J L Grem

University of Nebraska Medical Center, Omaha, Nebraska, United States

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Publications (162)1051.79 Total impact

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    ABSTRACT: BACKGROUND Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU).METHODS Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m2 on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m2/48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase.RESULTSMucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity.CONCLUSIONS The recommended dose of PDX was 148 mg/m2. A subset of heavily pretreated patients had PFS durations of ≥6 months with this regimen. Cancer 2015. © 2015 American Cancer Society.
    Cancer 08/2015; 121(21). DOI:10.1002/cncr.29504 · 4.89 Impact Factor
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    ABSTRACT: PurposeThis study evaluated the influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its metabolite M8 in pancreatic cancer patients.Methods Nelfinavir was administered orally to patients for over ten days. The plasma concentrations of nelfinavir and M8 were measured by HPLC. The genotypes of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were determined by the polymerase chain reaction-restriction fragment length polymorphism method.ResultsPharmacokinetic profiles of nelfinavir and M8 were characterized by wide interindividual variability. The mean Cmax of nelfinavir in CYP2C19*1/*1 patients was 3.89 ± 0.40 (n = 3) and 5.12 ± 0.41 (n = 30) µg/mL, while that of CYP2C19*1/*2 patients was 3.60 (n = 1) and 6.14 ± 0.31 (n = 5) µg/mL at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. For the M8 metabolite, the mean Cmax of CYP2C19*1/*1 patients was 1.06 ± 0.06 (n = 3) and 1.58 ± 0.27 (n = 30) µg/mL, while those of CYP2C19*1/*2 patients was 1.01 (n = 1) and 1.23 ± 0.15 (n = 5) µg/mL at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The area under the plasma concentration-time curve (AUC0-12h) values of nelfinavir for CYP2C19*1/*1 patients was 28.90 ± 1.27 and 38.90 ± 4.99 µg/mL∙h, and for CYP2C19*1/*2 patients, AUC0-12h was 28.20 (n = 1) and 40.22 ± 3.17 (n = 5) µg/mL∙h at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The Cmax of nelfinavir was significantly higher (p <0.05) in CYP2C19*1/*2 patients but there was no statistical difference in AUC0-12h.ConclusionCYP2C19*1/*2 genotype modestly affected the pharmacokinetic profiles of nelfinavir and M8 in patients with locally advanced pancreatic cancer.
    British Journal of Clinical Pharmacology 03/2015; 80(2). DOI:10.1111/bcp.12620 · 3.88 Impact Factor
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    ABSTRACT: Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m(2) and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.
    Evidence-based Complementary and Alternative Medicine 10/2013; 2013(6):964592. DOI:10.1155/2013/964592 · 1.88 Impact Factor
  • Shanmuga P. Subbiah · Jean L. Grem ·
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    ABSTRACT: Research assessing the worth of adjuvant chemotherapy for stage II colon cancer has been ongoing for several decades. The majority of studies have not demonstrated a significant improvement in survival. Despite this, many patients with stage II disease deemed to be at high-risk for recurrence do receive postoperative chemotherapy. The benefit of adjuvant therapy in such high-risk patients has been suggested by retrospective analyses of phase III trials. Molecular and genetic factors are being investigated to learn if they can predict those who might benefit most from adjuvant therapy. The results of randomized trials and pooled analyses will be reviewed to argue that the majority of stage II colon cancer patients should not receive adjuvant chemotherapy. Prospective studies addressing the benefit of adjuvant chemotherapy in high-risk patients are a high priority.
