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1.
J Clin Oncol ; 16(10): 3369-74, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9779714

ABSTRACT

PURPOSE: Kaposi's sarcoma (KS) is the most common tumor in patients with AIDS and can be fatal in patients with lung involvement. Systemic chemotherapy is the most effective treatment for pulmonary KS. We thus conducted this study to determine the efficacy of liposomal daunorubicin in the treatment of patients with pulmonary KS. METHODS: Patients with biopsy-proven, symptomatic pulmonary KS were accrued. Liposomal daunorubicin was given at a dose of 60 mg/m2 intravenously every 2 weeks. Response was monitored by chest radiographs, pulmonary function tests, arterial blood gases, and grading of pulmonary symptoms. RESULTS: Fifty-three male patients were accrued. The median CD4+ lymphocyte count was 13/microL (range, 0 to 200); 70% reported a prior AIDS-defining opportunistic infection. All patients were symptomatic, with cough reported in all patients, shortness of breath in 94%, and hemoptysis in 55%. The mean study entry diffusing capacity of carbon monoxide (DLCO) was 58.5% (percent of predicted). The median dose of liposomal daunorubicin delivered was 360 mg/m2 (range, 60 to 1,380). More than 75% of patients had complete or partial resolution of baseline pulmonary symptoms. Complete or partial improvement in DLCO was observed in 22%; complete or partial resolution of radiographic abnormalities was reported in 32%. The most common treatment-related toxicity was neutropenia, which occurred in 85%. There were no instances of cardiac toxicity observed, even at high cumulative doses. CONCLUSION: Liposomal daunorubicin at 60 mg/m2 is safe and active in patients with pulmonary KS. Trials combining liposomal daunorubicin with other active agents in KS should be considered.


Subject(s)
Acquired Immunodeficiency Syndrome/complications , Antibiotics, Antineoplastic/therapeutic use , Daunorubicin/therapeutic use , Lung Neoplasms/drug therapy , Sarcoma, Kaposi/drug therapy , Adult , Antibiotics, Antineoplastic/adverse effects , Daunorubicin/adverse effects , Drug Administration Schedule , Humans , Liposomes , Lung/drug effects , Lung Neoplasms/etiology , Male , Middle Aged , Prognosis , Prospective Studies , Sarcoma, Kaposi/etiology , Survival Analysis
2.
Clin Cancer Res ; 3(8): 1245-52, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9815806

ABSTRACT

Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by forming "cleavable complex," a high molecular weight DNA protein adduct. The formation of such cleavable complexes results in depletion of the Mr 100,000 "free" topo-1 band detectable by Western blot. The objectives of this study were to determine the maximally tolerated dose of prolonged topotecan infusion in previously untreated and minimally pretreated patients. A secondary objective was to measure the effect of prolonged topotecan infusion on topo-1 levels in peripheral blood mononuclear cells (PBMCs) as a pharmacodynamic end point. In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J. Clin. Oncol., 12: 553-559, 1994), the maximum tolerated dose for patients treated previously was 0.53 mg/m2/day for 21 days every 28 days. In this study, patients with no prior therapy were treated similarly at 0.7 mg/m2/day for 21 days, and doses were escalated in 0.1 mg/m2/day increments. Patients who had one prior chemotherapy regimen or radiation therapy to a portal of

Subject(s)
Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , DNA Topoisomerases, Type I/blood , Neoplasms/drug therapy , Topotecan/adverse effects , Topotecan/pharmacokinetics , Adult , Aged , Antineoplastic Agents/administration & dosage , Female , Humans , Infusions, Intravenous , Leukocytes, Mononuclear/enzymology , Leukopenia/chemically induced , Male , Middle Aged , Neoplasms/blood , Neoplasms/enzymology , Thrombocytopenia/chemically induced , Topotecan/administration & dosage
3.
J Clin Oncol ; 15(3): 1094-103, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9060550

