Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future.

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.

Immunotherapy to Treat Cancer.

This issue of Clinical Pharmacology & Therapeutics focuses on immunotherapy as an approach to treat cancer by generating or augmenting an immune response against it. The enthusiasm for immunotherapy has waxed and waned over the past century. Enthusiasm for immunotherapy has risen over the past decade due, in part, to data showing that cancer immunotherapy consistently improves overall survival in select patients with advanced-stage cancer. Antitumor immunotherapy has broad potential and could be used to treat many different types of advanced-stage cancer due to the durable and robust response that it elicits across a diverse spectrum of cancers. This issue covers various aspects of relevant therapeutic topics ranging from discovery of chimeric antigen receptor (CAR) T cells, development of novel immunotherapies using novel pharmacokinetic/dynamic modeling tools, to the utilization of immune checkpoint therapy. Regarding utilization, this issue addresses biomarker selection strategies for personalized treatment of non-small cell lung cancer (NSCLC) with immune checkpoint therapy and also the management of the unique immune response adverse events (irAEs).

Optimizing drug therapy in pediatric SCT: focus on pharmacokinetics.

Given age-related differences in drug metabolism and indications for hematopoietic SCT (HSCT), personalized drug dosing of the conditioning regimen and post-transplant immunosuppression may reduce graft rejection, relapse rates and toxicity in pediatric HSCT recipients. This manuscript summarizes the pharmacokinetic/dynamic data of HSCT conditioning and post-grafting immunosuppression, presented at the First Annual Pediatric Bone Marrow Transplant Consortium (PBMTC) meeting in April 2013. Personalized dosing of BU to a target plasma exposure reduces graft rejection in children and improves relapse/toxicity rates in adults. Current weight-based dosing achieves the target BU exposure in only a minority (24.3%) of children. The initial BU dose should be based on the European Medicines Agency nomogram or population pharmacokinetic models to improve the numbers of children achieving the target exposure. There are limited pharmacokinetic data for treosulfan, CY, fludarabine and alemtuzumab as HSCT conditioning in children. For post-grafting immunosuppression, mycophenolic acid (MPA) clearance may be increased in younger children (<12 years). The preferred MPA pharmacokinetic monitoring parameters and target range are still evolving in HSCT recipients. Multi-institutional trials incorporating properly powered pharmacokinetic/dynamic studies are needed to assess the effect of variability in the plasma exposure of drugs/metabolites on clinical outcomes in pediatric HSCT recipients.

Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.

Sirolimus and mycophenolate mofetil as GVHD prophylaxis in myeloablative, matched-related donor hematopoietic cell transplantation.

We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU-containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non-relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.

Patterns of blood product use among patients with myelodysplastic syndrome.

BACKGROUND AND OBJECTIVES: Most patients with myelodysplastic syndrome (MDS) require blood product support to manage the severe anaemias, which frequently accompany MDS. Our objective was to show the feasibility of linking the Surveillance, Epidemiology and End Results (SEER) database with records from Puget Sound Blood Center (PSBC) to characterize blood product use over time in successive cohorts of patients with MDS. MATERIALS AND METHODS: We identified patients with MDS in the SEER registry. The cohort was then linked to PSBC records to discern blood product use. RESULTS: Included in the analysis were 783 patients with MDS entered in the SEER database from 2001 to 2007 for whom data were also available in the PSBC database. Among patients with MDS who received transfusions, 97% received packed red blood cells; 52% received platelets. The proportion of patients with MDS receiving blood products declined from 2001 to 2007. CONCLUSION: These data show a recent decline in blood product use for patients with MDS. Future studies are needed to further evaluate the reasons for this finding, specifically exploring the impact of newer medications on blood product use in patients with MDS.

Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy.

