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William P Peters - One of the best experts on this subject based on the ideXlab platform.
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prospective randomized comparison of high dose chemotherapy with stem cell support versus intermediate dose chemotherapy after surgery and adjuvant chemotherapy in women with high risk primary breast cancer a report of calgb 9082 swog 9114 and ncic m
Journal of Clinical Oncology, 2005Co-Authors: William P Peters, James J Vredenburgh, Gary L Rosner, Elizabeth J Shpall, Michael Crump, Paul G Richardson, Michael W Schuster, Lawrence B Marks, Constance Cirrincione, Larry NortonAbstract:Purpose The prognosis for women with primary breast cancer involving multiple axillary nodes remains poor. High-dose chemotherapy with stem-cell support produced promising results in initial clinical trials conducted at single institutions. Patients and Methods Seven hundred eighty-five women aged 22 to 66 years with stage IIA, IIB, or IIIA breast cancer involving 10 or more axillary lymph nodes were randomized after surgery and standard adjuvant chemotherapy to either high-dose cyclophosphamide, cisplatin, and Carmustine (HD-CPB) with stem-cell support or intermediate-dose cyclophosphamide, cisplatin, and Carmustine (ID-CPB) with G-CSF support but without stem cells. Planned treatment for all patients included locoregional radiation therapy. Hormone-receptor–positive patients were to receive 5 years of tamoxifen. Event-free survival (EFS) was the primary end point. Results Median follow-up was 7.3 years. Event-free survival was not significantly different between the two treatment groups (P = .24). The p...
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association of high dose cyclophosphamide cisplatin and Carmustine pharmacokinetics with survival toxicity and dosing weight in patients with primary breast cancer
Clinical Cancer Research, 2002Co-Authors: William P Petros, James J Vredenburgh, Gloria Broadwater, Donald A Berry, Roy B Jones, Colleen J Gilbert, John P Gibbs, Michael O Colvin, William P PetersAbstract:This report investigates relationships between the pharmacokinetics and pharmacodynamics of high-dose alkylators used for the treatment of primary breast cancer. Eighty-five women with primary breast cancer involving >or=10 lymph nodes received four cycles of standard-dose chemotherapy followed by a high-dose regimen consisting of: cyclophosphamide (1875 mg/m(2) once daily x 3), cisplatin (165 mg/m(2) given over 72 h), Carmustine (600 mg/m(2)), and stem cell transplantation. Dosages were attenuated in patients whose body weight exceeded their calculated ideal weight by >20%. Pharmacokinetics of the high-dose chemotherapeutic agents were evaluated in each patient by collection and analysis of serial blood samples. Area under the concentration time curve (AUC) for cyclophosphamide and Carmustine was highly variable (>10-fold inter-patient range) with coefficients of variation > 50%, in contrast to cisplatin exposures (2-fold range; coefficient of variation 12%). The dosing method for overweight patients resulted in significantly lower systemic exposure to cisplatin (P = 0.035). The parent cyclophosphamide clearance on the 1st day of administration was significantly higher in patients who experienced acute cardiac toxicity (n = 5; P = 0.011), whereas Carmustine disposition was not found to be different in those developing pulmonary toxicity (n = 25; P = 0.96). Kaplan-Meier analysis (median follow-up of 5.9 years) demonstrated that patients with lower cyclophosphamide AUC (faster parent drug clearance to potentially cytotoxic compounds) survived longer (P = 0.031). Inter-individual differences in the pharmacokinetic disposition of high-dose chemotherapy may explain variability in both response and toxicity. Prospective strategies, which attempt to individualize AUC, should be evaluated in this setting.