    Current Colorectal Cancer Reports 09/2012; 8(3). DOI:10.1007/s11888-012-0136-3
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    Phytomedicine 10/2011; 18:S12. DOI:10.1016/j.phymed.2011.09.029 · 3.13 Impact Factor
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    ABSTRACT: To examine patterns of fatigue and other variables (sleep quality, sleep-wake variables, activity and rest, circadian rhythms, quality of life [QOL], blood counts, and demographic and medical variables) during colon and rectal cancer adjuvant chemotherapy, as well as feasibility of the study. Longitudinal, descriptive feasibility study. Two oncology clinics in the midwestern region of the United States. From April 2006-December 2008, 27% of screened subjects (n = 21) enrolled and 14 completed the study. Participants were middle aged, partnered, and employed and had postsecondary education. Measurements completed during the first week of three two-week cycles (chemotherapy 1-3) and at six weeks (before chemotherapy 4) were the Piper Fatigue Scale, Pittsburgh Sleep Quality Index, wrist actigraphy, Functional Assessment of Cancer Therapy-Colon, blood counts, and demographic and medical data form. Analysis included descriptive statistics and repeated-measures analysis of variance. Fatigue, sleep quality, sleep-wake variables, activity-rest, circadian activity rhythms, and QOL. Fatigue was mild at baseline and rose to moderate levels during chemotherapy 1-3. Sleep quality was poor the months prior to chemotherapy 1 and chemotherapy 4. Actigraphy data revealed disturbed sleep, low daytime activity, and impaired circadian activity rhythms during the first week after chemotherapy 1-3. QOL ratings were similar to those in other cancer populations. Fatigue increased, and white blood cell counts decreased significantly over time. During adjuvant chemotherapy, patients reported moderate fatigue and poor sleep quality; actigraphs confirmed problems with sleep maintenance as well as low daytime activity and disturbed circadian rhythms. Multiple barriers were encountered during the study. Clinicians should screen for fatigue and sleep-wake variables and use guidelines to select interventions.
    Oncology Nursing Forum 11/2010; 37(6):E359-69. DOI:10.1188/10.ONF.E359-E369 · 2.79 Impact Factor
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    ABSTRACT: National Institutes of Health (NIH) consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality (AHRQ); 2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session; 3) questions and statements from conference attendees during open discussion periods that are part of the public session; and 4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the U.S. government. The statement reflects the panel's assessment of medical knowledge available at the time the statement was written. Thus, it provides a "napshot in time" of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical research.
    Hepatology 05/2009; 49(5 Suppl):S4-S12. DOI:10.1002/hep.22946 · 11.06 Impact Factor

  • Annals of internal medicine 01/2009; 150(2):104-10. DOI:10.1053/gast.2002.1232082 · 17.81 Impact Factor
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    ABSTRACT: Over-expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in tumor tissue is associated with insensitivity to 5-fluorouracil (5-FU). Over-expression of ERCC1 correlates with insensitivity to oxaliplatin (OX) therapy, while high thymidine phosphorylase (TP) levels predict for increased sensitivity to capecitabine (Xel). Biopsies of metastatic tumor were taken before OX (130 mg/m2 day 1) given with Xel (1200-3000 mg/m2 in two divided doses days 1-5 and 8-12) every 3-weeks. Micro-dissected metastatic and primary tumors were analyzed for relative gene expression by real-time quantitative polymerase chain reaction. The clinical protocol prospectively identified the molecular targets of interest that would be tested. Endpoints for the molecular analyses were correlation of median, first and third quartiles for relative gene expression of each target with response, time to treatment failure (TTF), and survival. Among 91 patients participating in this trial; 97% had colorectal cancer. The median number of prior chemotherapy regimens was 2, and most had prior 5-FU and irinotecan. In paired samples, median mRNA levels were significantly higher in metastatic versus primary tumor (-fold): TS (1.9), DPD (3.8), ERCC1 (2.1) and TP (1.6). A strong positive correlation was noted between DPD and TP mRNA levels in both primary (r = 0.693, p < 0.0005) and metastatic tissue (r = 0.697, p < 0.00001). There was an association between TS gene expression and responsive and stable disease: patients whose intratumoral TS mRNA levels were above the median value had significantly greater risk of early disease progression (43% vs 17%), but this did not translate into a significant difference in TTF. ERCC1 gene expression above the third quartile was associated with a shorter TTF (median 85 vs 162 days, p = 0.046). Patients whose TS mRNA levels in metastatic tumor tissue were below the median had a longer overall survival (median 417 vs 294 days, p = 0.042). Target gene expression in primary tumor was significantly lower than that in paired metastatic tissue. High ERCC1 mRNA levels in metastatic tumor was associated with a shorter TTF. Lower expression of TS mRNA correlated with a lower chance of early PD with XelOX therapy and improved overall survival.
