Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.

The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1*28, UGT1A1*93 and SLCO1B1*1b in univariate analyses. For irinotecan area under the concentration-time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A1*28 and UGT1A1*93. In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.

Genetic features of Lynch syndrome in the Israeli population.

Diagnosis of Lynch syndrome (LS) may be complex. Knowledge of mutation spectrum and founder mutations in specific populations facilitates the diagnostic process. Aim of the study is to describe genetic features of LS in the Israeli population and report novel and founder mutations. Patients were studied at high-risk clinics. Diagnostics followed a multi-step process, including tumor testing, gene analysis and testing for founder mutations. LS was defined by positive mutation testing. We diagnosed LS in 242 subjects from 113 families coming from different ethnicities. We identified 54 different mutations; 13 of them are novel. Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2; 27% of the MSH2 mutations were large deletions. Seven founder mutations were detected in 61/113 (54%) families. Constitutional mismatch repair deficiency (CMMR-D) was identified in five families. Gene distribution in the Israeli population is unique, with relatively high incidence of mutations in MSH2 and MSH6. The mutation spectrum is wide; however, 54% of cases are caused by one of seven founder mutations. CMMR-D occurs in the context of founder mutations and consanguinity. These features should guide the diagnostic process, risk estimation, and genetic counseling.

Neutron skin of (208)pb from coherent pion photoproduction.

Information on the size and shape of the neutron skin on (208)Pb is extracted from coherent pion photoproduction cross sections measured using the Crystal Ball detector together with the Glasgow tagger at the MAMI electron beam facility. On exploitation of an interpolated fit of a theoretical model to the measured cross sections, the half-height radius and diffuseness of the neutron distribution are found to be c(n)=6.70±0.03(stat.) fm and a(n)=0.55±0.01(stat.)(-0.03)(+0.02)(sys.) fm, respectively, corresponding to a neutron skin thickness Δr(np)=0.15±0.03(stat.)(-0.03)(+0.01)(sys.) fm. The results give the first successful extraction of a neutron skin thickness with an electromagnetic probe and indicate that the skin of (208)Pb has a halo character. The measurement provides valuable new constraints on both the structure of nuclei and the equation of state for neutron-rich matter.

Determinants of Pouch-Related Symptoms, a Common Outcome of Patients With Adenomatous Polyposis Undergoing Ileoanal Pouch Surgery.

INTRODUCTION: Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is performed in patients with adenomatous polyposis syndromes (APSs). Data regarding pouch outcomes in APS are scarce. The purposes of this study were to determine the prevalence of pouch-related symptoms in patients with APS and to identify the contributing factors. METHODS: This is a prospective cohort study. Demographic, surgical, and clinical data were collected. Endoscopy was performed, and biopsies from the terminal ileum, pouch, and cuff were obtained in all patients and reviewed by a dedicated pathologist. RESULTS: Fifty-one patients with APS after IPAA were followed. Twenty patients (39.2%) had pouch-related symptoms. Single-stage IPAA had better outcomes than 2-stage IPAA: fewer daily bowel movements (42.9% vs 13.8% with ≤5 daily bowel movement, P = 0.02), more solid consistency (52.4% vs 6.9%, P < 0.001), and less abdominal pain (19% vs 48.3%, P = 0.034). Younger age at IPAA (<20) was also associated with better outcomes: fewer daily bowel movement (58.3% vs 17.9% with ≤5 daily bowel movement, P = 0.011), less watery consistency (8.3% vs 53.8%, P = 0.005), and abdominal pain (8.3% vs 43.6%, P = 0.037). Eighteen patients (35.3%) had endoscopic signs of inflammation, and 22 patients (43.1%) had histologic signs of pouchitis. However, no correlation was found between symptoms and endoscopic or histologic findings. The median pouchitis disease activity index was low (2, interquartile range 1-4) and did not correlate with clinical symptoms. DISCUSSION: Pouch-related symptoms are common in patients with APS after IPAA. One-stage IPAA and younger age at surgery are associated with better clinical outcomes. However, symptoms do not correlate well with endoscopic or histologic findings or with pouchitis disease activity index and might be attributed to a functional pouch disorder.