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high dose chemotherapy and autologous bone marrow support as consolidation after standard dose adjuvant therapy for high risk primary breast cancer
Journal of Clinical Oncology, 1993Co-Authors: William P Peters, James J Vredenburgh, Lawrence B Marks, Roy B Jones, Maureen Ross, Barry Meisenberg, Eric P Winer, Joanne Kurtzberg, Robert C Bast, Elizabeth J ShpallAbstract:PURPOSEWe studied high-dose cyclophosphamide, cisplatin, and Carmustine (CPA/cDDP/BCNU) with autologous bone marrow support (ABMS) as consolidation after standard-dose adjuvant chemotherapy treatment of primary breast cancer involving 10 or more axillary lymph nodes.PATIENTS AND METHODSOne hundred two women with stage IIA, IIB, IIIA, or IIIB breast cancer involving 10 or more lymph nodes at surgery were registered; 85 were eligible, treated, and assessable. Patients were treated with four cycles of standard-dose cyclophosphamide, doxorubicin, and fluorouracil (CAF), followed by high-dose CPA/cDDP/BCNU with ABMS.RESULTSActuarial event-free survival for the study patients at a median follow-up of 2.5 years is 72% (95% confidence interval, 56% to 82%). Comparison to three historical or concurrent Cancer and Leukemia Group B (CALGB) adjuvant chemotherapy trials selected for similar patients showed event-free survival at 2.5 years to be between 38% and 52%. Therapy-related mortality was 12%; pulmonary toxicity...
Lawrence Kleinberg - One of the best experts on this subject based on the ideXlab platform.
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polifeprosan 20 3 85 Carmustine slow release wafer in malignant glioma patient selection and perspectives on a low burden therapy
Patient Preference and Adherence, 2016Co-Authors: Lawrence KleinbergAbstract:Polifeprosan 20 with Carmustine (GLIADEL®) polymer implant wafer is a biodegradable compound containing 3.85% Carmustine (BCNU, bischloroethylnitrosourea) implanted in the brain at the time of planned tumor surgery, which then slowly degrades to release the BCNU chemotherapy directly into the brain thereby bypassing the blood-brain barrier. Carmustine implant wafers were demonstrated to improve survival in randomized placebo-controlled trials in patients undergoing a near total resection of newly diagnosed or recurrent malignant glioma. Based on these trials and other supporting data, Carmustine wafer therapy was approved for use for newly diagnosed and recurrent malignant glioma in the United States and the European Union. Adverse events are uncommon, and as this therapy is placed at the time of surgery, it does not add to patient treatment burden. Nevertheless, this therapy appears to be underutilized. This article reviews the evidence for a favorable therapeutic ratio for the patient and the potential barriers. Consideration of these issues is important for optimal use of this therapeutic approach and may be important as this technology and other local therapies are further developed in the future.
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polifeprosan 20 3 85 Carmustine slow release wafer in malignant glioma evidence for role in era of standard adjuvant temozolomide
Core Evidence, 2012Co-Authors: Lawrence KleinbergAbstract:The Polifeprosan 20 with Carmustine (BCNU, bis-chloroethylnitrosourea, Gliadel®) polymer implant wafer is a biodegradable compound containing 3.85% Carmustine which slowly degrades to release Carmustine and protects it from exposure to water with resultant hydrolysis until the time of release. The Carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events. Based on these trials and other supporting data, US and European regulatory authorities granted approval for its use in recurrent and newly diagnosed malignant glioma, and it remains the only approved local treatment. The preclinical and clinical data suggest that it is optimally utilized primarily in the proportion of patients who may have total or near total removal of gross tumor. The aim of this work was to review the evidence for the use of Carmustine implants in the management of malignant astrocytoma (World Health Organization grades III and IV), including newly diagnosed and recurrent disease, especially in the setting of a standard of care that has changed since the randomized trials were completed. Therapy has evolved such that patients now generally receive temozolomide chemotherapy during and after radiotherapy treatment. For patients undergoing repeat resection for malignant glioma, a randomized, blinded, placebo-controlled trial demonstrated a median survival for 110 patients who received Carmustine polymers of 31 weeks compared with 23 weeks for 122 patients who only received placebo polymers. The benefit achieved statistical significance only on analysis adjusting for prognostic factors rather than for the randomized groups as a whole (hazard ratio = 0.67, P = 0.006). A blinded, placebo-controlled trial has also been performed for Carmustine implant placement in newly diagnosed patients prior to standard radiotherapy. Median survival was improved from 11.6 to 13.9 months (P = 0.03), with a 29% reduction in the risk of death. When patients with glioblastoma multiforme alone were analyzed, the median survival improved from 11.4 to 13.5 months, but this improvement was not statistically significant. When a Cox’s proportional hazard model was utilized to account for other potential prognostic factors, there was a significant 31% reduction in the risk of death (P = 0.04) in this subgroup. Data from other small reports support these results and confirm that the incidence of adverse events does not appear to be increased meaningfully. Given the poor prognosis without possibility of cure, these benefits from a treatment with a favorable safety profile were considered meaningful. There is randomized evidence to support the use of Carmustine wafers placed during resection of recurrent disease. Therefore, although there is limited specific evidence, this treatment is likely to be efficacious in an environment when nearly all patients receive temozolomide as part of initial management. Given that half of the patients in the randomized trial assessing the value of Carmustine implants in recurrent disease had received prior chemotherapy, it is likely that this remains a valuable treatment at the time of repeat resection, even after temozolomide. There are data from multiple reports to support safety. Although there is randomized evidence to support the use of this therapy in newly diagnosed patients who will receive radiotherapy alone, it is now standard to administer both adjuvant temozolomide and radiotherapy. There are survival outcome reports for small cohorts of patients receiving temozolomide with radiotherapy, but this information is not sufficient to support firm recommendations. Based on the rationale and evidence of safety, this approach appears to be a reasonable option as more information is acquired. Available data support the safety of using Carmustine wafers in this circumstance, although special attention to surgical guidelines for implanting the wafers is warranted.
