Polyhydramnios as a first prenatal symptom of non-ketotic hyperglycinaemia.
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Adult↗
Biomedical subjects
R Mick
Publications and source records attributed to R Mick.
Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function.
The pharmacokinetics of mycophenolic acid (MPA), the immunosuppressant form of the prodrug mycophenolate mofetil (MMF), and the primary glucuronide metabolite, MPAG, were characterized in renal transplant patients with delayed graft function using random effects piecewise linear models. Eight patients were evaluated after receiving their first and subsequent daily oral doses of 1.5 g mycophenolate mofetil twice daily on study days 1 (n = 8), 7 (n = 8), 14 (n = 5), 21 (n = 2), and 28 (n = 7). The area under the concentration-time curve from zero to 12 hours (AUC0-12) for MPA, MPAG, MPA free fraction, and free MPA were analyzed in serial plasma samples using validated high-performance liquid chromatography and ultrafiltration procedures. Random effects piecewise linear models, fit by maximum likelihood methods, were applied to AUC0-12 of MPA and MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine concentration, the index of renal function used in this study. Two hemodialysis sessions did not lower MPA plasma concentration, although some MPAG was removed. The AUC0-12 of MPA increased as a function of time, although it was not possible to fit a statistical model to the data due to considerable among-patient variation in the pattern of increase with time. The AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA reached maximal values on day 7; each of these parameters had unique day 1 to 7 positive slope values and unique day 7 to 28 negative slope values. The average creatinine concentration was maximal at day 1 and a unique negative slope was obtained between days 7 and 28. Thus, this study provides statistical models for the alteration of AUC0-12 of MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine in renal transplant patients with delayed graft function. These results provide evidence that renal dysfunction is associated with altered pharmacokinetics of MPA, particularly increased AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA. The perturbed pharmacokinetics normalized with improving renal function.
Adult↗
Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: an active and tolerable outpatient regimen.
PURPOSE: To determine the toxicity and efficacy of an outpatient regimen of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium. PATIENTS AND METHODS: Patients received paclitaxel 150 to 225 mg/m2 over 3 hours followed by carboplatin (targeted area under the concentration-time curve [AUC], 6 mg/mL x min) every 3 weeks. During phase I accrual, 16 patients were treated; 17 additional patients were enrolled at the phase II dose. The median age was 70 years (range, 47 to 82). The median serum creatinine concentration was 1.1 mg/dL (range, 0.7 to 2.7) and the median estimated creatinine clearance was 52 mL/min (range, 24 to 110). RESULTS: During phase I accrual, the maximum-tolerated dose (MTD) of the regimen was not defined. Phase II accrual occurred at the paclitaxel 225 mg/m2 dose level. A total of 156 cycles were administered. The median number of cycles received was five (range, one to eight). Sensorimotor neuropathy was the principal nonhematologic toxicity. Significant granulocytopenia was common, but significant thrombocytopenia was not. Objective responses were demonstrated at all dose levels. At the phase II dose (paclitaxel 225 mg/m2 followed by carboplatin at AUC 6 mg/mL x min), the objective response rate was 50% (95% confidence interval [CI], 28% to 72%). CONCLUSION: Paclitaxel plus carboplatin is an active and tolerable outpatient treatment for patients with advanced carcinoma of the urothelium. The ability to administer this combination over multiple cycles even to patients with advanced age and abnormal renal function makes it well suited for this patient population. Confirmatory trials of this regimen are ongoing.
Aged↗
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↗
Melanoma of unknown primary site: presentation, treatment, and prognosis--a single institution study. University of Pennsylvania Pigmented Lesion Study Group.
