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Biomedical subjects

M J Ratain

Publications and source records attributed to M J Ratain.

At least 73 records · Page 4Linked to original sources
PubMed1998

Phase II trial of paclitaxel and topotecan with granulocyte colony-stimulating factor support in stage IV breast cancer.

PURPOSE: This multicenter phase II trial investigated the efficacy and safety of a combination of paclitaxel and topotecan in patients with pretreated metastatic breast cancer. Plasma levels of paclitaxel and topotecan were obtained during cycle 1 to correlate pharmacokinetic parameters with toxicity. PATIENTS AND METHODS: Paclitaxel was administered intravenously (i.v.) at 230 mg/m2 over 3 hours on day 1 followed by topotecan 1.0 mg/m2 i.v. over 30 minutes on days 1 to 5. Patients received an abbreviated premedication regimen that consisted of ranitidine 50 mg, diphenhydramine 50 mg, and a single 20-mg dose of dexamethasone, all administered i.v. 30 minutes before paclitaxel. Granulocyte colony-stimulating factor (GCSF) was administered at 5 micrograms/kg/d subcutaneously starting on day 6 and continuing until the absolute granulocyte count (AGC) was greater than 10,000/microL. Plasma paclitaxel and topotecan concentrations were assessed during the first cycle using limited-sampling strategies. RESULTS: Seventeen patients were treated. The majority had visceral metastases. Four patients experienced neutropenic fever and one had mild bronchospasm. Only one partial response (PR) was observed. Nadir AGC correlated strongly with both duration of paclitaxel levels greater than 0.05 mumol/L and maximum concentration (Cmax) of paclitaxel. CONCLUSION: This regimen does not produce a response rate superior to that expected with single-agent paclitaxel at doses that do not require growth factor support.

Adenocarcinoma↗
PubMed1998

Study of cohort-specific consent and patient control in phase I cancer trials.

PURPOSE: To address the challenging ethical dilemmas created from the participation of advanced cancer patients in phase I trials, we assessed the feasibility of a clinical trial design that uses an interactive informed consent process in which patient-subjects can choose to become directly involved in decisions of dose escalation. PATIENTS AND METHODS: Subjects were advanced cancer patients in the Hematology/Oncology Clinics at the University of Chicago who were eligible to participate in a phase I trial in which they underwent a three-step informed consent process that used cohort-specific consent and allowed them the option to choose their own doses of the chemotherapeutic agents under study, vinorelbine (NVB) and paclitaxel (TAX), within predetermined limits. NVB and TAX were administered in conventional 21- to 28-day cycles for two cycles while on study. Dose escalation occurred when a patient-subject chose a higher untested dose after they received information on all previously assessable patient-subjects. In addition to the phase I trial itself, a survey that consisted of structured interviews, which sought to evaluate patients' experiences with the interactive subject-choice phase I trial design and consent process, was conducted with participating subjects. The phase I trial itself sought to determine the associated toxicities of the agents under study. The survey results were compared with a similar survey of a matched control population of subjects who participated in other concurrently active conventional phase I trials at our institution. RESULTS: Twenty-nine patient-subjects participated in the phase I trial, with 24 who agreed to and completed the survey interviews. Seventy-six percent of patient-subjects opted to choose their dose of the agents under study, and 28% chose the highest available doses. More than half of the patient-subjects (56%) felt some degree of comfort in being asked to choose their dose of chemotherapy, with 53% stating that being asked to choose their dose made them feel in control, fully informed, or content. However, there were no statistically significant improvements in objective measures of the informed consent process, which included surveyed subjects' stated understanding of either provided information about phase I trials and alternatives to trial participation or of the research purpose of phase I trials. By making choices, the group of patients in the interactive subject choice trial changed the size of the dose cohorts and modified the process of dose escalation in this phase I study. CONCLUSION: Although complex, our innovative phase I trial design is feasible. In addition to the use of cohort-specific consent, the trial design may reduce the magnitude of many of the commonly recognized ethical dilemmas associated with this form of clinical research, which include difficulties with information provision and the understanding of possible risks and benefits of phase I trial participation, through direct subject involvement in research decision making by otherwise potentially vulnerable cancer patients.