This study investigates the efficacy and safety of personalized cyclophosphamide (CY) dosing in 50 patients receiving CY along with total body irradiation (TBI). Participants received CY 45 mg/kg with subsequent therapeutic drug monitoring using Bayesian parameter estimation to personalize the second CY dose to a target area under the curve (AUC) for carboxyethylphosphoramide mustard (CEPM) (a reporter molecule for CY-derived toxins) and for hydroxycyclophosphamide (to ensure engraftment). The mean second CY dose was 66 mg/kg; the total dose ranged from 45 to 145 mg/kg. After completion of this phase II study, we compared participants' clinical outcomes with those of concurrent controls (n = 100) who received TBI along with standard CY doses of 120 mg/kg. Patients receiving personalized CY dosing had significantly lower postconditioning peak total serum bilirubin (P = 0.03); a 38% reduction in the hazard of acute kidney injury (AKI) (P = 0.03); and nonrelapse and overall survival rates similar to those in the controls (P = 0.70 and 0.63, respectively) despite the lower doses of CY administered to most of the patients in the personalized dosage group.

Pharmacogenomic associations in ABCB1 and CYP3A5 with acute kidney injury and chronic kidney disease after myeloablative hematopoietic cell transplantation.

Renal disease is a major complication in patients following myeloablative allogeneic hematopoietic cell transplantation (HCT). Post-HCT patients receive immunosuppressive regimens containing calcineurin inhibitor (CNIs), cyclosporine or tacrolimus, for graft-versus-host disease prophylaxis. In this retrospective trial, we investigated pharmacogenomic associations in the multidrug resistance (ABCB1) and cytochrome P450 3A5 (CYP3A5) genes and acute kidney injury (AKI) and chronic kidney disease (CKD) in a cohort of 121 patients. ABCB1 and CYP3A5 are responsible for the renal disposition of CNIs, which are known to be nephrotoxic. AKI was defined as doubling of baseline serum creatinine during the first 100 days post-HCT, and CKD as at least one glomerular filtration rate <60 ml/min/m2 between 6 and 18 months post-HCT. Patients were genotyped for CYP3A5*1>*3 and ABCB1 single nucleotide polymorphisms (SNPs) (1199G>A, 1236C>T, 2677G>T/A and 3435C>T). Odds ratios were calculated using logistic regression. Haplotype estimation and univariate association analyses were performed because of strong ABCB1 linkage disequilibrium (LD). AKI occurred in 48 of 121 patients (39.7%) and CKD in 16 of 66 patients (24.2%). No pharmacogenomic associations were found between ABCB1 and CYP3A5 SNPs and the incidences of AKI or CKD. The degree of LD(r2) between ABCB1 SNPs was estimated as follows: 2677G>T/3435C>T (0.44), 1236C>T/3435C>T (0.42) and 1236C>T/2677G>T (0.72). ABCB1 1199G>A showed no LD to other SNPs (<0.05). No associations were found between the most common ABCB1 haplotypes and AKI or CKD. Since no significant pharmacogenomic associations were observed, tailoring CNIs dosing based on these genotypes is unlikely to lower significantly the risk of renal injury following myeloablative HCT.

Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation.

We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (C(SS)) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan C(SS) (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan C(SS). Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan C(SS) higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan C(SS) and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan C(SS) and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.

Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan.

Gender-based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil, and regularly menstruating women not receiving oral contraceptives. Thirty-three healthy volunteers participated in this 28-day pilot study (12 women receiving Triphasil) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7, 14, 21, and 28 using urinary ratios of DM:3-methoxymorphinan (3MM) and DM:dextrorphan (DX), respectively. Serial blood concentrations of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DX in the 28 extensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power (alpha = 0.05) to detect a +/- 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference between men, women on Triphasil, and women not receiving oral contraceptives is unlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were clearly demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.

Measured versus estimated glomerular filtration rate in the Calvert equation: influence on carboplatin dosing.