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Carmustine wafers localized delivery of chemotherapeutic agents in cns malignancies
Expert Review of Anticancer Therapy, 2008Co-Authors: Steven Hsesheng Lin, Lawrence KleinbergAbstract:High-grade glioma is a devastating disease that leaves the majority of its victims dead within 2 years. To meaningfully increase survival, a trimodality approach of surgery, radiation, and chemotherapy is needed. Carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea) is a nitrosourea alkylating agent that exerts its antitumor effect by akylating DNA and RNA. Systemic administration of nitrosoureas as a single agent or as part of procarbazine/3-cyclohexyl-1-nitroso-urea/vincristine has demonstrated little efficacy in the treatment of high-grade glioma. The development of Carmustine wafers (Gliadel® Wafer) as a method for controlled released delivery of Carmustine from biodegradable polymer wafers enhances the therapeutic ratio by fully containing the drug within the confines of the brain tumor environment while minimizing systemic toxicities. Preclinical and clinical studies have proven the safety and efficacy of Gliadel in the management of glioblastoma. From these results, Gliadel is currently approved for u...
Elizabeth J Shpall - One of the best experts on this subject based on the ideXlab platform.
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prospective randomized comparison of high dose chemotherapy with stem cell support versus intermediate dose chemotherapy after surgery and adjuvant chemotherapy in women with high risk primary breast cancer a report of calgb 9082 swog 9114 and ncic m
Journal of Clinical Oncology, 2005Co-Authors: William P Peters, James J Vredenburgh, Gary L Rosner, Elizabeth J Shpall, Michael Crump, Paul G Richardson, Michael W Schuster, Lawrence B Marks, Constance Cirrincione, Larry NortonAbstract:Purpose The prognosis for women with primary breast cancer involving multiple axillary nodes remains poor. High-dose chemotherapy with stem-cell support produced promising results in initial clinical trials conducted at single institutions. Patients and Methods Seven hundred eighty-five women aged 22 to 66 years with stage IIA, IIB, or IIIA breast cancer involving 10 or more axillary lymph nodes were randomized after surgery and standard adjuvant chemotherapy to either high-dose cyclophosphamide, cisplatin, and Carmustine (HD-CPB) with stem-cell support or intermediate-dose cyclophosphamide, cisplatin, and Carmustine (ID-CPB) with G-CSF support but without stem cells. Planned treatment for all patients included locoregional radiation therapy. Hormone-receptor–positive patients were to receive 5 years of tamoxifen. Event-free survival (EFS) was the primary end point. Results Median follow-up was 7.3 years. Event-free survival was not significantly different between the two treatment groups (P = .24). The p...