Adult↗
PubMed1998

Oral chemotherapy: rationale and future directions.

PURPOSE AND METHODS: The expanding role of oral chemotherapy in oncology is suggested by the abundance of orally formulated agents currently in development. The pharmacoeconomic principles that drive oral drug formulation are discussed. Patient preference for oral therapy is identified as a second major impetus for the design of oral cytotoxics. While the rationale for oral formulations is apparent, substantial patient compliance and pharmacokinetic limitations have been identified for this route of administration. Specific aspects of bioavailability limitations and patient compliance are discussed. Relevant pharmacokinetic data for each orally formulated chemotherapy agent are compared and selected novel oral cytotoxics and cytotoxic modulators are discussed. RESULTS: A review of pharmacokinetic literature suggests substantial variability in bioavailability for many orally formulated cancer cytotoxics. While these findings are observed for all classes of oral drugs, the issue is especially critical for cancer chemotherapy, in which a narrow therapeutic index is frequently observed. Improved bioavailability and reduced interpatient biovariability are therefore desirable for new cytotoxic formulations. Pharmacologic manipulations to improve bioavailability and reduce costs are examined. CONCLUSION: Oral chemotherapy represents a fundamental change in contemporary oncology practice, driven by pharmacoeconomic issues, patient convenience, and the potential for improved patient quality of life. Novel cytostatic therapies that require protracted drug administration periods will also favor an oral formulation. While the use of oral chemotherapy may initially be limited to metastatic disease palliation, demonstration of equivalent efficacy would allow for its subsequent use in adjuvant settings. This efficacy is contingent on circumventing bioavailability limitations and patient noncompliance. The development of specific, low-toxicity inhibitors of CYP3A4, P-glycoprotein (P-gp), and other drug metabolizing enzymes such as dihydropyrimidine dehydrogenase represents a major innovative step in the successful formulation of oral chemotherapy.

Administration, Oral↗
PubMed1998

Phase II and pharmacodynamic studies of pyrazine diazohydroxide (NSC 361456) in patients with advanced renal and colorectal cancer.

Pyrazine diazohydroxide (PZDH) is a novel antitumor agent that forms DNA adducts via the reactive pyrazine diazonium ion. In a recent Phase I study of PZDH, we identified a recommended Phase II dose of 100 mg/m2/day x 5, given as a 5-min i.v. bolus with the cycles repeated every 42 days (N. J. Vogelzang, et al, Cancer Res., 54: 114-119, 1994). There was a moderate negative correlation between serum chloride concentration and logarithm platelet nadir, suggesting the hypothesis that PZDH is activated in an acidic environment, leading to more toxicity in acidotic patients. Therefore, the University of Chicago Phase II cooperative network conducted two Phase II studies of PZDH in renal cancer (15 patients, 2 with liver metastases) and in 5-fluorouracil-refractory colorectal cancer (14 patients, 13 with liver metastases) to determine efficacy in each disease and to correlate safety and tolerance of the drug with PZDH pharmacokinetics/pharmacodynamics and with arterial blood gas measurements. There were no responses seen in either tumor type. The primary toxicity of PZDH was myelosuppression with neutropenia (absolute neutrophil count, < 1000/microl) and thrombocytopenia (<50,000 cells/microl), seen in 41 and 24% of all cycles, respectively. Other grade 3 and 4 toxicities were rare. Pharmacodynamic analysis revealed no significant correlation between plasma levels at 5, 60, and 120 min; WBCs; absolute neutrophil and platelet count nadirs; and initial serum chloride or blood pH levels. The colorectal patients experienced significantly more thrombocytopenia than did the renal cancer patients (median platelet nadir after cycle 1 was 151 x 10(3)/microl for renal patients versus 76 x 10(3)/microl for colon patients; P = 0.04), suggesting either that prior 5-fluorouracil and leucovorin reduced bone marrow reserve or that colorectal patients with liver metastases experienced more PZDH toxicity. Regression analyses revealed a possible relationship (P = 0.06) between serum pH and thrombocytopenia (i.e., for each increase of 0.03 in pH, there was a 34% increase in the platelet nadir), but there was no relationship between serum chloride and thrombocytopenia. Curiously, an increase in alkaline phosphatase was associated with an increase in the platelet nadir (P = 0.02). If PZDH continues to be developed as an antineoplastic agent, further studies of these relationships are suggested.

