ABSTRACT
PURPOSE: Thalidomide is a potent teratogen that causes dysmelia in humans. Recently, in vitro data suggested that it inhibits angiogenesis. Prostate cancer is dependent on the recruitment of new blood vessels to grow and metastasize. Based on those data, we initiated a Phase II trial of thalidomide in patients with metastatic androgen-independent prostate cancer. EXPERIMENTAL DESIGN: This was an open-label, randomized Phase II study. Thalidomide was administered either at a dose of 200 mg/day (low-dose arm) or at an initial dose of 200 mg/day that escalated to 1200 mg/day (high-dose arm). RESULTS: A total of 63 patients were enrolled onto the study (50 patients on the low-dose arm and 13 patients on the high-dose arm). Serum prostate-specific antigen (PSA) decline of > or = 50% was noted in 18% of patients on the low-dose arm and in none of the patients on the high-dose arm. Four patients were maintained for > 150 days. The most prevalent complications were constipation, fatigue, neurocortical, and neurosensory. CONCLUSION: Thalidomide, an antiangiogenesis agent, has some activity in patients with metastatic prostate cancer who have failed multiple therapies. A total of 27% of all patients had a decline in PSA of > or = 40%, often associated with an improvement of clinical symptoms. Because our preclinical studies had shown that thalidomide increases PSA secretion, we believe that the magnitude of PSA decline seen in our trial justifies further study.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Prostatic Neoplasms/drug therapy , Thalidomide/therapeutic use , Aged , Aged, 80 and over , Androgens/physiology , Dose-Response Relationship, Drug , Endothelial Growth Factors/blood , Fibroblast Growth Factor 2/blood , Fibroblast Growth Factor 2/drug effects , Follow-Up Studies , Humans , Lymphokines/blood , Lymphokines/drug effects , Lymphotoxin-alpha/blood , Male , Middle Aged , Mood Disorders/chemically induced , Neovascularization, Pathologic/pathology , Neutropenia/chemically induced , Prostate-Specific Antigen/blood , Prostate-Specific Antigen/drug effects , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/pathology , Survival Analysis , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolism , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.
Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Matrix Metalloproteinase Inhibitors , Neoplasms/drug therapy , Tetracyclines/therapeutic use , Adult , Aged , Antineoplastic Agents/pharmacokinetics , Endothelial Growth Factors/blood , Enzyme Inhibitors/pharmacokinetics , Female , Fibroblast Growth Factor 2/blood , Humans , Lymphokines/blood , Male , Matrix Metalloproteinase 2/blood , Matrix Metalloproteinase 9/blood , Matrix Metalloproteinases/blood , Middle Aged , Statistics, Nonparametric , Tetracyclines/pharmacokinetics , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Neoplasms/drug therapy , Quinolones/therapeutic use , Administration, Oral , Adult , Aged , Anemia/chemically induced , Biological Availability , Bone Marrow/drug effects , Capsules , Drug Administration Schedule , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Farnesyltranstransferase , Fatigue/chemically induced , Female , Half-Life , Headache/chemically induced , Humans , Hypotension/chemically induced , Male , Metabolic Clearance Rate , Middle Aged , Nausea/chemically induced , Peripheral Nervous System Diseases/chemically induced , Quinolones/adverse effects , Quinolones/pharmacokinetics , Solutions , Vomiting/chemically inducedABSTRACT
The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase I trial. After an initial phase in which the pharmacokinetics were assessed, 37 patients with AIDS or symptomatic HIV infection and 100-400 CD4 cells/mm3 were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not appreciably different in the fasting and post-prandial state. The dose limiting toxicity was hepatic transaminase elevation; this could be reduced by escalating the dose over 4 weeks. When administered this way, the maximum tolerated oral dose was 40 mg/kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2-0.3 log10 copies/ml plasma HIV RNA; these decreases persisted through 7-8 weeks of treatment. There was an upward trend in the CD4 count at the 40 mg/kg per day dose but not at other doses. Additional studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted.
Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , HIV Infections/drug therapy , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/pharmacokinetics , Oligopeptides/adverse effects , Oligopeptides/pharmacokinetics , Acquired Immunodeficiency Syndrome/metabolism , Adult , Anti-HIV Agents/adverse effects , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Dose-Response Relationship, Drug , Female , HIV Infections/metabolism , HIV Protease Inhibitors/therapeutic use , HIV-1/drug effects , HIV-1/physiology , Humans , Male , Middle Aged , Oligopeptides/therapeutic use , RNA, Viral/bloodABSTRACT
PURPOSE: To assess the efficacy and maximum dose-intensity of a new topoisomerase I (topo I)-targeting agent, 9-aminocamptothecin (9-AC), in patients with relapsed or refractory lymphomas. PATIENTS AND METHODS: Eligible patients had measurable disease and were considered incurable. 9-AC was infused over 72 hours at an initial dose rate of 40 microg/m2/h every 3 weeks with subsequent intrapatient escalations or reductions in 10-microg/m2/h increments based on toxicity. To assess the impact of granulocyte-colony stimulating factor (G-CSF) on dose-intensity, the first 16 patients received no G-CSF and the subsequent 29 patients received G-CSF on all cycles. RESULTS: Forty-five patients received a total of 142 cycles of 9-AC. The patients' median age was 55 years, 73% had stage IV disease, and histologies included indolent and aggressive non-Hodgkin's lymphoma (NHL) in 33% and 58% of patients, respectively, and Hodgkin's lymphoma in 9%. Patients had received a median of two prior chemotherapy regimens, and 67% of patients had chemotherapy-sensitive disease. Of 40 assessable patients, 10 (25%) achieved a partial response (PR). Chemotherapy-sensitive patients had a 32% response rate compared with 8% in chemotherapy-resistant patients. With a median follow-up duration of 35 months, the median event-free survival (EFS) and overall survival times were 1.5 and 12.5 months, respectively, and the median duration of response was 5 months (range, 1 to 10). G-CSF significantly reduced the incidence of neutropenia and diarrhea, but did not permit a significant increase in dose-intensity. CONCLUSION: 9-AC had a reasonable response rate of 25% in heavily pretreated patients. The low response rate in patients with chemotherapy-resistant disease suggests that there is cross-resistance between 9-AC and standard chemotherapy. However, there was no association between 9-AC response and the number of prior regimens. Due to dose-limiting thrombocytopenia, G-CSF support did not increase dose-intensity, although individual patients benefited from the use of G-CSF.
Subject(s)
Antineoplastic Agents/administration & dosage , Camptothecin/analogs & derivatives , Granulocyte Colony-Stimulating Factor/therapeutic use , Lymphoma/drug therapy , Adult , Aged , Antineoplastic Agents/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Disease-Free Survival , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Humans , Infusions, Intravenous , Lymphoma/pathology , Male , Maximum Allowable Concentration , Middle Aged , RecurrenceABSTRACT
Guidelines for describing cancer chemotherapy regimens in all aspects of drug development, including treatment protocols, order forms, and product labels, are proposed. To complement the approaches to reducing medication errors that have been recommended by ASHP and others, pharmacists at the National Institutes of Health and the National Cancer Institute, with the input of oncology pharmacists from diverse areas of practice, developed guidelines for expressing chemotherapy dosage schedules and treatment regimens. The guidelines present standards that are broadly applicable and can be adopted by other institutions. Clear and unambiguous expression of all medication orders and consistency of treatment descriptions are suggested. Written treatment plans and orders should contain enough information to allow health care providers from diverse disciplines to compare them with published treatment descriptions and investigational protocols and must therefore include planned dosages and schedules expressed in patient-specific units. In general, drug dosages should be expressed as the amount of drug administered from a single container. When ordering drugs that are part of complex or combination-drug regimens, prescribers should write as many of the orders at one time as is possible, so that continuity might be preserved. Standard rules are proposed for describing chemotherapy regimens.
Subject(s)
Antineoplastic Agents/administration & dosage , Drug Administration Schedule , Drug Labeling/standards , Practice Guidelines as Topic , Terminology as Topic , American Medical Association , American Nurses' Association , Education, Pharmacy/standards , Forms and Records Control/standards , Humans , Medication Errors , National Institutes of Health (U.S.) , Societies, Pharmaceutical , United StatesABSTRACT
PURPOSE: To determine if adequate intraocular levels of methotrexate are achieved after intravenous administration. METHODS: After intravenous administration, methotrexate levels were determined in the serum, the anterior chamber, and the cerebrospinal fluids of a patient with recurrent ocular lymphoma. A fluorescence polarization immunoassay was used to make the determinations. RESULTS: At seven hours into a 24-hour intravenous infusion, methotrexate was at cytotoxic level in all samples. At 74 hours, cytotoxic levels were present only in the aqueous humor. CONCLUSION: Sustained cytotoxic ocular methotrexate levels are achievable after systemic administration.
