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1.
Ann Intern Med ; 128(12 Pt 1): 975-81, 1998 Jun 15.
Article in English | MEDLINE | ID: mdl-9625683

ABSTRACT

BACKGROUND: Hepatic complications are a major cause of illness and death after bone marrow transplantation. OBJECTIVE: To confirm the results of a pilot study that indicated that ursodiol prophylaxis could reduce the incidence of veno-occlusive disease of the liver. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Tertiary care teaching hospital. PATIENTS: 67 consecutive patients undergoing transplantation with allogeneic bone marrow (donated by a relative) in whom busulfan plus cyclophosphamide was used as the preparative regimen and cyclosporine plus methotrexate was used to prevent graft-versus-host disease. INTERVENTION: Before the preparative regimen was started, patients were randomly assigned to receive ursodiol, 300 mg twice daily (or 300 mg in the morning and 600 mg in the evening if body weight was > 90 kg), or placebo. MEASUREMENTS: Patients were prospectively evaluated for the clinical diagnosis of veno-occlusive disease, the occurrence of acute graft-versus-host disease, and survival. RESULTS: The incidence of veno-occlusive disease was 40% (13 of 32 patients) in placebo recipients and 15% (5 of 34 patients) in ursodiol recipients (P = 0.03). Assignment to placebo was the only pretransplantation characteristic that predicted the development of veno-occlusive disease. The most significant predictor of 100-day mortality was the diagnosis of veno-occlusive disease. The difference in actuarial risk for hematologic relapse in patients with chronic myelogenous leukemia and nonhepatic toxicities between the two groups was not statistically significant (13% in the ursodiol group and 20% in the placebo group; P > 0.2). CONCLUSION: Ursodiol prophylaxis seemed to decrease the incidence of hepatic complications after allogeneic bone marrow transplantation in patients who received a preparative regimen with busulfan plus cyclophosphamide.


Subject(s)
Bone Marrow Transplantation/adverse effects , Cholagogues and Choleretics/therapeutic use , Hepatic Veno-Occlusive Disease/prevention & control , Ursodeoxycholic Acid/therapeutic use , Adult , Bone Marrow Transplantation/mortality , Busulfan/therapeutic use , Cyclophosphamide/therapeutic use , Double-Blind Method , Drug Therapy, Combination , Female , Graft vs Host Disease/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Placebos , Survival Rate , Transplantation, Homologous
2.
Bone Marrow Transplant ; 18(3): 573-7, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8879620

ABSTRACT

Acute decompensating cardiomyopathy induced by cyclophosphamide is usually irreversible. To investigate the clinical course and the outcome of therapy, 13 patients (1.7%) with grade III acute cardiomyopathy and hypotension who were treated with ablative transplant regimens between January 1980 and September 1995 were analyzed. Eight of nine patients died of acute fatal restrictive cardiomyopathy with unresponsive hypotension (ARCH), whereas three of four patients who survived the initial episode died of subacute congestive heart failure (SCHF). Acute fatal restrictive cardiomyopathy was characterized with extreme sensitivity to volume overload, myocardial edema and a rapidly fatal course. It was associated with progressive, unresponsive hypotension, reduced left ventricular stroke work index (LVSWI: 29.29 +/- 9.74 g-m/beat/m2) and markedly reduced systemic and pulmonary vascular resistance indices (SVRI: 429.72 +/- 168.84, PVRI: 58.63 +/- 45.08 dyne.sec/cm5.m2). Subacute CHF was identified by myocardial edema, dilated chambers and biventricular pump failure represented by decreases in fractional shortening (FS: 19.5 +/- 4.9%). Of 10 patients who received conventional therapy, nine died and one sustained chronic CHF. One of three patients with ARCH on antioxidant therapy of ascorbic acid and theophylline survived the episode. The data suggests peripheral vascular collapse may also be responsible for fatal ARCH.