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high dose chemotherapy and autologous bone marrow support as consolidation after standard dose adjuvant therapy for high risk primary breast cancer
Journal of Clinical Oncology, 1993Co-Authors: William P Peters, James J Vredenburgh, Lawrence B Marks, Roy B Jones, Maureen Ross, Barry Meisenberg, Eric P Winer, Joanne Kurtzberg, Robert C Bast, Elizabeth J ShpallAbstract:PURPOSEWe studied high-dose cyclophosphamide, cisplatin, and Carmustine (CPA/cDDP/BCNU) with autologous bone marrow support (ABMS) as consolidation after standard-dose adjuvant chemotherapy treatment of primary breast cancer involving 10 or more axillary lymph nodes.PATIENTS AND METHODSOne hundred two women with stage IIA, IIB, IIIA, or IIIB breast cancer involving 10 or more lymph nodes at surgery were registered; 85 were eligible, treated, and assessable. Patients were treated with four cycles of standard-dose cyclophosphamide, doxorubicin, and fluorouracil (CAF), followed by high-dose CPA/cDDP/BCNU with ABMS.RESULTSActuarial event-free survival for the study patients at a median follow-up of 2.5 years is 72% (95% confidence interval, 56% to 82%). Comparison to three historical or concurrent Cancer and Leukemia Group B (CALGB) adjuvant chemotherapy trials selected for similar patients showed event-free survival at 2.5 years to be between 38% and 52%. Therapy-related mortality was 12%; pulmonary toxicity...
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acute lung injury following treatment with high dose cyclophosphamide cisplatin and Carmustine pharmacodynamic evaluation of Carmustine
Journal of the National Cancer Institute, 1993Co-Authors: Roy B Jones, Elizabeth J Shpall, Steven Matthes, James H Fisher, Salomon M Stemmer, Christopher Dufton, Janet K Stephens, Scott I BearmanAbstract:BACKGROUND Therapy with high-dose cyclophosphamide, cisplatin, and Carmustine (BCNU) plus autologous bone marrow transplantation has been extensively studied as treatment for patients with stage II or III breast cancer who have a 70% or greater risk of developing metastatic disease. This therapy is being used in a cooperative intergroup phase III clinical trial. In the cyclophosphamide-cisplatin-BCNU regimen, cyclophosphamide and BCNU, but not cisplatin, have been reported to cause acute lung injury, suggesting that either cyclophosphamide or BCNU may contribute to this injury. PURPOSE The purpose of this study was to analyze clinical and pharmacokinetic data from our ongoing phase II trials and to determine whether there is an association between BCNU pharmacokinetics and acute lung injury following cyclophosphamide-cisplatin-BCNU therapy. METHODS We performed a retrospective study of 38 patients treated following induction therapy or relapse, 29 with stage II-IV breast cancer and nine with intermediate and high-grade stage III-IV non-Hodgkin's lymphoma. These patients received therapy with cyclophosphamide at a dose of 1875 mg/m2 daily as a 1-hour intravenous infusion for 3 days, cisplatin at 55 mg/m2 per day as a 72-hour continuous intravenous infusion, and BCNU at 600 mg/m2 as a 2-hour infusion immediately following completion of the cisplatin infusion. Data from analysis of blood samples were used to calculate pharmacokinetic parameters for BCNU, and acute lung injury was determined on the basis of pulmonary function test results and histologic examination of lung biopsy specimens. RESULTS Our analysis showed that 20 (53%) of the 38 patients developed pulmonary injury following treatment. Twelve (60%) of the 20 had values for area under the curve (AUC) for BCNU concentration x time that exceeded 600 (micrograms/mL) x minute, whereas only two (11%) of the 18 without pulmonary injury had values above this level (P < .03). Thus, 12 (86%) of 14 patients with BCNU AUC greater than 600 (micrograms/mL) x minute developed lung injury. CONCLUSIONS These results suggest that BCNU exposure greater than 600 (micrograms/mL) x minute is associated with increased risk of acute lung injury after cyclophosphamide-cisplatin-BCNU therapy and may be a major cause of pulmonary drug injury following this regimen. IMPLICATIONS Strategies aimed at more uniform drug exposure or selective neutralization of chlorethylisocyanate, one of the two major hydrolysis products of BCNU, might reduce the incidence of acute lung injury following this regimen without major compromise of antitumor effect.
James J Vredenburgh - One of the best experts on this subject based on the ideXlab platform.