PURPOSE: Carboplatin is frequently dosed to achieve a desired area under the plasma concentration-time curve (AUC) by using the Calvert or Chatelut equations to estimate carboplatin clearance. Accurate determination of glomerular filtration rate (GFR) is necessary to correctly calculate carboplatin clearance using the Calvert equation. In clinical practice, the Cockcroft-Gault formula is frequently used to estimate GFR, but this practice has been reported to under- and overestimate carboplatin clearance. The purpose of this trial was to compare determinations of carboplatin clearance using the Chatelut equation and four separate GFR determinations, including 99mTc-DTPA, the Cockcroft-Gault formula, a 24-h urine collection and a 2-h urine collection. METHODS: Carboplatin clearance was estimated in 21 previously untreated extensive-stage small-cell lung cancer patients. GFR was determined using 99mTc-DTPA, the Cockcroft-Gault formula, 24-h urine collection and 2-h urine collection. Serum and urine creatinine concentrations were measured using enzymatic assays. The carboplatin clearance was then calculated by individually adding 25 to the four GFR determinations based on the Calvert equation, which states that carboplatin clearance equals GFR + 25 (nonrenal clearance). The carboplatin clearance was also estimated using the Chatelut equation. The five determinations of carboplatin clearance were compared using Friedman's test and post-hoc Wilcoxon signed rank tests. Precision and bias for each carboplatin clearance determination were calculated assuming that 99mTc-DTPA provided the most accurate measure of GFR. RESULTS: A statistically significant difference was found between the five methods of estimating carboplatin clearance (P < 0.001). No difference was found between carboplatin clearance calculated using 99mTc-DTPA and the Chatelut equation, the Cockcroft-Gault formula or the 2-h urine collection. The Chatelut equation provided more precision and less bias than the 2-h urine collection (median precision 20% and 30%, median bias -1% and -18%, respectively). CONCLUSION: Compared to 99mTc-DTPA, the Chatelut equation more accurately estimates carboplatin clearance than the Cockcroft-Gault formula, the 2-h urine collection and the 24-h urine collection. The greater negative bias found for the latter three estimates of carboplatin clearance could result in underdosing of carboplatin.

Evaluation of outcomes in converting from intravenous ondansetron to oral granisetron: an observational study.

OBJECTIVE: To describe a systematic evaluation of the outcomes associated with revising institutional guidelines for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) to promote cost-effective use of the serotonin (5-HT3) antagonists. METHODS: The 5-HT3 antagonist of choice in the antiemetic guidelines was revised from intravenous ondansetron to oral granisetron in August 1995. Patient assessments were conducted immediately prior to (Period 1) and after (Period 2) guideline revision using validated questionnaires. The effectiveness of the two 5-HT3 antagonists were compared and reported to the prescribing oncologists. Outcomes were assessed one year after guideline revision (Period 3) using identical methods. RESULTS: No difference was found in the rate of total control (no emesis, no nausea) between patients receiving oral granisetron (60%) and intravenous ondansetron (56%) (p = 0.408, Period 1 vs. 2). Nausea severity, the number of emesis episodes, and use of rescue antiemetics were also equivalent. Prescriber compliance with using the 5-HT3 antagonist of choice and dose increased from 48% to 61% following adoption of oral granisetron. By Period 3, compliance increased to 78%, and satisfactory control of acute CINV was again documented. The costs for prevention of acute CINV decreased from $107 in Period 1 (intravenous ondansetron only) to $65 in Period 3 (oral granisetron). CONCLUSIONS: Outcomes associated with use of oral granisetron and intravenous ondansetron were equivalent in this patient population. Guideline revision and outcome documentation by the oncology pharmacists resulted in increased compliance with institution guidelines and a 40% cost savings.

In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone.

PURPOSE: The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures. METHODS: The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/L dexamethasone. RESULTS: The percent of erythromycin metabolized per hour increased from 2.20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%; P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r2 = 0.58). In hepatocytes, dexamethasone 2 to 250 micromol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r2 = 0.59). CONCLUSIONS: These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures.

Plasma concentration monitoring of busulfan: does it improve clinical outcome?

