Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil.

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and pharmacokinetics of oral fluorouracil (5-FU) administered twice daily in combination with oral eniluracil, an inactivator of dihydropyrimidine dehydrogenase, administered for 28 days every 35 days. PATIENTS AND METHODS: Oral 5-FU 1.35 mg/m(2) twice daily was administered with oral eniluracil 10 mg daily for 14 to 28 days, followed by a 1-week rest period. Eniluracil was started 1 day before 5-FU. Patients then received escalated doses of oral 5-FU 1. 35 to 1.8 mg/m(2) twice daily with an increased dose of eniluracil 10 mg twice daily for 28 days. A reduced dose of 5-FU 1.0 mg/m(2) with eniluracil 20 mg twice daily was evaluated. RESULTS: Thirty-six patients with solid malignancies were enrolled onto the study. Diarrhea was the principal dose-limiting toxicity of oral 5-FU and eniluracil given on this chronic schedule. The recommended phase II dose is 5-FU 1.0 mg/m(2) twice daily with eniluracil 20 mg twice daily. Mean (SD) values for terminal half-life, apparent volume of distribution, and systemic clearance of 4.5 hours (0.83 hours), 19 L/m(2) (3.0 L/m(2)), and 51 mL/min/m(2) (13 mL/min/m(2)), respectively. An average of 77% of 5-FU was excreted unchanged in urine after 28 days of treatment. The mean (range) 5-FU C(SS,min) values achieved at the 1.0 mg/m(2) dose level were 22 ng/mL (8 to 38 ng/mL). CONCLUSION: Chronic oral administration of 5-FU with oral eniluracil is tolerable and produces 5-FU steady-state concentrations similar to those achieved with protracted intravenous administration of 5-FU on clinically relevant dose schedules. Eniluracil provides an attractive means of administering 5-FU on protracted schedules.

Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer.

The purpose of this study is to characterize the absorption, metabolism, and excretion of carbon 14-labeled temozolomide (14C-TMZ) administered p.o. to adult patients with advanced solid malignancies. On day 1 of cycle 1, six patients received a single oral 200-mg dose of 14C-TMZ (70.2 microCi). Whole blood, plasma, urine, and feces were collected from days 1-8 and on day 14 of cycle 1. Total radioactivity was measured in all samples. TMZ, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) concentrations were determined in plasma, and urine and plasma samples were profiled for metabolite/degradation products. Maximum TMZ plasma concentrations were achieved between 0.33 to 2 h (mean, 1.2 h), and half-life, apparent volume of distribution, and oral clearance values averaged 1.9 h, 17 liters/m2, and 104 ml/min/m2, respectively. A first-order absorption, one-compartment linear model, which included first-order formation of MTIC from TMZ and elimination of MTIC via degradation to AIC, and a peripheral distribution compartment for AIC, adequately described the plasma TMZ, MTIC, and AIC concentrations. MTIC systemic clearance was estimated to be 5384 ml/min/m2, and the half-life was calculated to be 2.5 min. Metabolite profiles of plasma at 1 and 4 h after treatment showed that 14C-derived radioactivity was primarily associated with TMZ, and a smaller amount was attributed to AIC. Profiles of urine samples from 0-24 h revealed that 14C-TMZ-derived urinary radioactivity was primarily associated with unchanged drug (5.6%), AIC (12%), or 3-methyl-2,3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxyl ic acid (2.3%). The recovered radioactive dose (39%) was principally eliminated in the urine (38%), and a small amount (0.8%) was excreted in the feces. TMZ exhibits rapid oral absorption and high systemic availability. The primary elimination pathway for TMZ is by pH-dependent degradation to MTIC and further degradation to AIC. Incomplete recovery of radioactivity may be explained by the incorporation of AIC into nucleic acids.

Phase I and pharmacological study of CI-980, a novel synthetic antimicrotubule agent.