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overall survival of newly diagnosed glioblastoma patients receiving Carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy
Cancer, 2009Co-Authors: Mary Lou Affronti, David A. Reardon, Christopher R Heery, James E Herndon, Jeremy N Rich, Annick Desjardins, James J Vredenburgh, Allan H Friedman, Darell D Bigner, Henry S FriedmanAbstract:BACKGROUND: Glioblastoma multiforme (GBM), the most lethal type of brain tumor, has a 1-year median survival. The effect of Carmustine wafers on the survival of newly diagnosed GBM patients treated with radiotherapy (RT) and concurrent temozolomide (TMZ) plus RT plus rotational chemotherapy was investigated. METHODS: An institutional review board-approved retrospective study was conducted in 85 newly diagnosed GBM patients who received surgical resection with and without Carmustine wafers followed by RT and concurrent TMZ plus rotational chemotherapy. Treatment group comparisons were conducted using the log-rank test. Survival experience of the Duke cohort was examined within specific patient subgroups defined by the original Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA) class and compared with the European Organization for Research and Treatment of Cancer (Stupp) and RTOG trial. RESULTS: Overall 1- and 2-year survival for the nonCarmustine wafer cohort were 69% and 29%, respectively, with a median survival of 72.7 weeks. One- and 2-year survival for the Carmustine wafer cohort were 81% and 47%, with median survival of 89.5 weeks. Carmustine wafer was not an independent predictor (P = .110) of survival after adjustment for RPA class. The proportion of patients in the Carmustine wafer cohort who lived longer than predicted based upon Stupp regimen results was significantly greater than 0.5 (P<.006); similar results based upon the RTOG trial data were observed (P < .001). CONCLUSIONS: Carmustine wafer with concurrent TMZ and radiation followed by rotational chemotherapy is a well tolerated, effective therapy, and has a survival benefit compared with radiation alone. Prospective randomized trials are needed to rigorously compare the Carmustine wafer regimen to the Stupp and postradiation multimodality regimens. Cancer 2009. © 2009 American Cancer Society.
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prospective randomized comparison of high dose chemotherapy with stem cell support versus intermediate dose chemotherapy after surgery and adjuvant chemotherapy in women with high risk primary breast cancer a report of calgb 9082 swog 9114 and ncic m
Journal of Clinical Oncology, 2005Co-Authors: William P Peters, James J Vredenburgh, Gary L Rosner, Elizabeth J Shpall, Michael Crump, Paul G Richardson, Michael W Schuster, Lawrence B Marks, Constance Cirrincione, Larry NortonAbstract:Purpose The prognosis for women with primary breast cancer involving multiple axillary nodes remains poor. High-dose chemotherapy with stem-cell support produced promising results in initial clinical trials conducted at single institutions. Patients and Methods Seven hundred eighty-five women aged 22 to 66 years with stage IIA, IIB, or IIIA breast cancer involving 10 or more axillary lymph nodes were randomized after surgery and standard adjuvant chemotherapy to either high-dose cyclophosphamide, cisplatin, and Carmustine (HD-CPB) with stem-cell support or intermediate-dose cyclophosphamide, cisplatin, and Carmustine (ID-CPB) with G-CSF support but without stem cells. Planned treatment for all patients included locoregional radiation therapy. Hormone-receptor–positive patients were to receive 5 years of tamoxifen. Event-free survival (EFS) was the primary end point. Results Median follow-up was 7.3 years. Event-free survival was not significantly different between the two treatment groups (P = .24). The p...
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association of high dose cyclophosphamide cisplatin and Carmustine pharmacokinetics with survival toxicity and dosing weight in patients with primary breast cancer
Clinical Cancer Research, 2002Co-Authors: William P Petros, James J Vredenburgh, Gloria Broadwater, Donald A Berry, Roy B Jones, Colleen J Gilbert, John P Gibbs, Michael O Colvin, William P PetersAbstract:This report investigates relationships between the pharmacokinetics and pharmacodynamics of high-dose alkylators used for the treatment of primary breast cancer. Eighty-five women with primary breast cancer involving >or=10 lymph nodes received four cycles of standard-dose chemotherapy followed by a high-dose regimen consisting of: cyclophosphamide (1875 mg/m(2) once daily x 3), cisplatin (165 mg/m(2) given over 72 h), Carmustine (600 mg/m(2)), and stem cell transplantation. Dosages were attenuated in patients whose body weight exceeded their calculated ideal weight by >20%. Pharmacokinetics of the high-dose chemotherapeutic agents were evaluated in each patient by collection and analysis of serial blood samples. Area under the concentration time curve (AUC) for cyclophosphamide and Carmustine was highly variable (>10-fold inter-patient range) with coefficients of variation > 50%, in contrast to cisplatin exposures (2-fold range; coefficient of variation 12%). The dosing method for overweight patients resulted in significantly lower systemic exposure to cisplatin (P = 0.035). The parent cyclophosphamide clearance on the 1st day of administration was significantly higher in patients who experienced acute cardiac toxicity (n = 5; P = 0.011), whereas Carmustine disposition was not found to be different in those developing pulmonary toxicity (n = 25; P = 0.96). Kaplan-Meier analysis (median follow-up of 5.9 years) demonstrated that patients with lower cyclophosphamide AUC (faster parent drug clearance to potentially cytotoxic compounds) survived longer (P = 0.031). Inter-individual differences in the pharmacokinetic disposition of high-dose chemotherapy may explain variability in both response and toxicity. Prospective strategies, which attempt to individualize AUC, should be evaluated in this setting.