BACKGROUND: A retrospective analysis of 40 patients diagnosed with melanoma of unknown primary site (MUP) was undertaken to analyze the etiology and clinical behavior of this presentation. METHODS: The patient records were located by a computer search of the Pigmented Lesion Clinic data base at the University of Pennsylvania. With the Cox proportional hazards model, the survival of the MUP patients with lymph node presentation was compared with that of patients with lymph node disease and a known concurrent primary melanoma. RESULTS: Sixty-five percent of the patients presented with lymph node metastasis only, 28% presented with visceral lesions, and 8% presented with subcutaneous nodules. The prevalence of dysplastic nevi was 22.5%. The overall 4-year survival rate for the 40 MUP patients was 55% +/- 9%. The 4-year survival (57% +/- 12%) of patients with lymph node presentation was compared with that of patients presenting with lymph node disease and a known concurrent primary melanoma (19 +/- 6%). Survival was significantly different between the groups (P = 0.008). This survival difference remained significant (P = 0.02) even after adjustments for number of positive lymph nodes, year of diagnosis, and age at diagnosis. CONCLUSIONS: This analysis revealed that MUP patients with lymph node metastasis survived significantly longer than patients diagnosed with lymph node metastasis concurrent with a known cutaneous primary melanoma. The prevalence of dysplastic nevi in the MUP patient series was intermediate between that reported among primary melanoma patients and that reported among population controls, suggesting the likelihood of a primary cutaneous origin for the metastatic melanoma.
Adult↗
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↗
Cycles of dose-intensive chemotherapy with peripheral stem cell support in persistent or recurrent platinum-sensitive ovarian cancer.
OBJECTIVE: The objective was to determine the toxicity and surgically documented response rate of sequential high-dose chemotherapy with peripheral stem cell support in patients with persistent or recurrent cisplatin-sensitive ovarian cancer. METHODS: Fourteen patients (average age, 45 years) were treated with cyclophosphamide (4.5 g/m2), followed by granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral stem cell harvests. The subsequent regimen prescribed three courses of carboplatin (1 g/m2) and cyclophosphamide (1.5 g/m2 with 2-mercaptoethanesulfonate) every 2 weeks with stem cell support. This was followed by three courses of paclitaxel at 250 mg/m2 every 2 weeks with G-CSF support only. Six patients were entered on the basis of a positive second-look laparotomy and 8 patients had a first recurrence after at least a 6-month disease-free interval. RESULTS: Fourteen patients were entered and 12 patients completed all planned courses of therapy (mean time, 13 weeks). Normal hematopoiesis was reestablished after each cycle. Hospitalization for neutropenic fever occurred in 11/93 cycles (11.8%). Thirteen patients required blood transfusions and in 12 patients platelet transfusions were given. One patient had grade 3 neurotoxicity. An initial elevated CA 125 returned to normal in 7/8 patients (88%) and 71% of patients with measurable disease responded to therapy. There were 2 pathologic complete responders (PCR), making the PCR rate 2/14 or 14% (0-35%). CONCLUSION: Although this regimen was well tolerated and clinical response rates were high, the surgically documented response rate was not clearly superior to conventional salvage regimens in platinum-sensitive patients.
Adult↗
Performance and quality of life outcome in patients completing concomitant chemoradiotherapy protocols for head and neck cancer.
This study evaluated post-treatment performance and quality of life (QOL) outcome in head and neck cancer (HNC) patients treated with organ preservation, intensive chemoradiotherapy (FHX). Participants were 47 Stage II-IV HNC patients with no evidence of disease at least one year post-completion of organ preservation, concomitant FHX treatment. Patients were assessed via a semi-structured in-person interview, standardized measures of QOL (FACT-H&N, CES-D), performance (PSS-HN) and patients' perception of residual side effects. Disease, treatment and toxicity data were retrieved from medical charts and protocol records. The most salient performance impairment was inability to eat a normal solid food diet, with 50% of patients able to eat soft foods or take liquids only. This specific functional deficit was not related to global QOL, nor to specific quality of life dimensions. Dry mouth, the most frequent and severe residual effect, was not associated with outcome diet, depression or QOL. Residual pain, seen in only 15% of patients, appeared to influence both functional and QOL parameters as well as being a marker for other troublesome symptoms. Twenty-three per cent of patients were depressed; depression was associated with past problems related to alcohol abuse. Decreased QOL and increased depressive symptomatology were related to total number and severity of residual effects. The data highlight the importance of systematic study of QOL dimensions and caution against making assumptions about patients' experience of particular disease and treatment sequelae.