Adult↗
PubMed1997

Learning from our patients: one participant's impact on clinical trial research and informed consent.

This Perspective includes an essay on modifying phase I clinical trials, written by George Zimmer, who was a professor of English and a commentary on that essay. Professor Zimmer was a cancer patient who participated in the phase I clinical trial program at the University of Chicago. His ideas are eloquently expressed and have had a profound effect on our investigational research for anticancer agents. Although at times his suggestions may seem radical, Professor Zimmer urges us to reconsider the 50-year-old Nuremberg paradigm that participants in human research are ignorant and vulnerable and must be protected. Although we must protect patients who have life-threatening diseases from coercive inducements and misplaced hopes, we must also listen carefully and thoughtfully to our patients. This is particularly true when, as research participants in the face of sacrifice and the threat of a life-ending diagnosis, they have made the effort to express their concerns. With the effect of the acquired immunodeficiency syndrome movement on clinical studies and on drug research and development, a precedent has been set that allows patients to reshape their role as participants in research trials. On a personal level, the essay by Professor Zimmer has had a significant effect on our research methods and, indeed, the focus of our research efforts. Thus, it is with a sense of respect and honor that we share George Zimmer's thoughts and our comments about the influence he has had on our research practices.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Thymidylate synthase expression and response to neoadjuvant chemotherapy in patients with advanced head and neck cancer.

BACKGROUND: Thymidylate synthase (TS), an essential enzyme in DNA synthesis, is a target for the fluoropyrimidines, an important group of antineoplastic agents used widely in the treatment of head and neck cancer. PURPOSE: We evaluated relationships between the level and/or pattern of tumor TS expression and response to fluorouracil (5-FU)-based neoadjuvant chemotherapy in patients with advanced head and neck cancer. METHODS: Tumor specimens from 86 patients were available for this retrospective analysis. The patients were enrolled in four consecutive phase II studies that tested combinations of 5-FU, leucovorin, and cisplatin with or without added methotrexate plus piritrexim or interferon alfa-2b (IFN alpha-2b). TS protein expression in the tumors was assessed by use of the TS 106 monoclonal antibody and standard immunohistochemical staining techniques. TS immunostaining was classified according to its level of intensity (TS 0-1 = low, TS 2 = intermediate, and TS 3 = high) and according to its extent (focal pattern = less than 25% of tumor cells positive; diffuse pattern = greater than or equal to 25% of tumor cells positive). Data from 79 patients were available for an analysis of tumor TS expression and patient/tumor characteristics; 70 patients were assessable for their response to neoadjuvant chemotherapy. RESULTS: There was a statistically significant association between the level of tumor TS expression and the degree of tumor differentiation; a higher proportion of patients whose tumors exhibited TS 0-1 immunostaining had undifferentiated or poorly differentiated tumors than patients whose tumors exhibited TS 2 or TS 3 immunostaining (P = .04, Jonckheere-Terpstra trend test). Among the 70 patients who were assessable for response to neoadjuvant chemotherapy, TS 3 tumor immunostaining was associated with a lower rate of complete response (i.e., complete disappearance of clinically detectable disease for a minimum of 4 weeks from time of initial determination) than was TS 2 or TS 0-1 immunostaining, but this association was not statistically significant (P = .09, exact trend test); among the 39 patients who were treated with regimens that included 5-FU, leucovorin, cisplatin, and IFN alpha-2b, this inverse association between TS immunostaining intensity and response was statistically significant (P = .02, exact trend test). Tumor TS immunostaining intensity and overall survival were not found to be associated. Patients with tumors exhibiting a focal pattern of TS immunostaining have experienced significantly longer survival than patients with tumors exhibiting a diffuse pattern; for the 53 patients with diffuse tumor TS immunostaining, the median survival was 24.7 months, whereas the median survival has not yet been reached for the 22 patients with focal tumor TS immunostaining (P = .04, two-tailed logrank test). However, the survival advantage for the focal versus diffuse TS immunostaining pattern was limited to patients whose tumors also exhibited a TS 3 level of immunostaining intensity. CONCLUSIONS AND IMPLICATIONS: Characterization of tumor TS expression may be of value in identifying patients with advanced head and neck cancer who would benefit from fluoropyrimidine-based neoadjuvant chemotherapy.