High dosage busulfan (1 mg/kg orally every 6 hours x 16 doses) is frequently used in preparative regimens for haemopoietic stem cell transplantation (HSCT). Busulfan is well absorbed after oral administration, exhibits low protein binding and is metabolised through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as area under the plasma concentration-time curve (AUC) or average concentration at steady state (Css). Relative to that in adolescents and adults, patients less than 4 years of age have an increased apparent oral clearance (CL/F) of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte. Several investigators have identified relationships between busulfan Css and outcome in patients undergoing HSCT. Busulfan concentration-response relationships are regimen-, age- and disease-dependent. The busulfan/cyclophosphamide (BU/CY) regimen is the only regimen for which substantial concentration-outcome data exist. Generally, the risk of hepatic veno-occlusive disease is increased with busulfan Css > 900 microg/L. The impact of busulfan Css on veno-occlusive disease may be influenced by the age of the patient and the dose of cyclophosphamide. Lower rates of relapse in chronic myelogenous leukaemia occur in patients with a busulfan Css > 917 microg/L without an increased risk of toxicity. Busulfan Css is also related to the engraftment rate in children, and escalating busulfan doses to achieve a target Css > 600 microg/L improves graft retention. Therapeutic drug monitoring of busulfan should be performed to maximise the likelihood of engraftment and minimise the risk of toxicity and relapse in HSCT patients receiving the BU/CY preparative regimen.

Granulocyte colony-stimulating factor use in cancer patients.

OBJECTIVE: To conduct a retrospective drug utilization evaluation comparing the use of granulocyte colony-stimulating factor (G-CSF) at a university medical center with the American Society of Clinical Oncology (ASCO) CSFs Practice Guidelines. METHODS: Patients who received G-CSF from June 1, 1996, to December 31, 1996, were identified through the pharmacy computer system and the medical records were reviewed for a randomly selected sample of 26% of the 289 patients identified. Outpatient, inpatient, and electronic medical records were reviewed for the indication, dosage, day of initiation, day of discontinuation, and absolute neutrophil count (ANC) monitoring plan for each course of G-CSF; these records were subsequently compared with the ASCO guidelines. RESULTS: The use of G-CSF after chemotherapy was evaluated in 51 patients who received a total of 182 courses of G-CSF. The goal of chemotherapy was curative in 61% of courses. Sixty-five percent of G-CSF courses were prescribed for primary prophylaxis. Of these, 74% followed chemotherapy in patients with an expected incidence of febrile neutropenia > or =40% or followed chemotherapy in patients with compromised marrow reserve secondary to extensive prior therapy or in patients older than 60 years. Most of the G-CSF courses (75%) were rounded to the nearest vial size. The areas of greatest departure from the ASCO guidelines included aspects of initiation and discontinuation of G-CSF courses and inadequate documentation of ANC recovery. CONCLUSIONS: These results demonstrate a number of specific opportunities for oncology pharmacists to improve the use of G-CSF in patients receiving chemotherapy. Recommendations were made to the pharmacy and therapeutics committee and medical oncologists to improve compliance with the ASCO guidelines.

Perception of chemotherapy side effects cancer versus noncancer patients.