Subject(s)
Antimetabolites, Antineoplastic/pharmacokinetics , Aqueous Humor/metabolism , Methotrexate/pharmacokinetics , Anterior Chamber/metabolism , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/therapeutic use , Biological Availability , Cerebrospinal Fluid/metabolism , Eye Neoplasms/drug therapy , Eye Neoplasms/metabolism , Female , Fluorescence Polarization Immunoassay , Humans , Infusions, Intravenous , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/metabolism , Methotrexate/administration & dosage , Methotrexate/therapeutic use , Middle AgedABSTRACT
PURPOSE: In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients. PATIENTS AND METHODS: Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration. RESULTS: Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels. CONCLUSION: Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Paclitaxel/administration & dosage , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Blood Cell Count/drug effects , Cyclophosphamide/administration & dosage , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Hypersensitivity/drug therapy , Drug Hypersensitivity/etiology , Equipment Failure , Erythrocyte Transfusion , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematologic Diseases/blood , Hematologic Diseases/chemically induced , Hematologic Diseases/therapy , Hematuria/chemically induced , Hematuria/drug therapy , Home Infusion Therapy/instrumentation , Humans , Mesna/therapeutic use , Middle Aged , Neoplasm MetastasisABSTRACT
PURPOSE: Dexverapamil is a competitive inhibitor of the P-glycoprotein (Pgp) efflux pump, a potent mechanism of multidrug resistance (mdr-1) in vitro. We performed a phase I study to determine the maximum-tolerated dose (MTD) and pharmacokinetics of dexverapamil with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. PATIENTS AND METHODS: Eligible patients had relapsed or refractory lymphoma or sarcoma. Patients initially received EPOCH alone, and those with stable or progressive disease were crossed-over to received dexverapamil on subsequent cycles of EPOCH. Dexverapamil was administered orally for 6 days and escalated over eight dose levels ranging from 240 to 1,200 mg/m2/d. Pharmacokinetics of dexverapamil and its active metabolite, nor-dexverapamil, were obtained in most patients. In seven patients, pharmacokinetics of doxorubicin, doxorubicinol, and etoposide were determined on paired cycles of EPOCH with or without dexverapamil. RESULTS: Sixty-five patients received 130 cycles of dexverapamil/EPOCH chemotherapy. The MTD of dexverapamil was 150 mg/m2 every 4 hours (900 mg/m2/d), and hypotension was the principal dose-limiting toxicity. The dexverapamil area under the curve (AUC) increased proportionally with dexverapamil dose, but significant interpatient variation occurred. At the MTD, the median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 mumol/L, respectively. Dexverapamil did not affect the steady-state concentration (Css) of etoposide, but increased the Css of doxorubicin and doxorubicinol nearly twofold. The absolute neutrophil and platelet nadirs were significantly lower on the dexverapamil cycles compared with cycles of EPOCH alone, but other chemotherapy-related toxicities did not change. CONCLUSION: The phase II recommended dose of dexverapamil with EPOCH is 150 mg/m2 every 4 hours. This dose was well tolerated on an outpatient basis and achieved plasma concentrations of dexverapamil and nor-dexverapamil within the effective range for Pgp inhibition in vitro. Although dexverapamil increased the hematopoietic toxicity of EPOCH, it was mild, readily reversible, and offset by EPOCH dose reductions. Dexverapamil should be considered for further study.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Verapamil/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cross-Over Studies , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Doxorubicin/pharmacokinetics , Drug Resistance, Multiple , Etoposide/administration & dosage , Etoposide/adverse effects , Etoposide/pharmacokinetics , Female , Humans , Hypotension/chemically induced , Leukocyte Count/drug effects , Lymphoma/blood , Lymphoma/drug therapy , Male , Middle Aged , Neutrophils , Platelet Count/drug effects , Prednisone/administration & dosage , Prednisone/adverse effects , Sarcoma/blood , Sarcoma/drug therapy , Stereoisomerism , Verapamil/adverse effects , Verapamil/analogs & derivatives , Verapamil/blood , Verapamil/pharmacokinetics , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