Antimetabolites, Antineoplastic↗
PubMed1997

Evaluation of neuropathy in patients on suramin treatment.

Suramin, a promising chemotherapeutic agent, causes a dose-limiting sensorimotor polyneuropathy. We undertook a phase 1 study of suramin that included serial neurologic and electrophysiologic examinations as part of the safety evaluation. We found that 6 of 41 (15%) patients developed suramin-induced demyelinating neuropathy which resembled Guillain-Barre syndrome clinically. There was 1 asymptomatic patient with electrophysiologic abnormalities suggestive of a demyelinating neuropathy. In addition, 1 patient with mild axonal neuropathy at baseline had deterioration of his symptoms during suramin treatment. Four asymptomatic patients developed electrophysiologic findings suggestive of a mild axonal neuropathy. We conclude that: (1) serial electrophysiologic monitoring is helpful for early detection of suramin-induced neuropathy; and (2) fixed dosing schedule of suramin without adaptive control does not lead to an increased incidence of demyelinating neuropathy when compared to adaptively controlled dosing schedules.

Adult↗
PubMed1997

Phase I study of treatment with oral 13-cis-retinoic acid, subcutaneous interferon alfa-2a, cisplatin, and 24-hour infusion 5-fluorouracil/leucovorin.

UNLABELLED: A combination of oral 13-cis-retinoic acid (cis-RA) and subcutaneous interferon alfa-2a (IFN) has been reported to yield high response rates in patients with squamous cell carcinomas (SCCAs) of the cervix and skin. Cisplatin and 5-fluorouracil with leucovorin (5-FU/LV) are chemotherapeutic agents commonly used for SCCAs. PURPOSE: To determine the maximum tolerated doses (MTDs) of cisplatin and 5-FU/LV when combined with IFN and cis-RA, and to define a recommended phase II regimen for testing in cervical cancer and other appropriate tumor types. METHODS: Phase I cohort design. Cisplatin was administered every 3 weeks. 5-FU and LV were administered together as a weekly 24-h infusion. Cis-RA was given orally twice daily. IFN was initially given subcutaneously at a dose of 3 million units (MU) daily. RESULTS: A total of 31 patients were treated. The IFN dose was reduced to 3 MU three times weekly because of patient intolerance. Cytopenias prevented the administration of weekly 5-FU/LV. Single-agent cisplatin with three times weekly IFN and twice daily cis-RA was tolerable. Four partial responses were observed, in patients with adrenal cancer, bladder cancer, gastric cancer, and adenocarcinoma of unknown primary. CONCLUSIONS: The recommended phase II regimen is cisplatin 100 mg/m2 every 3 weeks, IFN 3 MU three times weekly, and cis-RA 1 mg/kg daily. This appears to be more toxic than single-agent cisplatin, but the preliminary activity observed warrants further testing.