PURPOSE: This study was conducted to identify and compare perceptions regarding the disruption in quality of life caused by chemotherapy side effects in patients with cancer receiving chemotherapy and in noncancer, chemotherapy-naive patients. DESCRIPTION OF STUDY: One hundred forty-six patients with cancer and 224 patients without cancer completed two instruments to assess the perceived magnitude of 41 physical and psychosocial chemotherapy side effects. Instrument 1 used a 5-point Likert scale (1 = not at all; 2 = a little bit; 3 = somewhat; 4 = quite a bit; and 5 = very much) to summarize patient responses to the question, "How much did or would each of the following side effects of chemotherapy bother you?" Instrument 2 was a serial ranking questionnaire that asked patients to select the 10 most bothersome side effects to numerically rank the top five. An index of the relative magnitude of chemotherapy side effects was calculated for each instrument. RESULTS: For patients with cancer, loss of hair 50%), changes in taste (46%), constantly being tired (42%), affects work duties (39%), changes in smell perception (35%) were most frequently perceived as bothering them "quite a bit" or "very much." Nausea and vomiting were ranked 11th and 22nd, respectively. With instrument 2, the five side effects perceived as most troublesome were, in decreasing order: nausea, loss of hair, constantly tired, vomiting, and changes in the way things taste. For noncancer patients, those factors potentially bothersome "quite a bit" or "very much" were: financial hardship (82%), hardship on family (78%), vomiting (73%), shortness of breath (70%), and ability to perform work duties (69%). Via instrument 2, the top five side effects, in decreasing order were: vomiting, hardship on family, loss of hair, financial hardship, nausea, having to move close to a treatment center. CLINICAL IMPLICATIONS: Noncancer, chemotherapy-naive patients perceived most chemotherapy-associated side effects as having greater impact on the quality of life than did cancer patients who had received chemotherapy. These findings can be used to direct patient education, education of the public, specific materials concerning cancer chemotherapy. The expertise of various members of the healthcare team can maximize the patient's comprehension of the adverse effects of the treatment options. The physician's knowledge of the overall treatment plan can assist in patient understanding; oncology pharmacists nurses are in a unique position to educate patients their families regarding potential chemotherapy side effects.

Cancer pain survey: patient-centered issues in control.

It is widely believed that patients' reluctance to report pain and adhere to treatment recommendations are significant barriers to cancer pain control. However, few investigators have examined barriers to cancer pain management from the cancer patient's perspective. Ambulatory patients with cancer who had experienced cancer-related pain in the previous month or were currently taking analgesics for cancer pain control were asked to participate in this study. Information regarding (a) pain assessment, (b) pain medication use, (c) concerns and barriers to compliance, (d) communication patterns regarding pain and pain control, and (e) demographics were collected during a 10-min structured interview. Approximately 20% of patients with a current cancer diagnosis who were approached reported that they had experienced pain or taken analgesic drugs during the preceding month. Eighty-eight percent of these patients ranked their pain as five or greater (scale, 0-10), and 81% reported impaired function due to pain. Major barriers to effective treatment included forgetfulness, the belief that pain should be tolerated, concerns about side effects, and fear and disdain of dependence, addiction, and tolerance. One-third of patients felt that their pain could not be better controlled than it currently was. Patients reported frequent communication regarding pain and pain control with physicians (52%), nurses (41%), and pharmacists (17%). The low pain prevalence, coupled with high pain intensity and associated dysfunction, appears to be a reflection of patient's unwillingness to report pain of mild to moderate intensity. In addition to previously recognized factors, stoicism and fatalism represent significant barriers to cancer pain control.

Precipitous fall in platelet count with anagrelide: case report and critique of dosing recommendations.

Thrombotic and hemorrhagic events may result from high circulating concentrations of platelets (> 1,000,000/mm3), and measures to reduce the platelet count are indicated in symptomatic or extreme thrombocytosis. The platelet count can be decreased quickly by plasmapheresis, but the effect is transient. Patients with thrombocytosis secondary to a myeloproliferative disease, such as chronic myelogenous leukemia (CML), frequently require more sustained suppression of the platelet count. Hydroxyurea, busulfan, and interferon are used to maintain a lower platelet count but are occasionally ineffective or intolerable. An alternative to these therapies is anagrelide, a quinazolin derivative that was approved by the Food and Drug Administration in March 1997. Because current dosing guidelines for anagrelide are scarce, the dosing method of the Anagrelide Study Group that published the largest study to date on the drug's efficacy in thrombocytosis was followed. Two unexpected episodes of anagrelide-induced thrombocytopenia occurred despite following these dosing methods. This prompted a critical evaluation of the pharmacodynamic response and the appropriateness of anagrelide dosage recommendations. A case of thrombocytosis treated with anagrelide in a patient with CML is described.