Investigation of the exclusive 3He(e,e' pn)1H reaction.

Cross sections for the 3He(e,e' pn)1H reaction were measured for the first time at energy transfers of 220 and 270 MeV for several momentum transfers ranging from 300 to 450 MeV/c. Cross sections are presented as a function of the momentum of the recoil proton and the momentum transfer. Continuum Faddeev calculations using the Argonne V18 and Bonn-B nucleon-nucleon potentials overestimate the measured cross sections by a factor 5 at low recoil proton momentum with the discrepancy becoming smaller at higher recoil proton momentum.

PARTICLE PHYSICS: Enhanced: How Strange Is the Proton?

Nucleons (protons and neutrons) have been extensively studied over the past 30 or 40 years, but our knowledge of their internal structure remains rather limited, largely because the nucleon's constituents, the quarks, are so tightly bound that the nucleon cannot be taken apart. As Rosner discusses in his Perspective, scattering experiments are providing increasingly detailed information about the spatial distribution of charges, spins, and currents within the nucleon. He highlights the work by Hasty et al., which goes a long way toward determining the role of "strange" quarks, originally thought not to play a role in ordinary matter.

Translocation and rearrangement of myeloperoxidase gene in acute promyelocytic leukemia.

Acute promyelocytic leukemia (subtype M3) is characterized by malignant promyelocytes exhibiting an abundance of abnormally large or aberrant primary granules. Myeloperoxidase (MPO) activity of these azurophilic granules, as assessed by cytochemical staining, is unusually intense. In addition, M3 is universally associated with a chromosomal translocation, t(15;17)(q22;q11.2). In this report, the MPO gene was localized to human chromosome 17 (q12-q21), the region of the breakpoint on chromosome 17 in the t(15;17), by somatic cell hybrid analysis and in situ chromosomal hybridization. By means of MPO complementary DNA clones for in situ hybridization and Southern blot analysis, the effect of this specific translocation on the MPO gene was examined. In all cases of M3 examined, MPO is translocated to chromosome 15. Genomic blot analyses indicate rearrangement of MPO in leukemia cells of two of four cases examined. These findings suggest that MPO may be pivotal in the pathogenesis of acute promyelocytic leukemia.

Acute hepatitis B in the era of immunisation: pitfalls in the identification of high risk patients.

BACKGROUND: Since the adoption of a universal hepatitis B immunisation strategy, the reported incidence of acute hepatitis B has declined dramatically worldwide including in Israel. However, new cases of acute hepatitis B still occur. The aim of this study was to describe the incidence of acute hepatitis B in a referral area, routes of transmission, and outcome. METHODS: The charts of all new hepatitis B patients, who visited the clinic in the years 2002 and 2003 (January 2002 to December 2003), were reviewed. The main criteria for a diagnosis of acute hepatitis B were transient increase of alanine transaminase activity, and hepatitis B surface antigen seroconversion. RESULTS: Twenty nine men and seven women were diagnosed with acute hepatitis B infection during the study period. Two patients were previously vaccinated with hepatitis B vaccine. One case of hepatitis D coinfection was reported. The incidence of acute hepatitis B in the referral area was estimated as 2.25 per 100,000 adult population. Mean age was 36 years (17-75). Twenty one patients (18 men and 3 women) acquired the virus through unprotected sexual contact, and seven patients through iatrogenic exposure. Thirty three patients underwent spontaneous seroconversion while three patients became chronic carriers. CONCLUSIONS: Despite a universal immunisation policy, frequent cases of acute hepatitis B in Israel are still seen. High risk heterosexual activity and iatrogenic exposure seem to be the commonest routes of transmission. Further recommendations regarding vaccination policy are discussed.

Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.

BACKGROUND: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. PURPOSE: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. METHODS: For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 micrograms/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. RESULTS: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts < 100/microL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%-85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. CONCLUSIONS: The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 micrograms/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. IMPLICATIONS: Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.

Combination versus single agent therapy in effecting complete therapeutic response in human bladder cancer: analysis of cisplatin and/or 5-fluorouracil in an in vivo survival model.