BACKGROUND: The growth-inhibiting and differentiating effects of sodium phenylacetate against hematopoietic and solid tumor cell lines has aroused clinical interest in its use as an anticancer drug. In an earlier Phase I trial of phenylacetate aimed at maintaining serum drug concentrations in the range that proved active in vitro (> 250 micrograms/ml) for 2 consecutive weeks, infusion rates approached the maximum velocity of drug elimination and commonly resulted in drug accumulation and reversible dose-limiting neurologic toxicity. In this study, the authors described the nonlinear pharmacokinetics, metabolism, toxicity, and clinical activity of phenylacetate. METHODS: The treatment regimen of this Phase I study was designed to expose patients intermittently to drug concentrations exceeding 250 micrograms/ml and to allow time for drug elimination to occur between doses to minimize accumulation. Sodium phenylacetate was administered as a 1-hour infusion twice daily (8 a.m., 5 p.m.) at two dose levels of 125 and 150 mg/kg for a 2-week period. Therapy was repeated at 4-week intervals for patients who did not experience dose-limiting toxicity or disease progression. RESULTS: Eighteen patients (4 of whom previously were treated with phenylacetate by continuous intravenous infusion) received 27 cycles of therapy. Detailed pharmacokinetic studies for eight patients indicated that phenylacetate induced its own clearance by a factor of 27% in a 2-week period. Dose-limiting toxicity, consisting of reversible central nervous system depression, was observed for three patients at the second dose level. One patient with refractory malignant glioma had a partial response, and one with hormone-independent prostate cancer achieved a 50% decline in prostate specific antigen level, which was maintained for 1 month. CONCLUSIONS: Phenylacetate administered at a dose of 125 mg/kg twice daily for 2 consecutive weeks is well tolerated. High grade gliomas and advanced prostate cancer are reasonable targets for Phase II clinical trials.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Neoplasms/drug therapy , Phenylacetates/administration & dosage , Phenylacetates/pharmacokinetics , Adult , Aged , Antineoplastic Agents/toxicity , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Phenylacetates/toxicityABSTRACT
BACKGROUND: Somatuline, a somatostatin analogue, has proven to be effective in several animal models of prostate cancer. Preliminary clinical studies also have suggested antitumor activity in patients with prostate cancer. The authors conducted a dose-escalation trial of 25 patients with metastatic hormone-refractory prostate cancer. METHODS: Dosages of 4, 7, 10, 13, 18, and 24 mg/day were administered by continuous intravenous infusion for at least 28 days. RESULTS: Plasma levels of insulin-like growth factor-I (IGF-I), but not those of IGF-II, declined modestly during therapy. Toxicities included grade I diarrhea, bloating, infection, nausea, and flatus. The gastrointestinal side effects were typically self-limiting and occurred during the initial portion of treatment cycles. In addition, three patients experienced grade II catheter-related infections. No clinical response was noted by either radiographic or tumor marker criteria. The maximally tolerated dose of somatuline was not determined. CONCLUSION: A continuous intravenous infusion of 24 mg/day of somatuline is well tolerated and could be evaluated in other types of cancer or possibly in less advanced prostate cancer, but no clinical activity was noted at this dose in patients with advanced metastatic hormone-refractory prostate cancer.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms, Hormone-Dependent/drug therapy , Octreotide/analogs & derivatives , Peptides, Cyclic , Prostatic Neoplasms/drug therapy , Somatostatin/analogs & derivatives , Aged , Aged, 80 and over , Amino Acid Sequence , Antineoplastic Agents/administration & dosage , Drug Administration Schedule , Humans , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor II/analysis , Male , Middle Aged , Molecular Sequence Data , Neoplasms, Hormone-Dependent/blood , Octreotide/administration & dosage , Octreotide/therapeutic use , Prostate-Specific Antigen/blood , Prostatic Neoplasms/bloodSubject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Metoclopramide/therapeutic use , Ondansetron/therapeutic use , Vomiting/chemically induced , Vomiting/prevention & control , Carboplatin/administration & dosage , Cisplatin/administration & dosage , Female , Humans , Research DesignABSTRACT
Paclitaxel is a novel antineoplastic that effects cytotoxicity by promoting intracellular tubulin polymerization and stabilizes abnormal microtubule structures against depolymerization. Although its clinical development had been hampered by misconceptions about its pharmacology, its scarcity, difficulties extracting it from its natural source, formulation problems, and frequent severe hypersensitivity reactions, paclitaxel recently was approved for treatment-refractory ovarian cancer. Two major adverse effects are dosage- and schedule-related myelosuppression and mucositis. Neurotoxicity is directly related to both the individual and cumulative doses. Other relevant toxicities are hypersensitivity reactions, effects on cardiac rate and rhythm, arthralgias and myalgias, generalized hair loss, and mild nausea and emesis. Continuing clinical studies will evaluate paclitaxel as initial therapy for ovarian cancer and its utility in other malignancies. In addition, major efforts are under way to develop alternative sources to increase the availability of taxene analogs and reduce our dependence on yew species.