ABSTRACT

PURPOSE: Patients with AIDS-related lymphoma usually have extensive lymphomatous disease, with relatively frequent involvement of the CNS. Approximately half may achieve complete remission after chemotherapy. Mitoguazone, an inhibitor of polyamine biosynthesis, has demonstrated efficacy in patients with de novo recurrent lymphoma. The drug is relatively nonmyelotoxic and may cross the blood-brain barrier. The current study was designed to assess the safety and potential efficacy of mitoguazone in patients with relapsed or refractory AIDS-lymphoma. PATIENTS AND METHODS: Thirty-five patients were accrued, all of whom had failed one (51%) or multiple (two to six) prior regimens. Mitoguazone (600 mg/m2) was given intravenously on days 1 and 8, and then every 2 weeks, until best response, progression, or toxicity. RESULTS: The median age was 39 years. High-grade lymphoma was diagnosed in 29 patients (83%). Extranodal disease was present in 30 patients (86%), with multiple extranodal sites (two to seven) in 18 (51%). The median CD4 cell count at study entry was 66/dL (range, zero to 549). Twenty-six patients were assessable for response. The objective response rate was 23% (95% confidence interval [CI], 6.9 to 39.3), with complete remission in three patients (11.5%), and partial remission (PR) in three patients (11.5%). Six patients experienced stable disease. Median survival from study entry was 2.6 months for the group as a whole; 21.5 months (range, 3.8 to 29.1) in complete responders, 5.6 months (range, 3.8 to 34.8) in partial responders. The most common toxicities occurred solely during drug infusion and included vasodilation (63%), paresthesia (86%), and somnolence (17%). Fourteen patients (40%) experienced nausea and 16 (46%) vomiting (grade 3 in one). Ten patients (29%) developed stomatitis, including grade 3 in two and grade 4 in one. Seven patients (20%) developed neutropenia, with grade 4 in one. Thrombocytopenia occurred in nine patients (26%). While on study, three patients developed sepsis, four had pneumonia, and two developed opportunistic infections. CONCLUSION: Mitoguazone is an effective agent in patients with multiply relapsed or refractory AIDS-related lymphoma, with acceptable toxicity. Further study in patients with newly diagnosed disease is warranted.


Subject(s)
Antineoplastic Agents/therapeutic use , Lymphoma, AIDS-Related/drug therapy , Mitoguazone/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Mitoguazone/adverse effects , Neutropenia/chemically induced , Recurrence , Remission Induction , Survival Analysis , Thrombocytopenia/chemically induced
5.
J Clin Oncol ; 14(8): 2353-64, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8708728

ABSTRACT

PURPOSE: To compare the safety and efficacy of liposomal daunorubicin (DaunoXome; NeXstar Pharmaceuticals, Inc, Boulder, CO) with a reference regimen of doxorubicin, bleomycin, and vincristine (ABV) in advanced AIDS-related Kaposi's sarcoma (KS). PATIENTS AND METHODS: In a prospective randomized phase III trial, 232 patients were randomized to receive DaunoXome 40 mg/m2 or a combination regimen of doxorubicin 10 mg/m2, bleomycin 15 U, and vincristine 1 mg, administered intravenously every 2 weeks. Treatment was continued until complete response (CR), disease progression, or unacceptable toxicity. RESULTS: Of 232 patients randomized, 227 were treated: 116 with DaunoXome and 111 with ABV. The overall response rate (CR or partial response [PR]) was 25% (three CRs and 26 PRs) for DaunoXome and 28% (one CR and 30 PRs) for ABV. The difference in response rates was not statistically significant. The median survival time was 369 days for DaunoXome patients and 342 days for ABV patients (P = .19). The median time to treatment failure was 115 days for DaunoXome and 99 days for ABV (P = .13). ABV patients experienced significantly more alopecia and neuropathy (P < .0001). DaunoXome patients experienced more grade 4 neutropenia (P = .021). Cardiac function remained stable, with no instances of congestive heart failure on either treatment arm. CONCLUSION: In this large phase III trial, the efficacy of DaunoXome was comparable to that of ABV. Response rates, time to treatment failure, and overall survival were similar on both treatment arms. DaunoXome is a safe and effective primary therapy for advanced AIDS-related KS.