An in vivo study of cisplatin (CDDP) and 5-fluorouracil (5FU) cytotoxicity was performed using a multidose matrix with a human bladder transitional cell carcinoma xenograft tumor line (DU4284) tested by subrenal capsule assay in 154 nude mice (NM-SRCA). Statistical analysis of initial growth inhibition at 20 days and host survival demonstrates therapeutic, cooperative interaction. Toxic doses of either CDDP or 5FU alone as well as low-dose combinations provided modest or no survival benefit. The single dose of CDDP (7 mg/kg) and of 5FU (100 mg/kg) was best (by analysis of efficacy and toxicity) of those tested and caused > 97% initial regression. While 94% of controls incurred tumor deaths by 225 days, 75% treated at this dose were tumor free and likely cured. Our conclusions were: (a) NM-SRCA human xenograft testing is excellent for rapid in vivo screening of promising treatment strategies to evaluate for efficacy at acceptable toxicity, but confirmation of true therapeutic impact should be sought by correlating initial growth inhibition with host survival; (b) enhanced survival seen only when CDDP/5FU are used together (versus either single agent) supports the value of pursuing histiotype-specific screening of potentially synergistic drug combinations; and (c) of clinical relevance, human transitional cell carcinoma is now identified as a histiotype in which a therapeutic, cooperative interaction between CDDP/5FU has been demonstrated in vivo.

Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565.

PURPOSE: To ascertain if hepatic or renal dysfunction leads to increased toxicity at a given dose of gemcitabine and to characterize the pharmacokinetics of gemcitabine and its major metabolite in patients with such dysfunction. PATIENTS AND METHODS: Adults with tumors appropriate for gemcitabine therapy and who had abnormal liver or renal function tests were eligible. Patients were assigned to one of three treatment cohorts: I-AST level less than or equal to two times normal and bilirubin level less than 1.6 mg/dL; II-bilirubin level 1.6 to 7.0 mg/dL; and III-creatinine level 1.6 to 5.0 mg/dL with normal liver function. Doses were explored in at least three patients within each cohort. Gemcitabine and its metabolite were to be measured in the blood in all patients. RESULTS: Forty patients were assessable for toxicity. Transient transaminase elevations were observed in many patients but were not dose limiting. Patients with AST elevations tolerated gemcitabine without increased toxicity, but patients with elevated bilirubin levels had significant deterioration in liver function after gemcitabine therapy. Patients with elevated creatinine levels had significant toxicity even at reduced doses of gemcitabine, including two instances of severe skin toxicity. There were no apparent pharmacokinetic differences among the three groups or compared with historical controls. CONCLUSION: If gemcitabine is used for patients with elevations in AST level, no dose reduction is necessary. Patients with elevated bilirubin levels have an increased risk of hepatic toxicity, and a dose reduction is recommended. Patients with elevated creatinine levels seem to have increased sensitivity to gemcitabine, but the data are not adequate to support a specific dosing recommendation.

Population pharmacodynamic study of amonafide: a Cancer and Leukemia Group B study.

PURPOSE: To determine if variability in toxicity of amonafide during phase II trials could be correlated with pharmacokinetic variability. PATIENTS AND METHODS: Seventy-three patients enrolled onto three Cancer and Leukemia Group B (CALGB) phase II trials of amonafide (300 mg/m2 daily for 5 days) were studied, using a limited sampling strategy (45 minutes and 24 hours) to estimate the amonafide area under the plasma concentration-time curve (AUC). Concentrations of N-acetyl-amonafide, an active metabolite, were also determined. RESULTS: The primary determinant of toxicity at a fixed dose of amonafide was the extent of N-acetylation. Fast acetylators (36% of patients) had significantly greater toxicity than slow acetylators (64% of patients), with median WBC nadirs of 500/microL and 3,400/microL, respectively (P < or = .001). In a multivariate analysis, lower pretreatment WBC count, lower albumin level, and nonwhite race were also independently associated with toxicity. Further analysis of interracial differences demonstrated that minority women had slower clearance of amonafide (P = .026) and a higher incidence of grade 4 leukopenia (P = .042). CONCLUSION: The highly variable toxicity of amonafide is primarily due to genetic differences in N-acetylation. Other genetic (race) and acquired factors (baseline WBC count and albumin level) also appear to influence the extent of toxicity observed following administration of this agent.