Subject(s)
Neoplasms/drug therapy , Ovarian Neoplasms/drug therapy , Paclitaxel , Clinical Trials as Topic , Female , Humans , Injections, Intraperitoneal , Paclitaxel/adverse effects , Paclitaxel/pharmacokinetics , Paclitaxel/pharmacology , Paclitaxel/therapeutic useABSTRACT
PURPOSE: Based on in vitro evidence that tumor cells are less resistant to prolonged exposure to low concentrations of the natural product class, compared with brief higher concentration exposure, we developed a chemotherapy regimen (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]) in which the natural products are administered as a continuous infusion. PATIENTS AND METHODS: This is a phase II study of etoposide, vincristine, and doxorubicin, administered as a 96-hour continuous infusion, with intravenous (IV) bolus cyclophosphamide and oral prednisone (EPOCH) in 74 consecutive patients who relapsed from or failed to respond to most of the same drugs administered on a bolus schedule. Patients with aggressive lymphomas who achieved a good response after EPOCH were eligible to undergo bone marrow transplantation. RESULTS: Patients with intermediate- or high-grade lymphoma comprised 76% of this series and 77% had stage IV disease. Seventy-one percent had previously received all of the drugs contained in the EPOCH regimen and 92% had received at least four of the drugs. Seventy patients were assessable for response, of whom 19 (27%) achieved a complete remission (CR) and 42 (60%) a partial remission (PR). Among 21 patients who had no response to prior chemotherapy, 15 (71%) responded, but only one achieved a CR. Patients who relapsed from an initial CR had a 100% response rate, with 76% CRs. With a median potential follow-up duration of 19 months, there was a 28% probability of being event-free at 1 year. Toxicity was primarily hematologic with neutropenia during 51% of cycles, but only a 17% incidence of febrile neutropenia. Gastrointestinal, neurologic, and cardiac toxicity were minimal. CONCLUSION: EPOCH chemotherapy was well tolerated and highly effective in patients who were resistant to or relapsed from the same drugs administered on a bolus schedule, suggesting that continuous infusion of the natural drug component of this regimen is capable of partially reversing drug resistance and reducing toxicity. Dose-intensity (DI) was > or = that achieved in primary treatment regimens for aggressive lymphomas.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Drug Administration Schedule , Drug Resistance , Etoposide/administration & dosage , Female , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Infusions, Intravenous , Male , Middle Aged , Neutropenia/chemically induced , Neutropenia/drug therapy , Prednisone/administration & dosage , Recurrence , Survival Analysis , Treatment Outcome , Vincristine/administration & dosageABSTRACT
Suramin, a drug used in the treatment of parasitic diseases, is currently being evaluated in clinical trials as an antineoplastic agent. The use of therapeutic drug monitoring and adaptive control with feedback in clinical trials of suramin was initially motivated by an association between acute neurologic toxicity and plasma suramin concentrations in excess of 350 micrograms/ml. We have prospectively examined the performance of both two- and three-compartment population pharmacokinetic models in controlling plasma suramin concentrations and have found that a three-compartment model best describes this drug. No correlation was found between the clearance of suramin and creatinine clearance, as had been previously hypothesized. The low systemic clearance of suramin and the number of parameters required to describe the three-compartment model suggest the need for a bayesian approach to the estimation of individual pharmacokinetics.