Administration, Oral↗
PubMed1997

Determination of vinca alkaloids in human plasma by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry.

A sensitive assay was developed for the quantitation of vinblastine, desacetylvinblastine and vincristine using liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MS). Analyses were performed on an Ultrasphere C18 microbore column using ammonium acetate as mobile phase. The calibration curves were linear across the range of 0.51-4.00 ng/ml (0.63-4.93 nM) for vinblastine, 0.74-3.93 ng/ml (0.96-5.11 nM) for desacetylvinblastine and 0.30-3.95 ng/ml (0.36-4.79 nM) for vincristine. Vinca alkaloid concentrations were measured with an accuracy and precision within 11%. This assay could be implemented to determine the plasma concentrations for pharmacokinetic studies of vinblastine, desacetylvinblastine and vincristine in conjunction with clinical trials.

Chromatography, Ion Exchange↗
PubMed1997

Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital.

PURPOSE: Irinotecan (CPT-11) is hydrolyzed to its active metabolite SN-38 which is subsequently conjugated by uridine diphosphate glucuronosyl transferase (UDP-GT) to the glucuronide (SN-38G). Both preclinical and clinical data indicate that conjugation is a primary clearance mechanism for SN-38 with the plasma glucuronide levels being substantially higher than those of SN-38. This investigation was designed to determine the possibility of modulation of glucuronidation of SN-38 and its effect on the disposition of the parent drug and metabolites. METHODS: Female Wistar rats were pretreated with 200 mg/kg valproic acid (VPA), an inhibitor of glucuronidation, 5 min prior to the administration of 20 mg/kg irinotecan. The control rats were given 20 mg/kg irinotecan only. To study the effect of inducers of UDP-GT activity, rats were pretreated with phenobarbital (PB) before irinotecan administration. RESULTS: Pretreatment with VPA caused a 99% inhibition in the formation of SN-38G leading to a 270% increase in the area under plasma concentration-time curve (AUC) of SN-38 compared with the control rats. The irinotecan estimations were unchanged in the two groups. PB pretreatment caused a 1.7-fold increase in the AUC of SN-38G and a concomitant 31% and 59% reduction in the AUCs of SN-38 and irinotecan, respectively. CONCLUSIONS: The most plausible explanation for the alterations in SN-38G disposition is inhibition of SN-38 conjugation by VPA and induction of the conjugation by PB.

Animals↗
PubMed1997

Interleukin-2 fusion protein: an investigational therapy for interleukin-2 receptor expressing malignancies.

DAB389IL-2 is an interleukin-2 receptor (IL-2R) specific fusion protein with a molecular weight of 58 kD containing the enzymatic and translocation domains of diphtheria toxin (DT) and human IL-2. This fusion protein is able to direct the cytocidal action of the DT enzymatic region only to cells which bear the IL-2R. The human IL-2R exists in three forms: low, intermediate and high affinity. The high-affinity form is believed to be the biologically relevant form on mature, activated T-lymphocytes, B-lymphocytes and monocytes. DAB389IL-2 is able to bind selectively to the high-affinity IL-2R in a concentration-dependent manner, and once bound is internalised via receptor-mediated endocytosis. Upon acidification of the formed vesicle, the enzymatic portion of the fusion protein is believed to pass into the cytosol where it ultimately inhibits protein synthesis by inactivation of elongation factor-2, resulting in cell death. The constitutive expression of the IL-2R on certain leukaemic and lymphomatous cells of T and B cell origin has been reported to occur in patients with chronic lymphocytic leukaemia, cutaneous T cell lymphoma (CTCL), Hodgkin's disease and non-Hodgkin's lymphomas (NHLs). A multicentre DAB389IL-2 dose-escalation study of patients with IL-2R expressing lymphomas has been conducted. A 10-fold range of doses were evaluated on a five-daily dose schedule. Patients received up to six courses, with an additional two courses permitted for patients with partial responses that appeared to be still improving after six courses. Most adverse experiences were transient and mild. Preliminary assessment of response indicated five complete responses (CR, duration ongoing at 20, 11, 7, 5 and 4 months) and seven partial responses (PR, duration 3-20 months) in the 35 patients with CTCL. One CR (duration > 20 months) in a patient with NHL (Lennett's lymphoma) and two PR (duration 9 and 2 months) in 17 patients with B-cell NHL have been observed. Based on the mode of action of DAB389IL-2, its safety profile, and the patient responses associated with the phase I/II clinical trials, a phase III programme in CTCL patients has been initiated and plans for additional trials in NHL patients are targeted for 1996.