CI-980 (NSC 613862) is one of a novel class of 1,2-dihydropyrido[3, 4-b]pyrazines that inhibits tubulin polymerization, presumably by binding to the colchicine binding site of tubulin. In a Phase I and pharmacological study, 16 patients with advanced solid neoplasms were treated with CI-980 on a continuous 72-h infusion schedule at doses ranging from 3.0-5.4 mg/m2/day every 3 weeks. High rates of central nervous system (CNS) toxicity and neutropenia occurred in both minimally and heavily pretreated patients who were treated with CI-980 doses above 3.75 mg/m2/day, which is the maximum tolerated dose and the recommended dose for additional evaluations. CNS effects, characterized by neurocortical, mood, and cerebellar manifestations, were generally observed toward the end of the infusion and immediately posttreatment and usually resolved within 48 h after the completion of treatment. Toxicity was mild to modest at the 3.75 mg/m2/day dose level. Neither clinical nor pharmacological risk factors that may predispose patients to the development of CNS effects were evident. Although no objective antineoplastic activity was observed in this Phase I study, CI-980 steady-state plasma concentrations achieved at the recommended dose of 3.75 mg/m2/day (mean +/- SE, 5.74 +/- 0.54 nM) approached and exceeded concentrations that have been associated with significant activity in preclinical studies, indicating that additional disease-directed evaluations of CI-980 may be warranted.

Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer.

This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m2 followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m2, which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m2 as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted.

Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence.

PURPOSE: A phase I and pharmacologic study was performed to evaluate the feasibility of administering the topoisomerase I (topo I) inhibitor topotecan (TPT) in combination with cisplatin (CDDP) in minimally pretreated adults with solid tumors. The study was designed to evaluate the magnitude of the toxicologic and pharmacologic differences between the two sequences of drug administration. MATERIALS AND METHODS: TPT was administered as a 30-minute infusion daily for 5 days and CDDP was given either before TPT on day 1 or after TPT on day 5. Each patient was treated with both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or CDDP resulted in three dosage permutation of TPT/CDDP (mg/m2): 0.75/50, 1/50, and 0.75/75. After the maximum-tolerated dose (MTD) level was achieved, the feasibility of using granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was studied. To examine the interaction of TPT and CDDP in vitro, human A549 lung cancer cells were exposed to these agents concurrently and sequentially. RESULTS: Dose-limiting neutropenia and thrombocytopenia resulted after the doses of TPT or CDDP were increased to greater than 0.75 and 50 mg/m2, respectively, without and with G-CSF. The sequence of CDDP before TPT induced significantly worse neutropenia and thrombocytopenia than the alternate sequence. In vitro studies failed to provide any evidence for the differences in the cytotoxicity of these two sequences. Instead, pharmacokinetic studies suggested that the differences in toxicity were due, in part, to lower TPT clearance and exposure when CDDP preceeds TPT, possibly due to subclinical renal tubular toxicity induced by CDDP. CONCLUSION: The sequence of CDDP before TPT at doses of 50 and 0.75 mg/m2, respectively, is recommended for subsequent clinical trials in tumor types in which both agents have significant single-agent activity. The potential for sequence-dependent cytotoxic, toxicologic, and pharmacologic effects should be evaluated in concurrent clinical and laboratory studies in the course of developing combination chemotherapy regimens that consist of topo I-targeting agents and other antineoplastic agents, particularly DNA-damaging agents.

Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase.