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high dose chemotherapy and autologous bone marrow support as consolidation after standard dose adjuvant therapy for high risk primary breast cancer
Journal of Clinical Oncology, 1993Co-Authors: William P Peters, James J Vredenburgh, Lawrence B Marks, Roy B Jones, Maureen Ross, Barry Meisenberg, Eric P Winer, Joanne Kurtzberg, Robert C Bast, Elizabeth J ShpallAbstract:PURPOSEWe studied high-dose cyclophosphamide, cisplatin, and Carmustine (CPA/cDDP/BCNU) with autologous bone marrow support (ABMS) as consolidation after standard-dose adjuvant chemotherapy treatment of primary breast cancer involving 10 or more axillary lymph nodes.PATIENTS AND METHODSOne hundred two women with stage IIA, IIB, IIIA, or IIIB breast cancer involving 10 or more lymph nodes at surgery were registered; 85 were eligible, treated, and assessable. Patients were treated with four cycles of standard-dose cyclophosphamide, doxorubicin, and fluorouracil (CAF), followed by high-dose CPA/cDDP/BCNU with ABMS.RESULTSActuarial event-free survival for the study patients at a median follow-up of 2.5 years is 72% (95% confidence interval, 56% to 82%). Comparison to three historical or concurrent Cancer and Leukemia Group B (CALGB) adjuvant chemotherapy trials selected for similar patients showed event-free survival at 2.5 years to be between 38% and 52%. Therapy-related mortality was 12%; pulmonary toxicity...
Roy B Jones - One of the best experts on this subject based on the ideXlab platform.
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association of high dose cyclophosphamide cisplatin and Carmustine pharmacokinetics with survival toxicity and dosing weight in patients with primary breast cancer
Clinical Cancer Research, 2002Co-Authors: William P Petros, James J Vredenburgh, Gloria Broadwater, Donald A Berry, Roy B Jones, Colleen J Gilbert, John P Gibbs, Michael O Colvin, William P PetersAbstract:This report investigates relationships between the pharmacokinetics and pharmacodynamics of high-dose alkylators used for the treatment of primary breast cancer. Eighty-five women with primary breast cancer involving >or=10 lymph nodes received four cycles of standard-dose chemotherapy followed by a high-dose regimen consisting of: cyclophosphamide (1875 mg/m(2) once daily x 3), cisplatin (165 mg/m(2) given over 72 h), Carmustine (600 mg/m(2)), and stem cell transplantation. Dosages were attenuated in patients whose body weight exceeded their calculated ideal weight by >20%. Pharmacokinetics of the high-dose chemotherapeutic agents were evaluated in each patient by collection and analysis of serial blood samples. Area under the concentration time curve (AUC) for cyclophosphamide and Carmustine was highly variable (>10-fold inter-patient range) with coefficients of variation > 50%, in contrast to cisplatin exposures (2-fold range; coefficient of variation 12%). The dosing method for overweight patients resulted in significantly lower systemic exposure to cisplatin (P = 0.035). The parent cyclophosphamide clearance on the 1st day of administration was significantly higher in patients who experienced acute cardiac toxicity (n = 5; P = 0.011), whereas Carmustine disposition was not found to be different in those developing pulmonary toxicity (n = 25; P = 0.96). Kaplan-Meier analysis (median follow-up of 5.9 years) demonstrated that patients with lower cyclophosphamide AUC (faster parent drug clearance to potentially cytotoxic compounds) survived longer (P = 0.031). Inter-individual differences in the pharmacokinetic disposition of high-dose chemotherapy may explain variability in both response and toxicity. Prospective strategies, which attempt to individualize AUC, should be evaluated in this setting.