    BMC Cancer 12/2008; 8(1):386. DOI:10.1186/1471-2407-8-386 · 3.36 Impact Factor
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    ABSTRACT: To provide health care providers, patients, and the general public with a responsible assessment of currently available data on the management of hepatitis B. A non-DHHS, nonadvocate 12-member panel representing the fields of hepatology and liver transplantation, gastroenterology, public health and epidemiology, infectious diseases, pathology, oncology, family practice, internal medicine, and a public representative. In addition, 22 experts from pertinent fields presented data to the panel and conference audience. Presentations by experts and a systematic review of the literature prepared by the Minnesota Evidence-based Practice Center, through the Agency for Healthcare Research and Quality. Scientific evidence was given precedence over anecdotal experience. The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was presented on the final day of the conference and circulated to the audience for comment. The panel released a revised statement later that day at http://consensus.nih.gov. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government. The most important predictors of cirrhosis or hepatocellular carcinoma in persons who have chronic HBV are persistently elevated HBV DNA and ALT levels in blood. Other risk factors include HBV genotype C infection, male sex, older age, family history of hepatocellular carcinoma, and co-infection with HCV or HIV. The major goals of anti-HBV therapy are to prevent the development of progressive disease, specifically cirrhosis and liver failure, as well as hepatocellular carcinoma development and subsequent death. To date, no RCTs of anti-HBV therapies have demonstrated a beneficial impact on overall mortality, liver-specific mortality, or development of hepatocellular carcinoma. Most published reports of hepatitis therapy use changes in short-term virologic, biochemical, and histologic parameters to infer likelihood of long-term benefit. Approved therapies are associated with improvements in intermediate biomarkers, including HBV DNA, HBeAg loss or seroconversion, decreases in ALT levels, and improvement in liver histology (Table). Although various monitoring practices have been recommended, no clear evidence exists for an optimal approach. The most important research needs include representative prospective cohort studies to define the natural history of the disease and large RCTs of monotherapy and combined therapies, including placebo-controlled trials, that measure the effects on clinical health outcomes. Table. Criteria Useful in Determining for Whom Therapy is Indicated: Patients for whom therapy is indicated: Patients who have acute liver failure, cirrhosis and clinical complications, cirrhosis or advanced fibrosis and HBV DNA in serum, or reactivation of chronic HBV after chemotherapy or immunosuppression; Infants born to women who are HBsAg-positive (immunoglobulin and vaccination). Patients for whom therapy may be indicated: Patients in the immune-active phase who do not have advanced fibrosis or cirrhosis. Patients for whom immediate therapy is not routinely indicated: Patients with chronic hepatitis B in the immune-tolerant phase (with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy); Patients in the inactive carrier or low replicative phase (with low levels of or no detectable HBV DNA in serum and normal serum ALT levels); Patients who have latent HBV infection (HBV DNA without HBsAg). We recommend routine screening for hepatitis B of newly arrived immigrants to the United States from countries where the HBV prevalence rate is greater than 2%. Screening will facilitate the provision of medical and public health services for infected patients and their families and provide public health data on the burden of disease in immigrant populations. The screening test should not be used to prohibit immigration.
    NIH consensus and state-of-the-science statements 11/2008; 25(2):1-29.
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    ABSTRACT: This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients. Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] >or= 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long. The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose. Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure.
    Journal of Clinical Oncology 03/2008; 26(4):570-6. DOI:10.1200/JCO.2007.13.3819 · 18.43 Impact Factor
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    ABSTRACT: To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD). Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588. In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (+/- SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) were 162 +/- 155, 171 +/- 72, 182 +/- 157, and 185 +/- 172 (mug/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups. Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.
    Journal of Clinical Oncology 03/2008; 26(4):563-9. DOI:10.1200/JCO.2007.11.0304 · 18.43 Impact Factor
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    ABSTRACT: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function. Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, >or=60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2. Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the beta-half-life was significantly prolonged by renal impairment, with values of 14.0 +/- 4.3, 20.3 +/- 17.7, 29.2 +/- 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 +/- 5.03, 39.7 +/- 11.5, and 44.6 +/- 14.6 mug.h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min). Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.