PURPOSE: To study the absolute bioavailability and pharmacokinetics of an oral solution of fluorouracil (5-FU) in patients treated with 776C85, an oral inactivator of dihydropyrimidine dehydrogenase (DPD), and to evaluate the feasibility of administering oral 5-FU and 776C85 on a multiple-daily dosing schedule. PATIENTS AND METHODS: Twelve patients with refractory solid tumors were enrolled onto this three-period study. In periods 1 and 2, patients were randomly assigned to treatment with 5-FU 10 mg/m2 on day 2 given by either the oral or intravenous (IV) route with oral 776C85 3.7 mg/m2/d on days 1 and 2. In period 3, patients received escalating doses of 5-FU (10 to 25 mg/ m2/d) orally for 5 days (days 2 to 6) with 776C85 3.7 mg/m2/d orally (days 1 to 7) every 4 weeks. Pharmaco-kinetic studies were performed in periods 1 and 2, and after the fifth oral dose of 5-FU in period 3. RESULTS: Twelve patients completed the bioavailability and pharmacokinetic studies. Following oral 5-FU 10 mg/m2, the bioavailability was 122% +/- 40% (mean +/- SD), the terminal half-life (t1/2 beta) was 4.5 +/- 1.6 hours, the apparent volume of distribution (V beta) was 21.4 +/- 5.9 L/ m2, and the systemic clearance (Clsys) was 57.6 +/- 16.4 mL/min/m2. A correlation was observed between oral 5-FU systemic clearance and calculated creatinine clearance (r = .74; P = .009). Multiple-daily dosing did not appear to affect the pharmacokinetics of oral 5-FU. Neutropenia was the principal toxicity of oral 5-FU and 776C85, precluding escalation of oral 5-FU to doses greater than 25 mg/m2/d for 5 days every 4 weeks with 776C85. CONCLUSION: The oral DPD inactivator 776C85 enables oral administration of 5-FU and may alter conventional 5-FU administration practices.

A phase I and pharmacological study of topotecan infused over 30 minutes for five days in patients with refractory acute leukemia.

The principal objectives of this study were to determine the feasibility of escalating doses of the hydrophilic topoisomerase I (topo I) inhibitor topotecan (TPT) as a 30-min infusion daily for 5 days in adults with refractory or relapsed acute leukemia and to study the pharmacokinetic behavior of high doses of TPT and pharmacodynamic determinants of TPT activity. Fourteen patients received 27 courses of TPT at doses ranging from 3.5 to 5.75 mg/m2/day every 3 weeks. A constellation of unusual adverse effects, consisting of high fever, rigors, precipitous anemia, and hyperbilirubinemia, was the principal dose-limiting toxicity of high doses of TPT on this schedule. These toxicities were consistently intolerable at the 5.75 mg/m2/day dose level; however, they were neither severe nor common at lower doses. Although the precise etiology of these effects is not known, high doses of TPT may induce acute hemolytic reactions in this patient population. Severe, albeit transient, mucositis was experienced by two of eight patients in 2 of 17 courses at the next lower dose level, 4.5 mg/m2/day, which was determined to be the maximum tolerated dose and the dose recommended for further trials. The pharmacokinetic behavior of TPT at high doses was not dose dependent and resembled that at lower doses. In view of preclinical data suggesting that TPT sensitivity might correlate with topo I levels, topo I content in leukemia blasts was assessed by Western blotting. Variations in topo I content were observed. Moreover, strong correlations were evident between topo I content and two markers of proliferation, proliferating cell nuclear antigen and nuclear protein B23, raising the possibility that differences in topo I content observed among various leukemia specimens might reflect differences in the proliferating fractions of cells in various leukemia samples. Although complete clearance of circulating leukemia blasts occurred in most courses, neither sustained responses nor hematopoietic recovery were observed in the heavily pretreated, poor-risk patients enrolled in this study, and it was not possible to correlate these differences in topo I content with clinical response. These results indicate that substantial dose escalation of TPT as a 30-minute infusion for a 5-day schedule above myelosuppressive doses is feasible in adults with refractory or relapsed leukemias; however, further development of alternate high-dose schedules in leukemia may be warranted in view of the nature of the dose-limiting toxicity and the lack of sustained clinical responses in this preliminary investigation.

Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topotecan with granulocyte colony-stimulating factor in patients with solid tumors.