Subject(s)
Antineoplastic Agents, Alkylating/adverse effects , Cardiomyopathies/chemically induced , Cyclophosphamide/adverse effects , Adult , Echocardiography , Female , Hemodynamics/drug effects , Humans , Male , Middle Aged
3.
Cancer Chemother Pharmacol ; 38(4): 323-8, 1996.
Article in English | MEDLINE | ID: mdl-8674154

ABSTRACT

PURPOSE: Intravenous dolasetron has been shown to be an effective antiemetic agent in patients receiving high-dose cisplatin-containing chemotherapy. Previous studies have suggested that 1.8 mg/kg is an optimal dose for achieving control of emesis and nausea. The objective of this study was to compare the efficacy and safety of a single intravenous (IV) dose of dolasetron with an equal divided multiple dose. METHODS: In this randomized, double-blind, parallel-group, multicenter study, the efficacy and safety of a single 1.8-mg/kg dose of dolasetron given 30 min prior to high-dose cisplatin ( > or = 80 mg/m2) chemotherapy was compared with the same total amount of dolasetron administered in three separate doses (0.6 mg/kg each) over a 12-h interval commencing 30 min prior to beginning chemotherapy and ending 11.5 h later. Antiemetic efficacy, safety, and tolerability were compared in 55 patients with various malignancies during the 24 h following the initiation of chemotherapy. The number of emetic episodes was the primary efficacy parameter. RESULTS: A single IV dose of dolasetron was generally more effective than a multiple-dose regimen in all measures of efficacy. There was a larger proportion of complete responders in the single-dose group compared with the multiple-dose group (48% vs 23%), although this difference did not reach statistical significance. Compared with the multiple-dose group, patients who received a single dose of dolasetron had a significantly (P = 0.034) longer median time to the first emetic episode (10.1 h vs > 24 h, respectively). Overall, 53% of patients had either a complete response or a major response to dolasetron, and only 40% of the total patient population received escape antiemetic medication in the 24 h after cisplatin administration. Except for headache, adverse events were similar with both regimens and were generally of mild or moderate intensity; no serious adverse events occurred. Neither dolasetron treatment regimen was associated with any clinically important events, trends in laboratory variables, or differences in safety profile. CONCLUSIONS: single-dose dolasetron was well tolerated and effectively controlled emesis and nausea in patients who received highly emetogenic, high-dose cisplatin chemotherapy. The greater antiemetic efficacy of a single prophylactic dose of dolasetron offers both convenience and potential cost savings, compared with a multiple-dose schedule of administration.


Subject(s)
Antiemetics/administration & dosage , Antineoplastic Agents/adverse effects , Cisplatin/adverse effects , Indoles/administration & dosage , Quinolizines/administration & dosage , Serotonin Antagonists/administration & dosage , Vomiting/drug therapy , Aged , Double-Blind Method , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Nausea/chemically induced , Nausea/drug therapy , Proportional Hazards Models , United States , Vomiting/chemically induced
4.
Anticancer Drugs ; 6(4): 489-97, 1995 Aug.
Article in English | MEDLINE | ID: mdl-7579552

ABSTRACT

Malignant melanoma, once disseminated, is associated with very short survival times and has proven highly resistant to systemic therapy. Although many chemotherapeutic agents can produce small response rates in these patients, the most consistent responses occur with dacarbazine (DTIC). Numerous combination regimens, with and without DTIC, have been tested against disseminated melanoma, with varying and inconsistent outcomes. The most encouraging results have occurred with the combination of DTIC, cisplatin, BCNU and tamoxifen. The use of high-dose chemotherapy with and without autologous bone marrow support and the addition of biologic agents such as inteferon-alpha and interleukin-2 to conventional chemotherapy have also been actively investigated. This paper reviews the various approaches taken against disseminated melanoma employing systemic chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Combined Modality Therapy , Humans , Melanoma/pathology , Skin Neoplasms/pathology
5.
Semin Oncol ; 20(4 Suppl 4): 33-8; quiz 39, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8342074