Subject(s)
Acquired Immunodeficiency Syndrome/complications , Antibiotics, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Daunorubicin/administration & dosage , Sarcoma, Kaposi/drug therapy , Adult , Alopecia/chemically induced , Antibiotics, Antineoplastic/adverse effects , Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/administration & dosage , Bleomycin/adverse effects , Canada , Daunorubicin/adverse effects , Daunorubicin/therapeutic use , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Carriers , Female , Humans , Liposomes , Male , Middle Aged , Neutropenia/chemically induced , Prospective Studies , Remission Induction , Sarcoma, Kaposi/etiology , Sarcoma, Kaposi/mortality , Survival Rate , Treatment Failure , United States , Vincristine/administration & dosage , Vincristine/adverse effects
6.
J Clin Oncol ; 14(7): 1993-9, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8683229

ABSTRACT

PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Cisplatin/administration & dosage , Cisplatin/adverse effects , Female , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects
7.
J Clin Oncol ; 12(3): 553-9, 1994 Mar.
Article in English | MEDLINE | ID: mdl-8120553

ABSTRACT

PURPOSE: The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer. PATIENTS AND METHODS: Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation. RESULTS: The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions). CONCLUSION: Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer.


Subject(s)
Antineoplastic Agents/administration & dosage , Camptothecin/analogs & derivatives , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Bone Marrow Diseases/chemically induced , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/pharmacokinetics , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasms/metabolism , Topotecan , Treatment Outcome
8.
J Acquir Immune Defic Syndr (1988) ; 6(3): 259-64, 1993 Mar.
Article in English | MEDLINE | ID: mdl-8450401

ABSTRACT

Fifty-three patients with AIDS-related Kaposi's sarcoma and no previous treatment with cytotoxic chemotherapy enrolled in a phase II multicenter study to evaluate the safety and efficacy of weekly doxorubicin treatment. Doxorubicin was given intravenously at a dose of 15 mg/m2. Patients were stratified for purposes of analyses by tumor burden and coexistence of HIV-associated signs and symptoms; stratum I included patients with cutaneous disease alone and no symptoms, and stratum II included patients with visceral disease, tumor-associated edema, a previous opportunistic infection, or systemic symptoms. Fifty-one patients were evaluable for toxicity and 50 for tumor response. Five patients had a partial response (10%); 32, a minor response (64%); 12, no change (24%); and one, progression (2%) as the best measurable response. Partial response durations ranged from 4 to 14 weeks. Fifteen patients subsequently showed progression while on treatment. A significantly greater number of patients in stratum I (20.1%) had a partial response compared with those in stratum II (0%, p = 0.009). The major toxicities included nausea (37%), stomatitis (9.8%), mucositis (13.7%), and moderate to severe neutropenia (71%). Neutropenia was dose limiting and resulted in discontinuation of doxorubicin in 18% of the patients. Two patients developed cardiac toxicity. In conclusion, doxorubicin treatment induced relatively few tumor responses and remission durations were short. Treatment was limited by a high rate of toxicity.


Subject(s)
Acquired Immunodeficiency Syndrome/complications , Doxorubicin/administration & dosage , Sarcoma, Kaposi/drug therapy , AIDS-Related Opportunistic Infections/complications , Adult , Doxorubicin/adverse effects , Drug Administration Schedule , Humans , Male , Middle Aged , Neutropenia/chemically induced , Sarcoma, Kaposi/blood , Sarcoma, Kaposi/etiology
9.
J Acquir Immune Defic Syndr (1988) ; 6(3): 265-71, 1993 Mar.
Article in English | MEDLINE | ID: mdl-7680712

ABSTRACT

The use of full-dose intensive regimens of chemotherapy in patients with HIV-associated lymphoma has often resulted in severe toxicity, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the toxicity of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with granulocyte-macrophage colony stimulating factor (GMCSF) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of GMCSF. Eight patients received standard dose m-BACOD plus GMCSF without experiencing dose-limiting hematologic toxicity, although significant nonhematologic toxicity was seen. We conclude that it is feasible to treat patients with HIV-associated lymphoma using standard dose m-BACOD plus GMCSF, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Lymphoma, AIDS-Related/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , AIDS-Related Opportunistic Infections/complications , Adult , Bleomycin/administration & dosage , Bleomycin/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects , HIV Core Protein p24/blood , Humans , Kidney/drug effects , Leucovorin/administration & dosage , Leucovorin/adverse effects , Leukocyte Count/drug effects , Lung/drug effects , Lymphoma, AIDS-Related/blood , Lymphoma, Non-Hodgkin/blood , Male , Methotrexate/administration & dosage , Methotrexate/adverse effects , Neutropenia/chemically induced , Remission Induction , Vincristine/administration & dosage , Vincristine/adverse effects
10.
J Chem Ecol ; 19(6): 1245-63, 1993 Jun.
Article in English | MEDLINE | ID: mdl-24249141