PURPOSE: To evaluate the feasibility of escalating doses of the topoisomerase I (topo I) inhibitor topotecan (TPT) with granulocyte colony-stimulating factor (G-CSF) in minimally pretreated adults with solid tumors and to study whether G-CSF scheduling variably affects the ability to escalate TPT doses. MATERIALS AND METHODS: Thirty-six patients received 121 courses of TPT as a 30-minute infusion daily for 5 days every 3 weeks at doses that ranged from 2.0 to 4.2 mg/m2/d. G-CSF 5 microg/kg/d subcutaneously (SC) was initiated concurrently with TPT (starting on day 1). Because the concurrent administration of TPT and G-CSF resulted in severe myelosuppression at the lowest TPT dose level, an alternate posttreatment G-CSF schedule in which G-CSF dosing began after TPT (starting on day 6) was subsequently evaluated. Plasma sampling was performed to characterize the pharmacologic behavior of high-dose TPT and to determine whether G-CSF altered the pharmacokinetic profile of TPT. RESULTS: Severe myelosuppression precluded the administration of TPT at the first dose, 2.0 mg/m2/d, with G-CSF on the concurrent schedule. However, dose escalation of TPT with G-CSF on a posttreatment schedule proceeded to 4.2 mg/m2/d. The dose-limiting toxicities (DLTs) were thrombocytopenia and neutropenia. One partial response was noted in a patient with colorectal carcinoma refractory to fluoropyrimidines. Pharmacokinetics were linear within the dosing range of 2.0 to 3.5 mg/m2/d, but TPT clearance was lower at the 4.2-mg/m2/d dose level. At 3.5 mg/m2/d, which is the maximum-tolerated dose (MTD) and recommended dose for subsequent-phase studies of TPT with G-CSF, the area under the concentration-versus-time curves (AUCs) for total TPT and lactone averaged 2.2- and 2.3-fold higher, respectively, than the AUCs achieved at the lowest TPT dose, 2.0 mg/m2/d. The pharmacologic behavior of high-dose TPT was not significantly altered by the scheduling of G-CSF. CONCLUSION: G-CSF administered after 5 daily 30-minute infusions of TPT permits a 2.3-fold dose escalation of TPT above the MTD in solid-tumor patients, whereas concurrent therapy with G-CSF and TPT results in severe myelosuppression.

The effects of food and divided dosing on the bioavailability of oral vinorelbine.

The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors. A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80 mg/m2 per week either in the fasting state or after ingestion of a standard meal. Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m2 per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22 +/- 28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (Tmax) increased from 1.3 +/- 1.6 h in the fasting state to 2.5 +/- 1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16 +/- 51% when vinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized Cmax and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbine indicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity.

Phase I study of paclitaxel as a 3-hour infusion followed by carboplatin in untreated patients with stage IV non-small cell lung cancer.

Preliminary results of a phase I study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given by 3-hour infusion, followed by carboplatin in chemotherapy-naive patients with stage IV non-small cell lung cancer indicate that both agents can be combined at clinically relevant single-agent doses. The paclitaxel (mg/m2)/carboplatin area under the concentration-time curve (mg.min/mL) dose level of 225/7 is projected to be the maximally tolerated and recommended phase II dose level for future evaluations. Dose-limiting neutropenia, thrombocytopenia, and nausea and vomiting preclude treatment with carboplatin doses estimated to target an area under the concentration-time curve of 9 mg.min/mL when given with paclitaxel 225 mg/m2. The heterogeneous nature of the principal toxicities, as well as the ability to administer clinically relevant single-agent doses of both agents in combination, also indicate that further dose escalation of paclitaxel and carboplatin using hematopoietic growth factors would not be feasible. The preliminary antitumor activity noted to data, as well as the safety associated with the clinically relevant single-agent doses that can be given in combination, indicate that phase II/III evaluations of this regimen are warranted in patients with both advanced and early stage non-small cell lung cancer.

Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors.