ABSTRACT

The combination of busulfan (Bu) and cyclophosphamide (Cy) has been found to be effective preparative therapy for patients treated with allogeneic bone marrow transplantation (BMT). We developed the BuCy2 regimen, which contains a lower dose of cyclophosphamide than the original BuCy regimen, in the hope of reducing regimen-related toxicities. We have studied the use of BuCy2 as preparation for allogeneic BMT in patients with acute myelogenous leukemia, acute lymphocytic leukemia, and multiple myeloma. In patients with acute myelogenous leukemia, the leukemia-free survival and regimen-related toxicity rates obtained in our study appear similar to those achieved with other preparative regimens, including those containing Cy and total body irradiation (TBI). BuCy2 is also an effective BMT preparative regimen in patients with acute lymphocytic leukemia and multiple myeloma. Treatment with BuCy2 results in a lower incidence of severe stomatitis and probably of interstitial pneumonia than does treatment with Cy/TBI, but hepatic veno-occlusive disease occurs more frequently in BuCy-treated patients. The incidence of veno-occlusive disease appears to be affected by agents used as prophylaxis for graft-versus-host disease. Compared with Cy/TBI regimens, BuCy treatment is likely to result in fewer delayed effects of treatment, such as impairment of fertility and second malignancies. Current clinical efforts are focusing on ways to improve the antileukemic activity of the BuCy preparative regimen and to reduce regimen-related toxicities.


Subject(s)
Bone Marrow Transplantation/methods , Busulfan/therapeutic use , Cyclophosphamide/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Busulfan/administration & dosage , Busulfan/adverse effects , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Humans , Leukemia, Myeloid, Acute/therapy , Multiple Myeloma/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transplantation, Homologous , Treatment Outcome
6.
Bone Marrow Transplant ; 10(4): 367-72, 1992 Oct.
Article in English | MEDLINE | ID: mdl-1422493

ABSTRACT

Ursodiol is a hydrophilic, non-hepatotoxic bile salt indicated for the medical treatment of cholesterol gallstones. This pilot study explored the use of prophylactic ursodiol in an attempt to decrease the incidence and severity of veno-occlusive disease (VOD) of the liver following allogeneic bone marrow transplantation (BMT). Between February 1991 and January 1992, 22 consecutive patients undergoing BMT for hematologic malignancies received the BU(4)/CY(2) preparative regimen and CSA/MTX for GVHD prophylaxis. Ursodiol, 600-900 mg daily by mouth was begun at least 1 day prior to beginning the preparative regimen. Results for this pilot group were compared to a control group of 28 consecutive patients transplanted between June 1989 and January 1991 with the same regimen without ursodiol. There were no significant differences in disease or clinical status between the groups pretransplant. However, mean baseline AST levels were significantly higher in the ursodiol group, 28.0 U/l vs 18.1 U/l in the control group (p = 0.001). The median maximum bilirubin observed post-transplant was 2.35 mg/dl (range 0.9-45) in the ursodiol group, and 5.05 mg/dl (range 0.7-29.4) in controls. The incidence of VOD was 2/22 (9.1%) in the ursodiol group and 18/28 (64.3%) in controls (p = 0.0001). Death due to VOD occurred in 1/22 patients (4.5%) in the ursodiol group and in 6/28 (21.4%) controls (p = 0.12). Our data suggest that ursodiol may decrease the incidence of VOD in allogeneic BMT patients.


Subject(s)
Bone Marrow Transplantation/adverse effects , Hepatic Veno-Occlusive Disease/prevention & control , Ursodeoxycholic Acid/pharmacology , Adolescent , Adult , Child , Female , Hepatic Veno-Occlusive Disease/etiology , Humans , Leukemia/surgery , Male , Middle Aged , Transplantation, Homologous
7.
Blood ; 79(10): 2784-8, 1992 May 15.
Article in English | MEDLINE | ID: mdl-1586725

