% of controls. Systemic administration did not extend survival compared to controls. We compared the efficacy of camptothecin delivered locally with a polymer to camptothecin injected directly into the tumor. Camptothecin increased survival only when delivered locally by polymer.

Animals↗
PubMed1995

Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group.

Chemotherapy for brain tumours has been limited because of difficulty in achieving adequate exposure to the tumour without systemic toxicity. We have developed a method for local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumour site allows prolonged local exposure with minimal systemic exposure. We conducted a randomised, placebo-controlled, prospective study to evaluate the effectiveness of biodegradable polymers impregnated with carmustine to treat recurrent malignant gliomas. In 27 medical centres, 222 patients with recurrent malignant brain tumours requiring re-operation were randomly assigned to receive surgically implanted biodegradable polymer discs with or without 3.85% carmustine. Randomisation balanced the treatment groups for all of the prognostic factors examined. Median survival of the 110 patients who received carmustine polymers was 31 weeks compared with 23 weeks for the 112 patients who received only placebo polymers (hazard ratio = 0.67, p = 0.006, after accounting for the effects of prognostic factors). Among patients with glioblastoma, 6-month survival in those treated with carmustine-polymer discs was 50% greater than in those treated with placebo (mortality = 32 of 72 [44%] vs 47 of 73 [64%], p = 0.02). There were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically. Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas.

Biodegradation, Environmental↗
PubMed1995

Interstitial chemotherapy of experimental brain tumors: comparison of intratumoral injection versus polymeric controlled release.

Interstitial chemotherapy with controlled release polymers is a clinical adjunct in the management of malignant gliomas. The need for polymer to release the chemotherapeutic drug rather than simply injecting the drug into the tumor warrants further investigation. Therefore, we compared the effects of direct intralesional injection of carmustine (BCNU) and 4-hydroperoxycyclophosphamide (4HC) into the rat brain tumor bed with those from the same agents delivered via controlled release polymers implanted intracranially. Treatment was initiated on the fifth day after intracranial implantation of 9L gliosarcoma into male rats; two doses of each drug were injected intratumorally, representing either the amount of drug typically released in vivo from polymer during the first 24 h, or the maximal drug loaded on each polymer. Control rats were treated with empty polymers. We found that the median lifespan was extended in the groups of rats treated with intratumoral injection of BCNU (23% and 36% for 1 mg and 2 mg doses), and 271% with BCNU-impregnated polymer. Similar results were found with intratumoral 4HC (21% and 36% for 0.1 mg and 2 mg injection doses), and 121% with 4HC-impregnated polymer. Overall survival after intraneoplastic injections, however, was not statistically significantly different from that of control rats (p > 0.05). Furthermore, improvement in survival was not consistent, and some animals subjected to 4HC injection died early in the course of treatment. Polymeric treatment resulted in statistically significant prolongation of survival, compared to control rats (p < 0.001 for both BCNU and 4HC). We concluded that direct intralesional injection of BCNU and 4HC is less effective than controlled release via polymers for the treatment of 9L gliosarcoma in the rat model.

Animals↗