PURPOSE: The feasibility of administering vinorelbine (Navelbine, Burroughs Wellcome Co, Research Triangle Park, NC), a semisynthetic vinca alkaloid with broad activity, as a liquid-filled gelatin capsule was evaluated in a bioavailability (F) and pharmacokinetic study. PATIENTS AND METHODS: Each of 17 cancer patients had pharmacokinetic studies performed after receiving vinorelbine 30 mg/m2 intravenously (IV), which is the maximum-tolerated dose (MTD) for weekly IV administration, and twice after receiving the oral formulation at a nominal dose of 100 mg/m2. Subsequently, these patients and 10 other subjects received the oral formulation at a dose of 100 mg/m2/wk to evaluate the feasibility of chronic oral administration. RESULTS: Plasma drug disposition was well described by a triphasic model. Mean central volume of distribution and steady-state volume of distribution (Vss) were large (0.66 +/- 0.46 L/kg and 20.02 +/- 8.55 L/kg, respectively); the mean harmonic terminal half-life (t1/2) was long (18 hours); and the high mean clearance (CI) rate (0.80 +/- 0.68 L/h/kg) approached hepatic blood flow. F was low (0.27 +/- 12), and absorption was rapid (mean time of maximum plasma concentration [Tmax], 0.91 +/- 0.22 hours). Absorption parameters after the first and second oral doses were similar, with mean F values of 0.27 +/- 0.14 and 0.25 +/- 0.11, respectively. Coefficients of variability (CVs) for F, maximum plasma concentration (Cmax), and Tmax were 32%, 42%, and 78%, respectively, indicating moderate intraindividual variability. The pharmacologic profile of this oral formulation indicates that there is a large first-pass effect. Neutropenia was the principal toxicity of oral vinorelbine. Grade 3 or 4 neutropenia occurred in 63% of patients, but only 11% developed neutropenia and infection. Nausea, vomiting, and diarrhea were also common with oral administration, but these effects were rarely severe and could be ameliorated by using a divided-dose schedule and/or prophylactic antiemetic and antidiarrheal agents. The mean nominal oral dose was 82 mg/m2, and the mean percentage of intended dose that was received was 92%. Although dose escalations were permitted for negligible toxicity, doses were not escalated to greater than 100 mg/m2/wk in any patient. Vinorelbine given as a liquid-filled gelatin capsule at 100 mg/m2 provided equivalent pharmacologic exposure as 30 mg/m2 IV. CONCLUSION: The oral administration of vinorelbine, specifically as a liquid-filled, soft gelatin capsule, is a feasible route of administration. Weekly oral dosing at 100 mg/m2 induces a consistent degree of myelosuppression, but the high frequency of grade 3 or 4 neutropenia, albeit brief and uncomplicated, warrants the recommendation of a slightly lower starting dose, ie, 80 mg/m2/d, for subsequent phase II evaluations, especially in heavily pretreated patients.

Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies.

Taxol is a novel antineoplastic agent that has demonstrated impressive clinical activity in breast, ovarian, lung, and head and neck cancers. This broad antitumor activity of taxol in cisplatin-sensitive tumors suggests that the combination of taxol and cisplatin may become one of the most commonly used taxol-based chemotherapeutic regimen in the treatment of solid tumors. Both taxol and cisplatin, however, are neurotoxic. To study the neurotoxic effects of these two agents when used in combination, we prospectively evaluated neurological function at baseline, during, and following treatment, in 21 cancer patients treated with taxol (135-350 mg/m2), cisplatin (75-100 mg/m2), and granulocyte-colony stimulating factor (5 micrograms/kg). Twenty of the 21 patients (95%) developed a sensory-motor neuropathy 1 to 21 weeks after the initiation of therapy, that was progressive with each additional course of chemotherapy. The neuropathy was symmetrical, length dependent, axonal in nature by physiological studies, and more pronounced in those patients who received higher doses of taxol. The neuropathy appeared earlier and at lower taxol doses in those patients with preexisting neuropathies. We conclude that sensory-motor neuropathy is a frequent dose-dependent toxicity of combined cisplatin and taxol use. Peripheral neuropathy is likely to become the major dose-limiting toxicity of taxol-cisplatin combination chemotherapy when higher doses of these agents are administered with granulocyte-colony stimulating factor.

Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11; Irinotecan), a semisynthetic analogue of camptothecin (CPT) with broad preclinical antitumor activity, has demonstrated impressive activity in phase II trials in Japan in advanced small and non-small cell lung, colorectal, cervical, and ovarian carcinomas, as well as in refractory lymphomas and leukemias. In this phase I and pharmacological study, 90-min infusions of CPT-11 were administered every 3 weeks at doses ranging from 100 to 345 mg/m2 to patients with solid malignancies. Acute, severe, and refractory vomiting, diarrhea, and/or abdominal cramps associated with flushing, warmth, and diaphoresis occurred in the immediate posttreatment period at the 240-mg/m2 dose level in several patients who were not treated with premedications. The characteristics and temporal nature of these toxicities, the prompt resolution of symptoms following treatment with diphenhydramine, and the successful use of a premedication regimen consisting of ondansetron and diphenhydramine in preventing these acute effects suggest that vasoactive substances are involved in the mediation of these acute toxicities. With the routine use of these premedications, there was no single toxicity type that limited the escalation of CPT-11 doses. Instead, a constellation of severe hematological and gastrointestinal effects precluded the repetitive administration of CPT-11 at doses above 240 mg/m2, the maximum tolerated dose and recommended phase II dose on this schedule. Major responses were observed in patients with advanced colorectal, cervical, and renal cancers. The disposition of total CPT-11 in plasma was fit by a biexponential kinetic model with renal elimination accounting for 37 +/- 4% (SE) of total drug disposition. The Cmax for the active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38), was achieved at 2.2 +/- 0.1 h after treatment, and mean residence times for both CPT-11 and SN-38 were long, 9.1 and 10.0 h, respectively. Compared with topotecan, another CPT analogue under development, a larger proportion of total drug exposure was accounted for by the active lactone (closed-ring) forms of CPT-11 and SN-38; areas under the time-versus concentration curve for their respective lactone were 44 and 50% of areas under the time-versus-concentration curve for total CPT-11 and SN-38. Although intermittent dosing schedules appear to be superior to single dosing schedules for CPT and some CPT analogues in preclinical tumor models, the maintenance of biologically relevant concentrations of SN-38 for relatively long durations may negate the potential pharmacological benefits of intermittent and continuous administration schedules for CPT-11.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting.

PURPOSE: To determine the maximum-tolerated doses (MTD), the principal toxicities, and the pharmacologic behavior of high doses of Taxol (paclitaxel; Bristol-Myers Squibb, New York, NY) combined with cisplatin and granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS: Untreated and minimally pretreated solid-tumor patients received 24-hour infusions of Taxol on day 1 followed by cisplatin on day 2 and G-CSF, 5 micrograms/kg/d subcutaneously (SC), beginning on day 3. Treatment was repeated every 3 weeks. Starting doses of Taxol and cisplatin were 135 and 75 mg/m2, respectively. RESULTS: The development of a severe peripheral neuropathy and/or severe myalgias precluded the chronic administration of Taxol and cisplatin with G-CSF at doses greater than 250 mg/m2 and 75 mg/m2, respectively. At this dose, the mean Taxol steady-state plasma concentration (Css) exceeds concentrations capable of inducing pertinent antimicrotubule effects in vitro. The severity of the neuropathy was related to the cumulative dose of Taxol, the magnitude of the dose administered during each treatment, and the presence of a pre-existing medical disorder associated with peripheral neuropathy. A proximal myopathy of modest severity also was documented. Although severe neutropenia occurred frequently, especially at the MTD, it was rarely associated with fever (8% of courses), and absolute neutrophil counts (ANCs) less than 500/microL never persisted for more than 5 days. Responses were noted in non-small-cell lung cancer (NSCLC) and head and neck, breast, and esophageal cancers. CONCLUSION: Taxol and cisplatin doses of 250 mg/m2 and 75 mg/m2, respectively, can be administered repetitively with G-CSF to untreated and minimally pretreated patients. However, these doses are not recommended for patients with pre-existing neuropathies until additional experience in high-risk patients is obtained. Although this Taxol dose is nearly 85% higher than the dose that can be combined with cisplatin in the absence of G-CSF, this high-dose regimen should not be used outside the investigational setting until a dose-response relationship has been demonstrated for Taxol in randomized clinical trials.