4-Hydroperoxycyclophosphamide purging of breast cancer from the mononuclear cell fraction of bone marrow in patients receiving high-dose chemotherapy and autologous marrow support: a phase I trial.

We designed an ex vivo bone marrow treatment for breast cancer patients receiving high-dose chemotherapy and autologous bone marrow support (ABMS), using 4-hydroperoxycyclophosphamide (4-HC), an active derivative of cyclophosphamide with known activity against breast cancer. This phase I bone marrow purging trial used ficoll-separated mononuclear cells (MNC) (devoid of granulocytes and RBCs), as opposed to the buffy coat. Twenty-five patients with metastatic breast cancer were studied. Patients received three cycles of the Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), fluorouracil, and methotrexate (Duke AFM) regimen, followed by marrow harvest. An MNC fraction of marrow was prepared and treated with 4-HC in concentrations of 20 micrograms/mL (four patients), 40 micrograms/mL (four patients), 60 micrograms/mL (nine patients), or 80 micrograms/mL (eight patients) and cryopreserved. Patients then received high-dose systemic cyclophosphamide, cisplatin, and carmustine, followed by infusion of the purged marrow. The study end point was marrow engraftment, defined as WBC count greater than 1,000 cells per microliter. At the first three dose levels (20, 40, and 60 micrograms/mL 4-HC), there was no significant delay in time to engraftment (19, 20, and 23 days, respectively) compared with the unpurged historical controls (17 days). At 80 micrograms/mL, engraftment was significantly delayed compared with the lower concentrations (P = .027), and further escalation of 4-HC was not attempted. A significant correlation was observed between the time of leukocyte engraftment and the 4-HC concentration (P = .017). With a methylcellulose-based tissue culture assay, we demonstrated a statistically significant correlation between the colony-forming unit-granulocyte-macrophage (CFU-GM) content in the purged marrow and the days to engraftment. Ninety-five percent of patients responded clinically to the entire program, 55% of them completely. Longer follow-up is required to assess the ultimate benefit of intensive therapy on long-term survival.

Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541.

PURPOSE: We examined data from a large clinical trial to determine if chemotherapy dosing according to actual body weight places obese patients at greater risk of toxicity. PATIENTS AND METHODS: Cancer and Leukemia Group B (CALGB) study 8541, a randomized study of schedule and dose of adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) for stage II breast cancer patients with positive regional lymph nodes, provided data on 1,435 women for analysis. Using body-mass index (BMI), we classified a woman as obese if her BMI was > or = 27.3 kg/m2; doses were considered weight-based if within 5% of values calculated using actual weight. Our primary analysis concerned toxicity risks during cycle 1. RESULTS: Among women who received weight-based doses of the most dose-intensive CAF regimen, 47% of obese and 51% of nonobese women experienced severe hematologic toxicity (grade > or = 3) during cycle 1 (P = .51, two-tailed). The overall risk ratio (obese v nonobese) of treatment failure among women who received weight-based doses during cycle 1 was 1.02 (95% confidence interval, 0.83 to 1.26), stratified by treatment and adjusted for number of positive nodes, menopausal status, hormone receptor status, and tumor size. The overall adjusted failure risk ratio (weight-based v reduced initial doses) was 0.73 (95% confidence interval, 0.53 to 1.00) among obese women. CONCLUSION: Obese patients initially dosed (within 5%) by actual weight did not experience excess cycle 1 toxicity or worse outcome compared with nonobese women dosed similarly. The data suggest that obese women who received reduced doses in cycle 1 experienced worse failure-free survival. We recommend that initial doses of CAF be computed according to actual body weight.

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

PURPOSE: The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS: Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS: Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION: Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

Phase I and pharmacologic study of continuous infusion topotecan in combination with cisplatin in patients with advanced cancer: a Cancer and LeukemiaGroup B study.