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high dose chemotherapy and autologous bone marrow support as consolidation after standard dose adjuvant therapy for high risk primary breast cancer
Journal of Clinical Oncology, 1993Co-Authors: William P Peters, James J Vredenburgh, Lawrence B Marks, Roy B Jones, Maureen Ross, Barry Meisenberg, Eric P Winer, Joanne Kurtzberg, Robert C Bast, Elizabeth J ShpallAbstract:PURPOSEWe studied high-dose cyclophosphamide, cisplatin, and Carmustine (CPA/cDDP/BCNU) with autologous bone marrow support (ABMS) as consolidation after standard-dose adjuvant chemotherapy treatment of primary breast cancer involving 10 or more axillary lymph nodes.PATIENTS AND METHODSOne hundred two women with stage IIA, IIB, IIIA, or IIIB breast cancer involving 10 or more lymph nodes at surgery were registered; 85 were eligible, treated, and assessable. Patients were treated with four cycles of standard-dose cyclophosphamide, doxorubicin, and fluorouracil (CAF), followed by high-dose CPA/cDDP/BCNU with ABMS.RESULTSActuarial event-free survival for the study patients at a median follow-up of 2.5 years is 72% (95% confidence interval, 56% to 82%). Comparison to three historical or concurrent Cancer and Leukemia Group B (CALGB) adjuvant chemotherapy trials selected for similar patients showed event-free survival at 2.5 years to be between 38% and 52%. Therapy-related mortality was 12%; pulmonary toxicity...
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acute lung injury following treatment with high dose cyclophosphamide cisplatin and Carmustine pharmacodynamic evaluation of Carmustine
Journal of the National Cancer Institute, 1993Co-Authors: Roy B Jones, Elizabeth J Shpall, Steven Matthes, James H Fisher, Salomon M Stemmer, Christopher Dufton, Janet K Stephens, Scott I BearmanAbstract:BACKGROUND Therapy with high-dose cyclophosphamide, cisplatin, and Carmustine (BCNU) plus autologous bone marrow transplantation has been extensively studied as treatment for patients with stage II or III breast cancer who have a 70% or greater risk of developing metastatic disease. This therapy is being used in a cooperative intergroup phase III clinical trial. In the cyclophosphamide-cisplatin-BCNU regimen, cyclophosphamide and BCNU, but not cisplatin, have been reported to cause acute lung injury, suggesting that either cyclophosphamide or BCNU may contribute to this injury. PURPOSE The purpose of this study was to analyze clinical and pharmacokinetic data from our ongoing phase II trials and to determine whether there is an association between BCNU pharmacokinetics and acute lung injury following cyclophosphamide-cisplatin-BCNU therapy. METHODS We performed a retrospective study of 38 patients treated following induction therapy or relapse, 29 with stage II-IV breast cancer and nine with intermediate and high-grade stage III-IV non-Hodgkin's lymphoma. These patients received therapy with cyclophosphamide at a dose of 1875 mg/m2 daily as a 1-hour intravenous infusion for 3 days, cisplatin at 55 mg/m2 per day as a 72-hour continuous intravenous infusion, and BCNU at 600 mg/m2 as a 2-hour infusion immediately following completion of the cisplatin infusion. Data from analysis of blood samples were used to calculate pharmacokinetic parameters for BCNU, and acute lung injury was determined on the basis of pulmonary function test results and histologic examination of lung biopsy specimens. RESULTS Our analysis showed that 20 (53%) of the 38 patients developed pulmonary injury following treatment. Twelve (60%) of the 20 had values for area under the curve (AUC) for BCNU concentration x time that exceeded 600 (micrograms/mL) x minute, whereas only two (11%) of the 18 without pulmonary injury had values above this level (P < .03). Thus, 12 (86%) of 14 patients with BCNU AUC greater than 600 (micrograms/mL) x minute developed lung injury. CONCLUSIONS These results suggest that BCNU exposure greater than 600 (micrograms/mL) x minute is associated with increased risk of acute lung injury after cyclophosphamide-cisplatin-BCNU therapy and may be a major cause of pulmonary drug injury following this regimen. IMPLICATIONS Strategies aimed at more uniform drug exposure or selective neutralization of chlorethylisocyanate, one of the two major hydrolysis products of BCNU, might reduce the incidence of acute lung injury following this regimen without major compromise of antitumor effect.