Antineoplastic Agents↗
PubMed1997

Phase I study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762, PNU 152243) administered on a daily x3 schedule.

BACKGROUND: 3'-Deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762, PNU 152243) is a highly lipophilic doxorubicin derivative which possesses potent in vitro and in vivo antitumor activity. Previous phase I studies had been conducted using a single bolus every 28 days. PATIENTS AND METHODS: We conducted a phase I study of FCE 23762 on a daily x3 every 28 days schedule. Thirty patients received 68 cycles of therapy at 5 dose levels (200-600 micrograms/m2/d). RESULTS: Prolonged neutropenia and thrombocytopenia were the dose-limiting toxicities. Other nonhematological toxicities included nausea and vomiting, anorexia, fatigue and transient elevations of serum creatinine and hepatic transaminases. No cardiac toxicity was demonstrated. There were no partial or complete antitumor responses. CONCLUSION: The recommended phase II dose using the schedule defined in this study is 500 micrograms/m2/dx3.

Adult↗
PubMed1997

Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients.

PURPOSE: We conducted a pharmacokinetic and pharmacodynamic evaluation of irinotecan (CPT-11) and determined the effect of race and sex on disposition and toxicity of CPT-11. We tested the efficacy of acetaminophen (AAP) to phenotype SN-38 glucuronidation. PATIENTS AND METHODS: Forty patients received a dose of 145 mg/m2 of CPT-11 as a 90-minute infusion. Total CPT-11, SN-38, and SN-38G were quantitated in plasma and urine samples. Following administration of 1 g AAP, urinary concentrations of AAP and AAP-glucuronide (AAP-G) were assessed. RESULTS: CPT-11 exhibited a mean elimination half-life (t1/2) of 8.8 hours, an average clearance (CL) of 14.6 L/h/m2, and a mean volume of distribution at steady-state (Vdss) of 136 L/m2. SN-38 and SN-38G had low plasma availabilities (3% and 10% relative to CPT-11), with mean t1/2 values of 11.6 and 10.5 hours, respectively. Urinary recovery accounted for 15% of the dose. Race and sex had no effect on the plasma availability of CPT-11, SN-38, and SN-38G. The applicability of biliary index (BI) in predicting dose-limiting intestinal toxicity was validated. Patients who developed grade 3 or 4 toxicity had significantly higher index values compared with patients with grade 0 to 2 toxicity (P = .001). There was no difference in the incidence and severity of toxicity based on race and sex. AAP was a poor predictor of SN-38 glucuronidation. CONCLUSION: The high degree of interpatient variability in parameter estimates suggests pharmacogenetic variation or differential induction or inhibition of the sequential metabolic pathway of CPT-11, as well as variability in transport systems. The low urinary recovery indicates substantial biliary excretion and supports the significant correlation between intestinal toxicity and BI. Black patients are not at increased risk of toxicity. An assessment of individual differences in SN-38 conjugation remains to be established.

Antineoplastic Agents↗
PubMed1997

New phase I trial methodology.

Phase I trial design is constantly evolving to adapt to deficiencies in traditional methods and to accommodate newer rationally designed agents. This article discusses some of the important aspects of the design of phase I studies with particular reference to identifying new methods of safer but rapid dose escalation and reproducible end points such as maximum tolerated dose and recommended phase II dose. Given the explosion of rationally designed drugs capable of pathway specific inhibition, we also discuss potential strategies in designing trials with these agents. It is hoped that future strategies incorporate the existing methodologies with newer dose titration examples to complete phase I trials in a rapid and timely fashion.