PURPOSE: Preclinical and clinical data suggest that topotecan may be more effective, and perhaps less toxic, when administered as a continuous intravenous infusion (CIVI). A previous Cancer and Leukemia Group B (CALGB) trial of topotecan, given on a daily bolus schedule in combination with cisplatin, produced more hematologic toxicity than expected with either drug alone. Therefore, we designed this phase I trial to define the dose-limiting toxicities (DLTs) and the recommended phase II doses of cisplatin in combination with topotecan administered as a CIVI. Population pharmacodynamic models for the combination also were investigated. PATIENTS AND METHODS: Patients with advanced solid tumors and a maximum of one prior chemotherapy regimen for metastatic disease were eligible if they had a performance status of 0 to 1 and adequate renal, hepatic, and bone marrow function. Prior treatment with camptothecins or platinum compounds and prior pelvic irradiation were not allowed. The initial schedule consisted of a fixed dose of topotecan 0.4 mg/m2/d administered as a CIVI for 21 days and escalating doses of cisplatin administered on days 1, 8, and 15 of a 28-day schedule, until the maximum tolerated dose (MTD) was achieved. After severe hematologic toxicity was observed in the first two patients, the topotecan infusion was shortened to 14 days, and the total dose of cisplatin was administered on day 1 in all subsequent patients. After the MTD was defined, that cohort was expanded to include a total of 12 assessable patients. Hematopoietic growth factors were not allowed. For the pharmacologic studies, total topotecan plasma concentrations were measured by high-pressure liquid chromatography (HPLC) during infusion on days 3, 8, and 11 on the first cycle, and the median steady-state concentration (Tss) was determined. Platinum plasma concentrations on day 3 were measured by atomic absorption spectrometry. RESULTS: Of the 32 patients enrolled, 28 were assessable for toxicity and 24 for response. The primary toxicity was hematologic, with both neutropenia and thrombocytopenia being dose-limiting. The MTD of cisplatin was 75 mg/m2 on day 1 in combination with topotecan 0.4 mg/m2/d for 14 days. At this dose level, three of a total of 12 assessable patients had DLT. The pharmacodynamic relationship between Tss and the absolute neutrophil count at the nadir (ANCn) was described by the following equation: log10 (ANCn)=4.23 - 0.47 x Tss - 0.01 x cisplatin dose (P < .0001; R2=0.64). The substitution of platinum concentration for cisplatin dose in this model did not result in a significant improvement. Three patients had a partial response: one with duodenal carcinoma; a second with small-cell lung cancer; and a third with melanoma. CONCLUSION: Cisplatin can be given safely in combination with CIVI topotecan. However, toxicity was still substantial. Based on the current results and our previous trial of this combination, we conclude that, when combined with cisplatin, CIVI topotecan does not seem to be advantageous compared with the more traditional daily bolus schedule.

Evaluation of the combination of nelarabine and fludarabine in leukemias: clinical response, pharmacokinetics, and pharmacodynamics in leukemia cells.

PURPOSE: A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the prodrug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate. PATIENTS AND METHODS: Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m(2)) was infused on days 1, 3, and 5. On days 3 and 5, fludarabine (30 mg/m(2)) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days. RESULTS: Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P =.001) in responders (890 micromol/L, n = 6) and nonresponders (30 micromol/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27). CONCLUSION: Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine.

Phase I study of paclitaxel and topotecan in patients with advanced tumors: a cancer and leukemia group B study.