Activities of Daily Living↗
CCR5 genotypes in sexually active couples discordant for human immunodeficiency virus type 1 infection status.
Persons who are homozygous for the delta32 polymorphism of the CCR5 chemokine receptor gene are highly protected against human immunodeficiency virus type 1 (HIV-1) infection. Previous studies described 54 HIV-1-discordant couples in whom no virus transmission occurred despite extensive sexual contact. The possible role of the delta32 polymorphism in the lack of HIV-1 transmission between these partners was studied. No participants were homozygous for the delta32 allele, but the proportion that was heterozygous was higher among HIV-1-seronegative than HIV-1-seropositive partners (28% vs. 11%, P = .05). This association was seen in heterosexual couples (P = .03) but not in homosexual couples (P = .74). Among white persons, who are most likely to carry the delta32 allele, 38.9% of HIV-1-uninfected and 5.6% of HIV-1-infected heterosexual partners were heterozygous (P = .04). These data are consistent with a possible association between the heterozygous delta32 genotype in heterosexual sex partners and partial protection against HIV-1 infection, and they emphasize the importance of analyzing different risk groups in studies of host factors that influence infection.
Alleles↗
Phase I study of vinorelbine and ifosfamide in advanced non-small-cell lung cancer.
PURPOSE: We designed a phase I dose-escalation study of vinorelbine on a novel (daily-times-three) schedule with ifosfamide with granulocyte colony-stimulating factor (G-CSF) support to define the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of vinorelbine in this combination. PATIENTS AND METHODS: Cohorts of patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) and no prior chemotherapy received vinorelbine starting at 15 mg/m2 on days 1, 2, and 3, and ifosfamide starting at 2.0 g/m2 on days 1, 2, and 3 with G-CSF support for all patients. Cycles were repeated every 21 days. Plasma vinorelbine concentrations were also analyzed. RESULTS: Forty-two patients were treated. The median age was 58 years (range, 34 to 75) and 41 had a performance status of 0 or 1. The DLT was neutropenia and sepsis at a maximum-administered vinorelbine dose of 35 mg/m2 for 3 days. The recommended phase II dose was vinorelbine 30 mg/m2 with ifosfamide 1.6 g/m2 both given on 3 consecutive days. The overall response rate was 40% (17 of 42; all partial responders). The median survival duration was 50 weeks, with a 1-year survival rate of 48%. Pharmacokinetic analysis showed that vinorelbine in this combination and on this schedule is cleared 1.5 to two times faster than in single-agent once-weekly studies. CONCLUSION: Myelosuppression is the DLT of this regimen with no major subjective toxicities. With tolerable toxicity and an encouraging 1-year survival rate of 48%, further investigation of this new vinorelbine schedule is warranted in this and other combination regimens.
Adult↗
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↗
Loss of heterozygosity from the short arm of chromosome 8 is associated with invasive behavior in breast cancer.