ABSTRACT

Two experiments were conducted to examine the influence of foliar nitrogen, terpenes, and phenolics of Douglas-fir on the development of gypsy moth larvae. In the first experiment, foliar concentrations of nitrogen and allelochemicals were manipulated by fertilizing 3-year-old potted seedlings with 0 or 200 ppm nitrogen. Concentrations of foliar nitrogen (0.33-2.38%) were negatively correlated with the phenolics (15.8-24.4 mg/g). Sixth-instar larvae previously reared on current-year Douglas-fir needles were allowed to feed on these seedlings. Pupal weights (312.8-995.6 mg) were positively correlated with levels of foliar nitrogen, negatively correlated with amounts of foliar phenolics, and uncorrelated with terpene concentrations. In the second experiment, terpene and phenolic extracts from Douglas-fir foliage were incorporated at natural levels into artificial diets with high and low levels of protein nitrogen. Neonate larvae grew faster and were larger on the high nitrogen control diet (4.1-4.5%), however, fourth instars performed better on the control diet with low nitrogen levels (2.5-2.7%). Foliar terpenes incorporated into diet had little effect on neonate fitness, but may induce subtle physiological changes in later instar larvae. Phenolics, alone or in combination with terpenes, excessively suppressed growth and survival, with no individuals living through the fourth instar, regardless of the nitrogen level. Incorporating foliar phenolic extracts into artificial diet caused unnatural levels of toxicity and failed to clarify the effects of Douglas-fir phenolics on gypsy moth fitness. Foliar nitrogen is a key factor influencing gypsy moth development on Douglas fir, but may be mitigated to some degree by phenolics.

11.
J Natl Cancer Inst ; 84(22): 1725-30, 1992 Nov 18.
Article in English | MEDLINE | ID: mdl-1433357

ABSTRACT

BACKGROUND: Although doxorubicin is an anticancer agent with a wide spectrum of activity, therapy with this anthracycline must often be discontinued at a time of benefit to the patient because of the drug's cumulative cardiotoxicity. ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin. PURPOSE: Our objectives in this study were to determine the maximum tolerated dose of ADR-529 (which uses a different vehicle than ICRF-187) when given with a fixed doxorubicin dose and to determine whether ADR-529 alters doxorubicin pharmacokinetics. METHODS: Twenty-five patients were treated with doxorubicin (60 mg/m2) preceded by administration of ADR-529 in escalating dosages (i.e., 60, 300, 600, 750, and 900 mg/m2) to groups of three to nine patients. ADR-529 was administered over a 15-minute period beginning 30 minutes before doxorubicin treatment; the protocol was repeated every 3 weeks. Blood was sampled frequently for drug levels, which were determined by high-pressure liquid chromatography with fluorescence (doxorubicin) and electrochemical detection (ADR-529). RESULTS: Dose-limiting neutropenia occurred in four of six previously treated patients at an ADR-529 dose of 600 mg/m2; the dose ratio of ADR-529 to doxorubicin was 10:1. For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2. Doxorubicin's estimated terminal half-life was 39.5 +/- 18.3 (mean +/- SD) hours; the area under the curve for plasma concentration of drug x time (AUC) was 1.74 +/- 0.40 (micrograms/microL) x hour. Total-body clearance was 598 +/- 142 microL/m2 per minute (N = 20), and it did not vary with ADR-529 dose. Estimated distribution and elimination phase half-lives for plasma ADR-529 were 0.46 +/- 0.30 hours and 4.16 +/- 2.94 hours, respectively. Total-body clearance was 111 +/- 87 microL/m2 per minute (N = 18); AUC was linear (r2 = .92), and the clearance rate was constant (r2 = .18) from 60 to 900 mg/m2. CONCLUSIONS: Myelotoxicity was dose limiting for ADR-529 at 600-750 mg/m2 when given with a fixed dose of doxorubicin at 60 mg/m2 (dose ratios of ADR-529 to doxorubicin ranged from 10:1 to 12.5:1). When used in combination, ADR-529 did not perturb doxorubicin's distribution, metabolism, or excretion; therefore, other mechanisms of cardioprotection must be involved. IMPLICATIONS: We recommend that an ADR-529 dose of 600 mg/m2 be given with single-agent doxorubicin at a dose of 60 mg/m2 in future studies.