Clinical Trials, Phase I as Topic↗
PubMed1997

Rationale for phase I study of UFT plus leucovorin and oral JM-216.

Both cisplatin (Platinol) and fluorouracil (5-FU) have demonstrated single-agent clinical efficacy in a variety of solid neoplasms. The combination of these agents has revealed synergistic cytotoxicity in models in vitro and in vivo, which may explain the clinical effectiveness of 5-FU-cisplatin regimens. UFT (tegafur and uracil) and bis-aceto-ammine-dichloro-cyclohexyl-amine platinum(IV)(JM-216) are novel oral analogues of 5-FU and cisplatin, respectively. In preclinical models, JM-216 has demonstrated equivalent cytotoxicity to cisplatin, while phase I trials suggest its dose-limiting toxicity is myelosuppression. In contrast to cisplatin, JM-216 has not demonstrated significant neurotoxicity or nephrotoxicity. UFT has been used extensively in Japan, where phase II data suggest disease response rates similar to single-agent 5-FU in colorectal, gastric, and breast carcinomas. Combination studies of prolonged administration UFT and single-dose cisplatin have shown efficacy, but also significant hematologic toxicity. We propose a phase I study of UFT and JM-216 administered daily over 14 consecutive days with leucovorin (90 mg/d). Ease of administration and continuous drug exposure are potential advantages of this regimen. Several disease specific investigations may be warranted given demonstrated feasibility in this phase I study.

Administration, Oral↗
PubMed1997

Pharmacology of 21-day oral etoposide given in combination with i.v. cisplatin in patients with extensive-stage small cell lung cancer: a cancer and leukemia group B study (CALGB 9062).

This was a pharmacological companion study to a randomized Phase III trial comparing 21-day oral versus 3-day i.v. etoposide in combination with i.v. cisplatin in patients with extensive-stage small cell lung cancer. Etoposide plasma concentrations were measured in patients randomized to the 21-day schedule and correlated with toxicity and tumor response. Patients were treated with etoposide (50 mg/m2/day) orally for 21 days and cisplatin (33 mg/m2/day) i.v. for 3 consecutive days every 28 days for 6 courses. Plasma samples before the daily etoposide dose (trough concentrations) and complete blood counts were obtained weekly during treatment. The average of three etoposide concentrations (EC) per course was calculated. Of 158 patients registered to this schedule of the study, 150 were eligible. In 106 patients, etoposide samples were obtained at least in the first course in which the mean EC was 0.39 microgram/ml (SD = 0.29). In 102 patients (missing albumin values in 4 of 106 patients), the concentration of etoposide not bound to protein (Efree) was estimated based on the following equation: percentage unbound = (1.4 x total bilirubin) - (6.8 x albumin) + 34.4. Regression analysis revealed that increasing age was correlated with higher EC (r = 0.27; two-tailed P < 0.01) and Efree (r = 0.31; two-tailed P < 0.01). Higher EC and Efree values were associated with lower WBC counts and absolute neutrophil counts after the first treatment course in 83 patients with nadir counts. Using multiple linear regression, a pharmacodynamic model was developed that included EC or Efree, age, and alkaline phosphatase. An interaction with bone marrow results at diagnosis was found, indicating a sharper decline in nadir counts with increasing EC or Efree when the marrow was involved with small cell lung cancer. This model explained 29% of the variation for WBC nadirs (P < 0.001) and 31% of the variation for absolute neutrophil count nadirs (P < 0. 001). Neither EC nor Efree showed a significant correlation with tumor response. A pharmacokinetic relationship between EC or Efree and age was found. A pharmacodynamic model could be developed for toxicity but not for tumor response.

Administration, Oral↗