    Clinical Cancer Research 08/2007; 13(16):4832-9. DOI:10.1158/1078-0432.CCR-07-0475 · 8.72 Impact Factor
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    ABSTRACT: Oxaliplatin, an effective cytotoxic treatment in combination with 5-fluorouracil for colorectal cancer, is associated with sensory, motor and autonomic neurotoxicity. Motor symptoms include hyperexcitability while autonomic effects include urinary retention, but the cause of these side-effects is unknown. We examined the effects on motor nerve function in the mouse hemidiaphragm and on the autonomic system in the vas deferens. In the mouse diaphragm, oxaliplatin (0.5 mM) induced multiple endplate potentials (EPPs) following a single stimulus, and was associated with an increase in spontaneous miniature EPP frequency. In the vas deferens, spontaneous excitatory junction potential frequency was increased after 30 min exposure to oxaliplatin; no changes in resting Ca2+ concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected. In both tissues, an oxaliplatin-induced increase in spontaneous activity was prevented by the voltage-gated Na+ channel blocker tetrodotoxin (TTX). Carbamazepine (0.3 mM) also prevented multiple EPPs and the increase in spontaneous activity in both tissues. In diaphragm, β-pompilidotoxin (100 μM), which slows Na+ channel inactivation, induced multiple EPPs similar to oxaliplatin's effect. By contrast, blockers of K+ channels (4-aminopyridine and apamin) did not replicate oxaliplatin-induced hyperexcitability in the diaphragm. The prevention of hyperexcitability by TTX blockade implies that oxaliplatin acts on nerve conduction rather than by effecting repolarisation. The similarity between β-pompilidotoxin and oxaliplatin suggests that alteration of voltage-gated Na+ channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin. British Journal of Pharmacology (2005) 146, 1027–1039. doi:10.1038/sj.bjp.0706407
    British Journal of Pharmacology 01/2006; 146(7):1027-39. DOI:10.1038/sj.bjp.0706407 · 4.84 Impact Factor
  • Jean L Grem ·

    Clinical Cancer Research 08/2005; 11(14):5067-8. DOI:10.1158/1078-0432.CCR-05-0769 · 8.72 Impact Factor
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    ABSTRACT: We have reported that increasing the length of infusion from 5 min to 1 h appeared to substantially reduce the toxicity associated with fluorouracil (5-FU) modulated by leucovorin (LV) and interferon alpha-2a (IFN-alpha). This phase II study assessed the antitumor efficacy of this regimen. Patients (n=38) with colorectal cancer received IFN-alpha 5 MU/m(2) SC on days 1-6; on days 2-6, LV 200 mg/m(2) IV was given with 5-FU at initial doses of 370-425 mg/m(2)/h. The regimen was well-tolerated with no grade 4 toxicity. At 425 mg/m(2) 5-FU, grade 3 toxicities included diarrhea (8.6%), anorexia, fever and fatigue (5.7% each), neutropenia and nausea/vomiting (2.9% each). Individuals tolerated 5-FU doses up to 644 mg/m(2). Objective responses occurred in 27% of 37 patients; median time to progression and survival were 6.1 and 12.9 months. Only 1 of 25 informative tumor samples had high-frequency microsatellite instability (MSI), while 7 of 23 assessable patients (30%) with MSI-negative tumors had an objective response. With 425 mg/m(2), the average 5-FU Cp and AUC(0-1 h) were 37.4 microM and 1161 microM/h. Some 6 patients had extended sampling, and the half-lives of 5-FU and FBAL (apparent) were 8.6 and 100.0 min, respectively. A 1-h infusion of 5-FU is well tolerated; individual dose escalation of 5-FU allows each patient to receive the maximum tolerable dose.
    Oncology Reports 07/2005; 13(6):1145-52. DOI:10.3892/or.13.6.1145 · 2.30 Impact Factor
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    ABSTRACT: In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions. CPT-11 was first given at four levels (70-140 mg/m(2)/24 hours), followed by leucovorin 500 mg/m(2)/0.5 hours and 5-FU 2,000 mg/m(2)/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m(2)/48 hours. Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 micromol/L at 3,900 mg/m(2)/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m(2)/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with >/=1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype. Doses (mg/m(2)) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.