Subject(s)
Razoxane/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols , Bone Marrow/drug effects , Doxorubicin/administration & dosage , Doxorubicin/toxicity , Heart Diseases/chemically induced , Humans , Razoxane/administration & dosage , Razoxane/toxicity
12.
J Clin Oncol ; 10(1): 117-27, 1992 Jan.
Article in English | MEDLINE | ID: mdl-1727913

ABSTRACT

PURPOSE: To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS: Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS: We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION: By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.


Subject(s)
Breast Neoplasms/drug therapy , Doxorubicin/adverse effects , Heart Failure/prevention & control , Razoxane/therapeutic use , Ventricular Function, Left/drug effects , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Doxorubicin/administration & dosage , Doxorubicin/antagonists & inhibitors , Female , Heart Failure/chemically induced , Humans , Life Tables , Middle Aged , Regression Analysis , Survival Analysis
13.
JAMA ; 266(1): 84-8, 1991 Jul 03.
Article in English | MEDLINE | ID: mdl-1710673

ABSTRACT

OBJECTIVE: --To ascertain if low-dose multiagent chemotherapy, with central nervous system prophylaxis and antiretroviral therapy, might be associated with increased efficacy and decreased risk of intercurrent infection in patients with malignant lymphoma related to the acquired immunodeficiency syndrome (AIDS). DESIGN: --A phase II prospective clinical trial, with median follow-up of 33 months. SETTING: --Eight university hospitals, within the context of the AIDS Clinical Trials Units, sponsored by the National Institute of Allergy and Infectious Diseases. PATIENTS: --Forty-two patients with AIDS-related malignant lymphoma. All were evaluable for toxicity assessment, and 35 for response. INTERVENTION: --A low-dose modification of the M-BACOD regimen (day 1): cyclophosphamide, 300 mg/m2 intravenously (IV); doxorubicin, 25 mg/m2 IV; vincristine sulfate, 1.4 mg/m2 IV; bleomycin, 4 mg/m2 IV; dexamethasone, 3 mg/m2 orally on days 1 through 5; methotrexate, 500 mg/m2 IV on day 15, with leucovorin rescue. Intrathecal cytosine arabinoside (50 mg) to all on days 1, 8, 21, and 28, with radiation therapy to a helmet field to those with central nervous system involvement. Zidovudine for 12 months after completion of four to six cycles of chemotherapy. MAIN OUTCOME MEASURES: --Response rate and number of opportunistic infections. RESULTS: --Response rate was 51% with a complete response of 46%. Of 16 complete responses, relapse occurred in four, none isolated to the central nervous system. Opportunistic infections occurred in 21% of those receiving treatment. Median duration of survival among all 42 patients is 5.6 months, 6.5 months in 35 patients evaluable for response, and 15 months in patients with complete response. Lower concentration of CD4 cells, history of prior AIDS, bone marrow involvement, and stage IV disease were independently associated with decreased survival. CONCLUSIONS: --Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance may be associated with durable remissions in AIDS-related lymphoma with fewer opportunistic infections than noted in prior reports.


Subject(s)
Acquired Immunodeficiency Syndrome/complications , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols , Central Nervous System Diseases/prevention & control , Lymphoma/prevention & control , Zidovudine/therapeutic use , Acquired Immunodeficiency Syndrome/mortality , Adult , Bleomycin/administration & dosage , Central Nervous System Diseases/drug therapy , Cyclophosphamide/administration & dosage , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , HIV Seropositivity/drug therapy , Humans , Leucovorin/administration & dosage , Lymphoma/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/prevention & control , Male , Methotrexate/administration & dosage , Middle Aged , Opportunistic Infections/complications , Prospective Studies , Vincristine/administration & dosage
14.
J Clin Oncol ; 9(5): 809-17, 1991 May.
Article in English | MEDLINE | ID: mdl-2016624