Subject(s)
Adrenal Gland Neoplasms/drug therapy , Antineoplastic Agents/administration & dosage , Drug Monitoring/methods , Suramin/administration & dosage , Adrenal Gland Neoplasms/blood , Bayes Theorem , Creatinine/pharmacokinetics , Humans , Infusions, Intravenous , Models, Biological , Nervous System Diseases/blood , Nervous System Diseases/chemically induced , Prospective Studies , Software , Suramin/adverse effects , Suramin/pharmacokineticsABSTRACT
The physicochemical properties, pharmacology, pharmacokinetics, serum concentrations and clinical effects, adverse effects and contraindications, and dosage of transdermally administered fentanyl are described, and clinical studies evaluating the use of a transdermal fentanyl system in the treatment of postoperative pain and chronic cancer-associated pain are reviewed. After application of a transdermal system, fentanyl is absorbed into the skin beneath the patch, where a depot forms in the upper skin layers. Plasma fentanyl concentrations are barely detectable for about two hours after patch placement. Eight to 12 hours after patch placement, concentrations approximate those achieved with equivalent i.v. doses of fentanyl. Some studies comparing transdermally administered fentanyl with placebo in postoperative patients showed that the patients who received fentanyl required fewer supplementary analgesics and reported less pain than the patients who received placebo. However, the overall efficacy and safety of the transdermal fentanyl system for the treatment of postoperative pain have not been adequately evaluated. Studies of cancer patients showed that transdermally administered fentanyl appears to be effective in the management of chronic, cancer-related pain. Dermatological reactions to the fentanyl patch are generally transient and mild. Other adverse effects are those that are commonly associated with narcotic analgesics. The 25-micrograms/hr patch should be used for initial treatment in patients not previously treated with narcotics. The dosage may be gradually increased until effective analgesia is obtained. Although experience with the product is limited, transdermally administered fentanyl appears to be effective for the long-term management of cancer-related pain.
Subject(s)
Fentanyl/administration & dosage , Pain/drug therapy , Administration, Cutaneous , Animals , Chronic Disease , Contraindications , Fentanyl/pharmacokinetics , Fentanyl/pharmacology , Humans , Neoplasms/physiopathology , Pain, Postoperative/drug therapy , Patient Education as Topic , Tissue DistributionABSTRACT
Goserelin acetate implant is a newly approved depot formulation of a luteinizing hormone-releasing hormone (LHRH) agonist indicated for palliation of advanced prostate cancer. LHRH superagonists suppress gonadotropin release from the pituitary gland by causing down-regulation of receptors. The sustained-release dosage form contains goserelin acetate dispersed in a biodegradable copolymer matrix and is designed to release active drug over 28 days. Pharmacokinetic studies have demonstrated that, despite nonzero order release of goserelin from the matrix, goserelin acetate implant maintains serum concentrations of testosterone in the range normally found in castrated men (less than 2 nmol/L) throughout the recommended 28-day dosing interval. Response rates similar to those for orchiectomy and estrogen administration have been demonstrated. Combination therapy with either diethylstilbestrol or flutamide has produced favorable results, although the major advantage appears to be a reduction in the tumor flare seen during the first week of LHRH agonist therapy rather than an increase in response rate or survival. Adverse effects are similar to other LHRH agonists and include tumor flare during the first week of therapy, decreased libido, decreased erectile potency, hot flashes, and gynecomastia. In combination with flutamide, additional adverse effects include diarrhea, nausea, vomiting, and elevated hepatic aminotransferases, all of which can be attributed to flutamide administration. Local reactions are minimal; however, some patients require a local anesthetic before goserelin acetate implant injection. The recommended dose is 3.6 mg administered subcutaneously into the upper abdominal wall every 28 days. The average wholesale cost is approximately +320 per month. Formulary addition is recommended.
Subject(s)
Buserelin/analogs & derivatives , Prostatic Neoplasms/drug therapy , Amino Acid Sequence , Buserelin/administration & dosage , Buserelin/chemistry , Buserelin/pharmacokinetics , Buserelin/therapeutic use , Delayed-Action Preparations , Drug Implants , Goserelin , Humans , Male , Molecular Sequence DataABSTRACT
Ondansetron represents a new class of drugs that exert their antiemetic activity by selective inhibition of a serotonin receptor subtype (5-HT3). Ondansetron has marked activity against emesis associated with cisplatin and other highly emetogenic drugs. Compared with high doses of metoclopramide, the antiemetic "gold standard," it demonstrates equal or superior efficacy. Although ondansetron is moderately well absorbed after oral administration, only a parenteral formulation will initially be available. Ondansetron is eliminated almost entirely by hepatic metabolism; less than five percent of an intravenously administered dose is recovered intact in urine. The half-life of ondansetron is approximately 3.5 hours; slightly shorter in children and prolonged in the elderly. Neither clinical efficacy nor adverse effects have correlated with serum concentrations. Ondansetron is generally well tolerated. Clinically relevant adverse effects include headache, diarrhea or constipation, sedation, and transient minor elevations of liver function tests. It is not associated with extrapyramidal reactions. Ondansetron is indicated as prophylaxis for nausea and vomiting associated with emetogenic chemotherapy. Studies to further evaluate and define its use are ongoing.