Loss of heterozygosity (LOH) from the short arm of chromosome 8 (8p) is frequent in many human cancers, including breast, colon, prostate, and bladder cancers. LOH occurs in two regions of 8p, 8p21 and 8p22, and suggests the presence of two separate tumor suppressor genes. In breast cancers, 8p LOH occurs in both early and late clinical stage tumors, while in colon, prostate, and bladder cancers, there is an association between 8p LOH and advanced clinical stage. We investigated this discrepancy by comparing 8p LOH in infiltrating ductal carcinomas (IDC) to breast cancers of earlier clinical stage, i.e., tumors with no invasion [ductal carcinoma in situ (DCIS)-only tumors]. We used three markers which sample several reported loci of 8p LOH. We microdissected tumor from paraffin blocks of 39 IDC and 23 DCIS-only breast cancers and amplified tumor/normal DNA pairs for the microsatellite markers D8S254 (8p22), D8S133 (8p21.3), and NEFL (8p21). All cases of IDC were informative with at least one marker, with a combined rate of LOH of 46%. The results for each marker were [no. LOH/no. informative (%)]: D8S254, 8/26 (31%); D8S133 12/31 (39%), and NEFL, 9/25 (36%). In the DCIS-only group, all 23 were informative for at least one marker, but 8p LOH was absent. We conclude that 8p LOH from 8p21-22 is frequent in IDC of the breast, but absent in DCIS-only cases, and may play a role in breast cancer progression by conferring invasive ability.
Breast Neoplasms↗
Peripheral blood mononuclear cell dihydropyrimidine dehydrogenase activity in volunteers with and without diabetes mellitus.
It has been reported that cancer patients with diabetes mellitus receiving a continuous infusion of 5-fluorouracil (5-FU) have more toxicity and higher plasma 5-FU levels that patients without diabetes mellitus. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. DPD activity in peripheral blood mononuclear cells has been reported to correlate inversely with 5-FU plasma levels in patients. We therefore undertook a study to compare the activity of DPD in peripheral blood mononuclear cells of human subjects with and without diabetes mellitus. The study groups comprised 43 volunteers with and 39 without diabetes mellitus, and peripheral blood mononuclear cell DPD activity was assayed on samples obtained between 8 a.m. and 11 a.m. DPD activity was not decreased in diabetic subjects. There was no relationship between DPD activity and gender body mass index, or race. There was a modest correlation between DPD activity and age (r=0.19, P =0.08). We conclude that increases in 5-FU-related toxicities in diabetics must be related to factors other than peripheral blood mononuclear cell DPD activity.
Adult↗
Etoposide combined with interferon alfa-2b: novel exploitation of established etoposide pharmacokinetics and pharmacodynamics.
PURPOSE: To construct an efficient pilot study design to determine whether interferon alfa-2b modifies the pharmacokinetics and pharmacodynamics of continuous-infusion etoposide. PATIENTS AND METHODS: A two-stage randomized 2 X 2 factorial design was used to evaluate interferon alfa-2b at two doses (2 or 10 MU/m2/day SQ for 3 days) and two schedules (interferon alfa-2b administered before or concurrent with 72-hour continuous-infusion etoposide). Etoposide was administered at 75, 100, or 125 mg/m2/day. In lieu of comparing the experimental arms to an etoposide-alone control arm to determine effect of interferon alfa-2b dose and schedule, a novel analytic approach was used. The effect of interferon alfa-2b on etoposide-induced leukopenia was assessed indirectly by comparison of the observed white blood cell (WBC) nadir to the nadir predicted from an established pharmacodynamic model for single agent etoposide. RESULTS: Based on 29 patients, dose-normalized 24-hour total and estimated free etoposide concentrations did not differ with interferon alfa-2b dose or schedule. Patients treated with interferon alfa-2b before etoposide had, on average a WBC nadir 545 +/- 225 cells microliter lower than that predicted by a pharmacodynamic model for etoposide alone. An optimal nonlinear model for leukopenia was defined by interferon alfa-2b schedule in addition to 24-hour etoposide concentration. CONCLUSION: A novel study design and statistical analysis provided an efficient preliminary evaluation of the combination of interferon alfa-2b with etoposide in a modest number of patients. Exploitation of a previously validated pharmacodynamic model allowed evaluation of interferon alfa-2b effect and eliminated the need for an etoposide-alone control arm. The pharmacokinetics of continuous-infusion etoposide at doses from 75 to 125 mg/m2/day appear to be unchanged by interferon alfa-2b at the doses and schedules tested and the combination appears to be feasible. We hypothesize that leukopenia may be enhanced when interferon alfa-2b is administered before etoposide, especially at a higher dose of interferon alfa-2b.