ABSTRACT

The use of cyclosporine-A/methotrexate (CyA/MTX) for graft-versus-host disease (GVHD) prophylaxis is safe and effective for patients undergoing allogeneic bone marrow transplantation after preparation with cyclophosphamide and total body irradiation. We report 87 patients prepared for allogeneic transplant with busulfan 4 mg/kg/d orally for 4 days, followed by cyclophosphamide 60 mg/kg/d intravenously for 2 days (Bu4Cy2). A marked increase in hepatotoxicity was observed in 20 patients administered CyA/MTX, compared with 67 historical control patients who received CyA/methylprednisolone (CyA/MP) for GVHD prophylaxis with all other treatment and support variables remaining constant. The incidence of hyperbilirubinemia (bilirubin greater than or equal to 2 mg/dL) increased from 48% to 80% (P = .02), and the mean maximal bilirubin increased from 4.67 +/- 7.27 to 8.72 +/- 8.73 mg/dL (P = .04), when CyA/MTX was used in place of CyA/MP for GVHD prophylaxis. In addition, the incidence of veno-occlusive disease (VOD) increased from 18% to 70% (P = .0001), and death caused by VOD increased from 4.5% to 25% (P = .02). Survival was not significantly different for the two groups because of a higher non-VOD death rate in patients receiving CyA/MP for GVHD prophylaxis (P = .77). We suggest caution when using Bu4Cy2 in combination with CyA/MTX for GVHD prophylaxis.


Subject(s)
Bone Marrow Transplantation/immunology , Busulfan/therapeutic use , Cyclophosphamide/therapeutic use , Graft vs Host Disease/prevention & control , Hepatic Veno-Occlusive Disease/chemically induced , Leukemia/surgery , Methotrexate/adverse effects , Methotrexate/therapeutic use , Methylprednisolone/therapeutic use , Actuarial Analysis , Adult , Bone Marrow Transplantation/methods , Busulfan/adverse effects , Female , Follow-Up Studies , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/surgery , Leukemia, Myeloid, Acute/surgery , Male , Methylprednisolone/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/surgery , Time Factors , Whole-Body Irradiation
8.
Sel Cancer Ther ; 7(2): 85-91, 1991.
Article in English | MEDLINE | ID: mdl-1754731

ABSTRACT

Crisnatol is an arylmethylaminopropanediol derivative that has shown promise as an antitumor agent in preclinical testing. In a phase I trial using a monthly six-hour infusion schedule the recommended dose for future phase II trials was found to be 388 mg/m2. Neurologic toxicity was dose-limiting in that trial and correlated with the attainment of a threshold plasma concentration of greater than 4.5 micrograms/ml. In this study we treated 15 patients with escalating doses of crisnatol from 450 mg/m2 to 900 mg/m2 administered at a rate of 50 mg/m2/hr over 9, 12, 15, and 18 hours. Toxicity was mild to moderate at all dose levels. However, serious central nervous system effects were noted in one patient at 900 mg/m2 over 18 hours whose plasma level was 6.5 micrograms/ml. This study has demonstrated higher total doses of crisnatol can be given if the drug is administered as a prolonged infusion in an attempt to avoid high plasma levels of the agent.


Subject(s)
Antineoplastic Agents/therapeutic use , Chrysenes/therapeutic use , Neoplasms/drug therapy , Propylene Glycols/therapeutic use , Aged , Antineoplastic Agents/adverse effects , Chrysenes/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Evaluation , Humans , Infusions, Intravenous , Middle Aged , Nervous System Diseases/chemically induced , Propylene Glycols/adverse effects
9.
Cancer Res ; 48(18): 5353-7, 1988 Sep 15.
Article in English | MEDLINE | ID: mdl-2842047