    Clinical Cancer Research 06/2005; 11(11):4144-50. DOI:10.1158/1078-0432.CCR-04-2439 · 8.72 Impact Factor
  • Jean L Grem ·
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    ABSTRACT: Identification of molecular markers at either the intragenic, chromosomal, mRNA, or protein level that might predict whether colorectal cancer patients are likely to benefit from adjuvant or palliative therapy is a high priority. The majority of clinical studies addressing this issue, particularly those done in the adjuvant setting, analyzed tumor samples from patients treated in the era when 5-fluorouracil (5-FU) alone or combined with leucovorin or levamisole were the mainstay of therapy. This review highlights some of the intratumoral molecular markers that may have importance as predictors of benefit with 5-FU-based therapy. Although the goal of these investigations is to one day permit selection of therapy for an individual patient based on the tumor phenotype, prospective studies have yet to be conducted that test whether selection of therapy based on molecular markers results in an improved outcome.
    Seminars in Oncology 03/2005; 32(1):120-7. DOI:10.1053/j.seminoncol.2004.09.027 · 3.90 Impact Factor
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    ABSTRACT: To determine the clinical toxicities of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks. Nineteen patients received 17-AAG over six dose levels (10 to 56 mg/m(2)) using an accelerated titration scheme. Drug levels of 17-AAG were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored by changes in the content of target proteins by immunoblot analysis of lysates prepared from peripheral-blood mononuclear cells. Toxicity was acceptable at doses up to 28 mg/m(2). The cohort was expanded to three patients at 40 mg/m(2) because a second occurrence of grade 2 hepatic transaminitis occurred. Two of six assessable patients who received 56 mg/m(2) had reversible, grade 3 hepatic transaminitis. Five additional patients were enrolled at 40 mg/m(2); none had dose-limiting toxicity. The maximum plasma concentrations (C(max)) of 17-AAG at 40 and 56 mg/m(2) were 1,724 and 2,046 ng/mL, respectively; the average plasma exposures (AUC) were 2,809 and 6,708 hours.ng/mL, respectively. Less than 3% of the daily dose was excreted into the urine. Clearance did not correlate with body-surface area. Possible biologic activity was suggested by apparent increased protein content of either glucose-related 78 kd protein or heat shock protein 70 with >/= 14 mg/m(2) and decreased protein content of either Lck or Raf1 with >/= 28 mg/m(2) of 17-AAG. 17-AAG 40 mg/m(2) (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.
    Journal of Clinical Oncology 03/2005; 23(9):1885-93. DOI:10.1200/JCO.2005.12.085 · 18.43 Impact Factor
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    ABSTRACT: New chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity. A detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity. Eighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients. Oxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity.
    BMC Cancer 02/2005; 5(1):116. DOI:10.1186/1471-2407-5-116 · 3.36 Impact Factor

Publication Stats

5k Citations
1,051.79 Total Impact Points


  • 2004-2015
    • University of Nebraska Medical Center
      • • Department of Pharmaceutical Sciences
      • • Division of Oncology and Hematology
      Omaha, Nebraska, United States
  • 2011-2013
    • University of Nebraska at Omaha
      Omaha, Nebraska, United States
  • 2004-2012
    • The Nebraska Medical Center
      Omaha, Nebraska, United States
  • 2008
    • Translational Genomics Research Institute
      Phoenix, Arizona, United States
    • West Virginia University
      MGW, West Virginia, United States
  • 2003-2007
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2006
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
  • 1993-2004
    • National Institutes of Health
      • • Center for Cancer Research
      • • Branch of Surgery
      • • Branch of Medical Oncology Branch and Affiliates
      Maryland, United States
  • 1987-2004
    • National Cancer Institute (USA)
      • • Center for Cancer Research
      • • Cancer Therapy Evaluation Program
      • • Developmental Therapeutics Program
      • • Community Clinical Oncology Program (CCOP)
      • • Surgery Branch
      Maryland, United States
  • 1990
    • Northern Inyo Hospital
      BIH, California, United States
  • 1988
    • University of Pretoria
      Πρετόρια/Πόλη του Ακρωτηρίου, Gauteng, South Africa
  • 1985-1988
    • University of Wisconsin–Madison
      • Department of Human Oncology
      Madison, Wisconsin, United States