Nursing considerations in paclitaxel (Taxol) administration.

The administration of paclitaxel (TAXOL) presents some challenges unique among chemotherapeutic agents. Information published and presented to date has focused primarily on the most threatening and clinically significant aspects of paclitaxel administration and resultant side effects. However, there are a number of other issues that, while not as acutely dangerous, can be very significant to the success of paclitaxel therapy and to those medical, pharmacy, and nursing personnel involved in drug administration and patient management. This review will focus on the collaborative role of the nurse in the recognition and prevention of side effects related to paclitaxel therapy. A nursing plan of care describes the pertinent paclitaxel toxicities and suggests interventions related to patient care issues.

Phase I and pharmacological study of the pulmonary cytotoxin 4-ipomeanol on a single dose schedule in lung cancer patients: hepatotoxicity is dose limiting in humans.

4-Ipomeanol (IPO), a naturally occurring pulmonary toxin, is the first cytotoxic agent to undergo clinical development based on a biochemical-biological rationale as an antineoplastic agent targeted specifically against lung cancer. This rationale is based on preclinical observations that metabolic activation and intracellular binding of IPO, as well as cytotoxicity, occurred selectively in tissues and cancers derived from tissues that are rich in specific P450 mixed function oxidase enzymes. Although tissues capable of activating IPO to cytotoxic intermediates in vitro include liver, lung, and kidney, IPO has been demonstrated in rodents and dogs to undergo in situ activation, bind covalently, and induce cytotoxicity preferentially in lung tissue at doses not similarly affecting liver or kidneys. Although the drug was devoid of antitumor activity in the conventional murine preclinical screening models, cytotoxic activity was observed in human lung cancers in vitro and in human lung cancer xenografts in vivo, adding to the rationale for clinical development. Somewhat unexpectantly, hepatocellular toxicity was the dose-limiting principal toxicity of IPO administered as a 30-min infusion every 3 weeks to patients with lung cancer. In this study, 55 patients received 254 courses at doses almost spanning 3 orders of magnitude, 6.5 to 1612 mg/m2. Transient and isolated elevations in hepatocellular enzymes, predominantly alanine aminotransferase, occurred in the majority of courses of IPO at 1032 mg/m2, which is the recommended IPO dose for subsequent phase II trials. At higher doses, hepatocellular toxicity was more severe and was often associated with right upper quadrant pain and severe malaise. Toxic effects were also noted in other tissues capable of activating IPO, including possible nephrotoxicity in a patient treated with one course of IPO at 154 mg/m2 and severe, reversible pulmonary toxicity in another patient who received nine courses of IPO at doses ranging from 202 to 826 mg/m2. Although individual plasma drug disposition curves were well described by a two-compartment first order elimination model, The relationship between IPO dose and area under the disposition curve was curvilinear, suggesting saturable elimination kinetics. At the maximum tolerated dose, the mean half-lives (lambda 1 and lambda 2) were 6.7 and 114.5 min, respectively. Renal excretion of parent compound accounted for less than 2% of the administered dose of IPO. An unidentified metabolite was detected in the plasma of patients treated at higher doses. No objective antitumor responses were observed; however, stable disease persisted for at least eight courses in 27% of patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Multiple systems organ failure in the patient with cancer. Part I: pathophysiologic perspectives.