PURPOSE: To define the dose-limiting toxicities (DLTs) and the recommended phase II doses of paclitaxel combined with topotecan, without and with filgrastim support. PATIENTS AND METHODS: Patients with advanced solid tumors and a maximum of one prior chemotherapy regimen for metastatic disease were eligible if they had a performance status of 0 to 1 and normal renal, hepatic, and bone marrow function. Prior treatment with taxanes or comptothecin analogs, and prior pelvic irradiation were not allowed. Patients with a history of cardiac disease or on medications known to affect cardiac conduction were excluded. The dose of topotecan was fixed at 1.0 mg/m2/d for 5 days. The dose of paclitaxel was escalated until the maximum-tolerated dose (MTD), without and with filgrastim 5 micrograms/kg subcutaneously (SC) on days 6 to 14, was reached. Paclitaxel was administered over 3 hours on day 1 before topotecan. Treatment cycles were repeated every 21 days. RESULTS: Of 46 patients entered, 45 were assessable for toxicity and 34 for response. The principal toxicity was neutropenia. Without filgrastim, the MTD of paclitaxel was 80 mg/m2 on day 1 in combination with topotecan 1.0 mg/m2/d for 5 days. With filgrastim, the dose of paclitaxel was escalated to 230 mg/m2 in combination with the same dose of topotecan. At this dose level, one patient had hematologic DLT and a second patient developed neuromuscular DLT. Three patients had a partial response (PR): one with head and neck cancer, a second with non-small-cell lung cancer, and the third with colon cancer. CONCLUSION: We conclude that paclitaxel can be given at clinically relevant doses in combination with topotecan and filgrastim. The recommended dose for phase II studies is paclitaxel 230 mg/m2 on day 1 and topotecan 1.0 mg/m2/day for 5 days with filgrastim 5 micrograms/kg on days 6 to 14.

Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264.

PURPOSE: To characterize the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of paclitaxel in patients with abnormal liver function. PATIENTS AND METHODS: Adults with tumors appropriate for paclitaxel therapy who had abnormal liver function tests were eligible. Patients were assigned to one of three treatment cohorts: I, AST level twofold normal and bilirubin level less than 1.5 mg/dL; II, bilirubin level 1.6 to 3.0 mg/dL; and III, bilirubin level greater than 3.0 mg/dL. Doses were explored in at least three patients within each cohort. Although designed to assess a 24-hour infusion schedule, the trial was extended to also assess a 3-hour regimen. Pharmacokinetics were to be studied in all patients. RESULTS: Eighty-one patients were assessable for toxicity. Patients with bilirubin levels greater than 1.5 mg/dL had substantial toxicity at all doses explored, whereas the toxicity for patients with elevated AST levels occurred at doses that ranged from 50 to 175 mg/m2 administered over 24 hours. In most patients, the DLT was myelosuppression. The pharmacokinetic data were insufficient to adequately evaluate the relationship between pharmacokinetics and toxicity in patients who received 24-hour infusions but provided evidence of a longer exposure to paclitaxel than anticipated for the doses used in this study in the 3-hour infusion group. CONCLUSION: If paclitaxel is used for patients with elevated levels of AST or bilirubin, dose reductions are necessary, and an increase in toxicity can be anticipated. The increased myelosuppression observed is at least partially because of altered paclitaxel pharmacokinetics in such patients.

Hyperthermia increases accumulation of technetium-99m-labeled liposomes in feline sarcomas.

The effect of hyperthermia on the accumulation of technetium-99m-labeled liposomes was studied in feline sarcomas. Each cat received two separate injections of liposomes. The first was used to quantify the amount of technetium-99m-labeled liposomes within the tumor under normothermic conditions. The second injection was made at the beginning of a 60-min hyperthermia procedure. Planar scintigraphy was used to measure the activity of technetium-99m-labeled liposomes within the tumor at predetermined times up to 18 h after injection. Regions of interest were drawn for the tumor, lungs, liver, kidney, and aorta. Counts in the regions of interest were decay corrected. Counts/pixel in the tumor under normothermic and hyperthermic conditions were normalized to aorta counts/pixel. A total of 16 cats were eligible for the study. In two of the 16 cats, incomplete count data precluded analysis. In the remaining 14 cats, hyperthermia resulted in a significant increase in liposome accumulation in the tumor (P = 0.001). Tumor volume ranged from 1.2 to 236.2 cm3, and thermal dose ranged from 2.0 to 243.3 CEM43CT90 (equivalent time that the 10th percentile temperature was equal to 43 degrees C). There was not a relationship between either tumor volume or hyperthermia dose on the magnitude of increased liposome accumulation, suggesting that this method has application across a range of tumor volumes and degrees of heatibility.