Adult↗
Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender.
Amonafide is extensively metabolized, including conversion by N-acetylation to an active metabolite. Our previous studies have shown that fast acetylators of amonafide have increased toxicity, and we have recommended doses of 250 and 375 mg m-2 day-1 for 5 days, for fast and slow acetylators, respectively. Despite phenotype-specific dosing, significant variability in leukopenia persisted. The goal of this study was to construct and validate a pharmacodynamic model-based dosing strategy for amonafide, to try to further decrease inter-patient variability in leukopenia. The model was based on a training data set of 41 patients previously treated with amonafide. The first cycle nadir WBC was modelled as a function of dose, acetylator phenotype and baseline patient factors. This model was validated prospectively on patients similar to those in our previous studies. Based on the training data set, the optimal model was defined by three factors: acetylator phenotype, gender, and pretreatment WBC. Using this model and a target WBC nadir of 1700 microliters-1, six dosing strata were prospectively evaluated. A total of 24 fast acetylators received either 238 or 276 mg m-2 day-1 and 20 slow acetylators received between 345 and 485 mg m-2 day-1. The mean (+/- SE) error (deviation from target nadir) was 430 (+/- 240) cells microliters-1. Submaximal treatment (yielding grade 0-1 leukopenia) was limited to 20% of patients, while 55% experienced grade 2-3 toxicity. A complex dosing strategy for amonafide is feasible, employing prospective acetylator phenotyping, model-guided dosing, and adaptive control.
Acetylation↗
Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies.
PURPOSE: The optimal dose and schedule for cladribine (2CdA) therapy of malignant hematologic diseases have not been determined. This dose-escalation study was designed to assess toxicity when 2CdA is given using five daily 1-hour intravenous infusions. PATIENTS AND METHODS: Forty-two adults with advanced hematologic malignancies were treated in one of nine cohorts, starting at 2.5 mg/m2/d for 5 days. Plasma drug concentrations were measured by high-performance liquid chromatography. Responses were assessed by bone marrow biopsy on day 15 of the first course and by clinical measurements after each course. Patients received one to four courses each. RESULTS: Nonhematologic toxicity was mild, and dose-limiting nonhematologic toxicity was not observed, even at the highest dose level of 21.5 mg/m2/d. In particular, neurotoxicity was not observed. The maximum-tolerated dose (MTD) was not identified. However, prolonged cytopenias and severe infections were more common in the higher 2CdA dose cohorts. Logistic regression analysis suggested that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were identified as having a PS of 0 and platelet count > or = 80,000/microL, PS of 1 and platelet count > or = 120,000/microL, or PS of 2 and platelet count > or = 160,000/microL. Sustained complete responses (CRs) and partial responses (PRs) were observed in eight patients. CONCLUSION: 2CdA can be administered using five daily 1-hour infusions at 21.5 mg/m2/d without dose-limiting nonhematologic toxicity. Unlike continuous intravenous infusions, neurotoxicity was not observed using this schedule. Further dose escalation may be possible in good PS patients with adequate platelet counts.
Adult↗
Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer.