Multiple systems organ failure (MSOF), a phenomenon observed in many critically ill patients with cancer, is the progressive failure of two or more organ systems, which results from nonspecific systemic responses to abnormal intravascular inflammation. It is triggered by a number of cellular, humoral, and biochemical mediators. MSOF in the patient with cancer has been associated with aggressive antineoplastic treatment regimens, which often cause profound alterations in the body's normal homeostatic balance. Part I of this two-part review will discuss the pathophysiology of MSOF, including epidemiology, prognosis, and clinical manifestations. Key relational factors, as well as current and future therapeutic considerations, also will be described.

Multiple systems organ failure in the patient with cancer. Part II: nursing implications.

Because of the expansion of aggressive therapeutic modalities, multiple systems organ failure (MSOF)--a sequential deterioration in vital organ function, is being diagnosed with increasing frequency in today's cancer population. The high mortality rate associated with this complex syndrome demands that oncology nurses become knowledgeable about its potential for development. Part II of this two-part review focuses on the collaborative role of the nurse in the recognition and prevention of MSOF. Key criteria for determining systemic failure are described, and pertinent oncologic risk factors are identified. A clinical evaluation guideline outlines important assessment criteria, laboratory studies, and nursing priorities for each system.

Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor.

PURPOSE: A phase I and pharmacologic study was undertaken to determine the maximum-tolerated dose (MTD), describe the principal toxicities, and characterize the pharmacologic behavior of topotecan, which is a semisynthetic analog of camptothecin with broad preclinical antitumor activity and the first topoisomerase I-targeting agent to enter clinical development in the United States since studies of sodium camptothecin over 2 decades ago. PATIENTS AND METHODS: Thirty-minute infusions of topotecan were administered daily for 5 consecutive days every 3 weeks to patients with advanced solid malignancies at doses ranging from 0.5 to 2.5 mg/m2/d. RESULTS: At doses of 1.5 and 2.0 mg/m2, grade 3 and 4 neutropenia occurred in most courses; however, neutropenia was brief and rarely associated with fevers or treatment delays. Neutropenia was more severe in patients with extensive prior treatment than in minimally pretreated patients, but these differences were not substantial. At 2.5 mg/m2, topotecan induced profound and prolonged neutropenia that was frequently associated with fever and treatment delays in minimally pretreated patients. Topotecan also induced mild depressions in the hematocrit level in the majority of courses; however, precipitous drops requiring transfusional therapy occurred in 14% of courses and suggested a drug-induced hemolytic effect. Unlike sodium camptothecin, hemorrhagic cystitis was not observed. Thrombocytopenia, skin rash, diarrhea, and vomiting occurred infrequently and were modest in severity. Responses were observed in non-small-cell lung carcinoma and platinum-refractory ovarian carcinoma. Drug disposition in plasma was described by a biexponential model, with renal elimination accounting for 38.7% of drug disposition. Topotecan was rapidly hydrolyzed in vivo to a less active, open-ring form. CONCLUSIONS: Neutropenia is the dose-limiting toxicity, and 1.5 mg/m2 is the recommended starting dose of topotecan for both minimally and heavily pretreated patients in future phase II trials, with escalation to 2.0 mg/m2 if treatment is well tolerated. Non-small-cell lung and platinum-refractory ovarian carcinomas should be among those evaluated in phase II trials of topotecan.

Sequences of taxol and cisplatin: a phase I and pharmacologic study.

Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50 or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean neutrophil count nadir was 98/microL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. Although neurotoxicity was initially thought to be a potentially serious effect of the combination, mild to modest neurotoxicity occurred in only 27% of patients. Adverse effects also included myalgias, alopecia, vomiting, diarrhea, bradycardia, and asymptomatic ventricular tachycardia. Objective responses were noted in melanoma, as well as non-small-cell lung, ovarian, breast, head and neck, colon, and pancreatic carcinomas. Based on these results, the sequence of taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is recommended for phase II/III trials, with escalation of taxol to 170 mg/m2 if treatment is well tolerated.