ABSTRACT

Carbetimer (carbethimer, N-137, NED-137, carboxyimamidate) is a low molecular weight polyelectrolyte with antitumor activity in a variety of tumor models. This phase I trial evaluated a single dose of carbetimer infused over 1-2 h every 28 days. Forty-three patients received 71 courses of the drug at doses ranging from 180 to 8500 mg/m2. The dose-limiting toxicity was hypercalcemia (serum calcium greater than 12.5 mg/dl) noted in two of three patients at a dose of 8500 mg/m2. Serum calcium levels between 10.5 and 12.5 mg/dl were noted in an additional three patients treated at doses greater than or equal to 1600 mg/m2. Calcium balance studies in three patients treated at 6500 mg/m2 revealed an increase in urinary cyclic AMP and phosphate excretion after treatment accompanied by a mild elevation of serum parathyroid hormone. Immunological studies in these patients revealed a statistically significant increase in the percentage of peripheral T-helper cells. An increase in the T-helper/suppressor cell ratio was observed in two of the three patients studied. Interleukin 2 production by phytohemagglutinin-stimulated peripheral mononuclear cells was increased in two of three patients. One patient with a renal cell carcinoma showed a mixed response. The recommended dose for phase II trials as assessed from this study is 6500 mg/m2 as a single dose every 28 days.


Subject(s)
Neoplasms/drug therapy , Polymers/therapeutic use , Adult , Aged , Antibodies, Monoclonal , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Calcium/blood , Calcium/urine , Cyclic AMP/urine , Drug Evaluation , Female , Humans , Interleukin-2/biosynthesis , Male , Middle Aged , Phosphates/urine , Polymers/adverse effects , Serum Albumin/analysis
10.
Cancer Res ; 48(16): 4706-10, 1988 Aug 15.
Article in English | MEDLINE | ID: mdl-3396016

ABSTRACT

Crisnatol is a novel lipophilic arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models which functions as a DNA intercalator. In this Phase I trial, a 6-h infusion of the drug was administered i.v. in 700 to 1500 ml of 5% dextrose in water every 28 days. Eighty-five courses at doses of 7.5 to 516 mg/m2 were administered to 43 patients with refractory solid tumors. Reversible neurological toxicity was dose limiting at 516 mg/m2 and was manifested as somnolence, dizziness, blurred vision, unsteady gait, and alpha-slowing on electroencephalogram at the end of infusion. All neurological signs and symptoms were reversible. No hematological toxicity was observed. Other toxicities included phlebitis, mild to moderate nausea and vomiting, reversible sinus node arrest in one patient, and hypertension. Crisnatol plasma concentrations were determined by high-pressure liquid chromatography. After infusion, plasma concentrations declined biexponentially with a terminal t1/2 of 2.9 h. Using a two-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 58.8 liters/m2 and 18.3 liters/h/m2, respectively, indicative of extensive tissue distribution and rapid hepatic clearance. Peak plasma levels occurred at the end of infusion and correlated with the onset of neurological toxicity. The recommended Phase II dose for this schedule is 388 mg/m2.


Subject(s)
Antineoplastic Agents/adverse effects , Chrysenes/adverse effects , Neoplasms/drug therapy , Phenanthrenes/adverse effects , Propylene Glycols , Adult , Aged , Antineoplastic Agents/administration & dosage , Arrhythmias, Cardiac/chemically induced , Blood Pressure/drug effects , Digestive System/drug effects , Drug Administration Schedule , Drug Evaluation , Electroencephalography , Female , Humans , Male , Middle Aged , Nervous System/drug effects
11.
Am J Med ; 84(1): 165-8, 1988 Jan.
Article in English | MEDLINE | ID: mdl-3337120

ABSTRACT

Hypercalcemia has been infrequently associated with Hodgkin's disease. When seen, most cases have been attributable to skeletal invasion by disease. Herein is described a 40-year-old man with a 15-year history of Hodgkin's disease. Each of four disease recurrences was heralded by hypercalcemia occurring in the absence of bone disease or elevation of parathyroid hormone levels. Marked elevations of 1,25-dihydroxyvitamin D levels were observed that paralleled his disease course and response to therapy. The repetitive association of hypercalcemia with an elevation of 1,25-dihydroxyvitamin D in this case provides further evidence of lymphoma-associated production of this vitamin.


Subject(s)
Dihydroxycholecalciferols/blood , Hodgkin Disease/complications , Hypercalcemia/etiology , Adult , Dihydroxycholecalciferols/biosynthesis , Hodgkin Disease/metabolism , Humans , Male
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