PURPOSE AND METHODS: To optimize the biochemical modulation of fluorouracil (5-FU), we administered the pure I-stereoisomer of leucovorin (LV) as a 132-hour continuous intravenous infusion (CIV) with cisplatin 100 mg/m2, 5-FU 640 mg/m2/d as a 120-hour CIV, and interferon alfa-2b (IFN) at 2 MU/m2/d for 6 days for three cycles (I-PFL-IFN). Pharmacologic parameters included morning (AM) and afternoon (PM) plasma concentrations of 5-FU, LV and its active metabolite 5-methyl tetrahydrofolate (MTHF), and dihydropyrimidine dehydrogenase (DPD) activity in peripheral mononuclear cells. RESULTS: Eighty-nine patients were treated (86 stage IV). Neutropenia and mucositis were the most common toxicities. Sixty-six percent achieved a complete remission (CR). There was a trend for higher PM versus AM 5-FU concentrations (median, 1.64 v 1.51 mumoles/L; P = .08), but not for LV plus MTHF (P = .66). The mean +/- SD DPD activity was 0.21 +/- 0.14 nmol/min/mg and did not correlate with plasma concentrations of 5-FU or LV plus MTHF or clinical toxicities. Higher PM 5-FU concentrations correlated with worse leukopenia (P = .04) and severity of mucositis (P = .04). PM 5-FU concentration was higher in women than in men (P = .07), with no apparent difference in severity of toxicities. The maximum 5-FU concentration was higher in CR than non-CR patients (median, 2.01 v 1.54 mumoles/L; P = .02) and higher in women than men who achieved a CR (median, 2.77 v 1.91 mumoles/L; P = .03). No correlation of CR with dose-intensity was found. CONCLUSION: L-PFL-IFN is active in stage IV head and neck cancer. 5-FU concentration is a significant predictor of toxicity. In women, optimization of response outcome requires a higher 5-FU concentration. Individualized 5-FU dosing to obtain higher 5-FU plasma concentrations may be indicated.
Adolescent↗
Limited-sampling models for irinotecan pharmacokinetics-pharmacodynamics: prediction of biliary index and intestinal toxicity.
PURPOSE: To construct limited-sampling models (LSMs) for irinotecan (CPT-11) pharmacokinetic (PK) measures. MATERIALS AND METHODS: The recommended phase II dose of weekly CPT-11 administered as a 90-minute infusion is 145 mg/m2 with granulocyte colony-stimulating factor (G-CSF) and maximal antidiarrheal support. Diarrhea is the dose-limiting toxicity. Previously, we demonstrated a highly significant correlation between severity of diarrhea and biliary index (BI), the estimated biliary exposure of SN-38. BI was the product of total CPT-11 area under the concentration-time curve (AUC) and the relative area ratio of SN-38 to SN-38 glucuronide (SN-38G). At 145 mg/m2, PK data were available for 40 patients; 36 were also assessable for intestinal toxicity. Total plasma concentrations of CPT-11, SN-38, and SN-38G from 1.0 to 11.5 hours from the start of the infusion were evaluated. CPT-11 concentration at each time point, t, is denoted by CPT-11t. LSMs were constructed by stepwise linear regression, on a training set (n = 25), and were validated on a test set (n = 15). RESULTS: LSMs for CPT-11, SN-38, and SN-38G AUCs displayed excellent fit to the training set (R2 = .87, 0.75, and .98, respectively). AUCCPT-11 = 5.25 x CPT-11(3.0) + 20.60 x CPT-11(11.5) + 1,520.53; AUCSN-38 = 5.38 x SN-38(3.5) + 33.61 x SN-38(11.5) - 7.73; and AUCSN-38G = 10.73 x SN-38G9.5 + 20.66 x SN-38G11.5 + 142.69. BI at each time point (denoted BIt) was calculated as CPT-11t x (SN-38t/SN-38Gt). Several promising LSMs were defined by BI3.5 paired with BI7.5 (R2 = .63) or BI9.5 (R2 = .76), or BI5.5 paired with BI9.5 (R2 = .76). Predicted BI from each model (categorized into low, intermediate, or high) accurately predicted observed intestinal toxicity grade (P < or = .005). CONCLUSION: These LSMs appear to accurately predict PK parameters of CPT-11. Notably, BI, predicted from several LSMs, accurately predicted intestinal toxicity and thus may be useful for future trials that use adaptive control with feedback.
Antineoplastic Agents, Phytogenic↗