ABSTRACT

Seventy-five patients with advanced epithelial ovarian cancer were treated with a combined modality regimen of systemic, induction chemotherapy followed by intraperitoneal therapy (IPT). All patients underwent initial surgery for staging and/or cytoreduction followed by cisplatin 20 mg/m2 intravenously (IV) for 5 days and cyclophosphamide 600 mg/m2 on day 4 every 3 to 4 weeks for two to four cycles. Patients were then evaluated for IPT and, if eligible, had an intraperitoneal (IP) catheter placed. IPT consisted of cisplatin 60 mg/m2 in 2 L on day 1 and IV cyclophosphamide 600 mg/m2 on day 2 every 3 weeks for three to six cycles. Patients who demonstrated a clinical complete response (CCR) were then referred for second-look laparotomy (SLL). Of 71 patients who completed the induction phase, 53 (75%) were eligible for IPT, and 49 patients entered the therapy phase. Toxicity of the combined modality approach was acceptable and did not differ from our previous experience using the same drugs systemically. Thirty-two of the 49 patients who completed IPT achieved a CCR, which was confirmed by SLL in 20 patients. Twenty recurrences were documented in the 32 CCR patients, 13 occurred in patients after SLL. Projected median survival of all patients is 38 months. Median survival correlated with amount of residual disease following initial surgery (23 months for bulky v 45 months for minimal residual; P less than .001) and with performance status ([PS]; 24 months for PS 2, 3 v greater than 46 months for PS O; P less than .001). Patients who presented with bulky tumors were less likely to reach the consolidation IPT phase. Incorporation of IP cisplatin into the first-line regimen for treatment of ovarian cancer does not appear to have major impact on the survival of all treated patients when compared with our historical control series. Combined IV and IPT cisplatin and cyclophosphamide is feasible with acceptable toxicity. Its impact on response and survival may be limited to only "good-prognosis" patients.


Subject(s)
Cisplatin/therapeutic use , Neoplasm Recurrence, Local/prevention & control , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Cisplatin/adverse effects , Combined Modality Therapy , Drug Evaluation , Female , Humans , Infusions, Parenteral , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , Remission Induction , Survival Analysis
15.
J Chem Ecol ; 17(9): 1783-99, 1991 Sep.
Article in English | MEDLINE | ID: mdl-24257920

ABSTRACT

Individual families of gypsy moth collected from a single population exhibited different degrees of fitness when fed diets of white alder, a suitable broadleaf host, and Douglas-fir, an unsuitable conifer host. Members of families on diets of Douglas-fir had significantly lower survival, longer larval periods, lower pupal weights, and shorter pupal periods than members of the same families fed alder. Foliar nutritional quality, including nitrogen level and allelochemical composition (terpenes and phenols), was considered the key factor responsible for these differences. Growth parameters differed significantly for families within diet treatments, indicating that the genetic resources of a family did affect performance somewhat. The influence of a family's genetic resources on larval survival was most notable when larvae were under the greatest nutritional stress.

17.
J Biol Response Mod ; 9(4): 345-54, 1990 Aug.
Article in English | MEDLINE | ID: mdl-2395000

ABSTRACT

Prior studies with the XMMME-001-RTA immunoconjugate composed of an antimelanoma monoclonal antibody and ricin A chain demonstrated some antitumor activity. However, almost all patients studied developed human antimurine antibodies and antiricin antibodies. In an effort to abrogate these host anti-immunotoxin immune responses and thus enhance antitumor activity, we treated 20 patients with the immunoconjugate plus a single dose of intravenous cyclophosphamide. An overall response rate of 20% was observed-predominantly in pulmonary and soft tissue nodules. There was no diminution in antibody responses against either the murine antibody or the ricin moiety. Further studies to elucidate the role of cyclophosphamide in monoclonal antibody therapy are planned.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Adult , Aged , Antibodies, Anti-Idiotypic/biosynthesis , Antibodies, Anti-Idiotypic/immunology , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Antibodies, Neoplasm/administration & dosage , Antibodies, Neoplasm/immunology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Drug Evaluation , Female , Humans , Immunosuppression Therapy , Immunotoxins/administration & dosage , Immunotoxins/immunology , Male , Melanoma/immunology , Melanoma/secondary , Middle Aged , Ricin/administration & dosage , Ricin/immunology
18.
J Clin Oncol ; 8(8): 1335-41, 1990 Aug.
Article in English | MEDLINE | ID: mdl-2199620

ABSTRACT

From August 1985 to November 1989 we conducted a trial of intraperitoneal (IP) carboplatin including a dose-escalation design in 25 women with advanced gynecologic malignancies. All had extensive prior therapy with cisplatin (median cumulative dose, 525 mg/m2). Carboplatin was administered IP in 2 L of 1.5% dextrose with a 4-hour dwell time every 4 weeks for six cycles at a starting dose of 200 mg/m2. Patients with reduced creatinine clearance (30 to 60 cc/min) were escalated more slowly than those with high (greater than 60 cc/min) clearance. Thrombocytopenia was dose-limiting and often more severe in patients with compromised renal function; there was no local drug toxicity. The median time of follow-up is 25 months. Complete responses (CRs) were documented in six of 23 assessable patients (26%) by repeat laparotomy, and an additional 11 patients (48%) had no disease evident by noninvasive restaging. Five of the CRs and six of the patients with no clinically evident disease have relapsed from 3 to 40 months after therapy. Six patients (26%) are alive and free of disease 8 to 47 (median, 20) months after therapy. IP carboplatin is effective against relapsed ovarian cancer, even after prior cisplatin therapy.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Organoplatinum Compounds/therapeutic use , Ovarian Neoplasms/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/physiopathology , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carboplatin , Creatinine/metabolism , Drug Evaluation , Female , Follow-Up Studies , Humans , Infusions, Parenteral , Kidney/physiopathology , Middle Aged , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Ovarian Neoplasms/mortality , Ovarian Neoplasms/physiopathology , Peritoneal Cavity , Remission Induction , Survival Rate , Thrombocytopenia/chemically induced
19.
Invest New Drugs ; 8(3): 333-6, 1990 Aug.
Article in English | MEDLINE | ID: mdl-2272774

ABSTRACT

Sixteen patients with metastatic ovarian cancer who had not previously been treated with anthracyclines were treated with 4'deoxydoxorubicin at a dose of 30 mg/m2 intravenously every 3 weeks. There were no clinical responses in this group of patients. Toxicities were infrequent with neutropenia and thrombocytopenia being dose limiting. Nausea and vomiting occurred in only 4 patients. We conclude that 4'deoxydoxorubicin is an inactive drug in this patient population and does not warrant further investigation in this disease.


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Doxorubicin/analogs & derivatives , Ovarian Neoplasms/drug therapy , Adult , Aged , Doxorubicin/administration & dosage , Doxorubicin/therapeutic use , Drug Administration Schedule , Drug Evaluation , Female , Humans , Middle Aged
20.
Cancer Chemother Pharmacol ; 26(4): 297-300, 1990.
Article in English | MEDLINE | ID: mdl-2369795

ABSTRACT

Idarubicin (4-demethoxydaunorubicin) is an orally active anthracycline. We treated 26 patients with 37 courses of the drug on a schedule of oral administration weekly x 3 followed by a 3-week rest period. The maximum tolerated dose on this schedule was 22.5 mg/m2 weekly x 3 every 6 weeks, with consistent myelosuppression being the dose-limiting toxicity; other toxicity was minimal. Pharmacologic studies showed a mean alpha half-life of 1.6 +/- 0.3 h and a beta half-life of 39 +/- 8.4 h for idarubicin. This schedule was well tolerated, with consistent toxicity patterns seen. Pharmacologic studies confirmed prolonged exposure to the drug and its active metabolite. In comparison with other schedules, this one may offer advantages in terms of consistent hematologic toxicity and prolonged exposure to both the parent compound and its active metabolite. Dose intensity was comparable with that on other schedules.


Subject(s)
Digestive System Neoplasms/drug therapy , Idarubicin/therapeutic use , Lung Neoplasms/drug therapy , Urinary Bladder Neoplasms/drug therapy , Adult , Aged , Drug Administration Schedule , Drug Evaluation , Female , Half-Life , Hematologic Diseases/chemically induced , Humans , Idarubicin/adverse effects , Idarubicin/pharmacokinetics , Male , Middle Aged
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