Meeting of oncology residency program directors.
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Congresses as Topic↗
Biomedical subjects
C Lindley
Publications and source records attributed to C Lindley.
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.
Adult↗
Documentation of pain assessment and treatment: how are we doing?
The purpose of this analysis was to evaluate documentation of practice provided by a multidisciplinary team of nurses, physicians, and pharmacists who participated in an educational program on postoperative pain management. Chart audit of 787 patient charts at 6 sites revealed documentation of pain histories in approximately 75% of the charts, most often in the surgeon's history and physical examination. Examination of multiple assessment items indicated that the experimental group, relative to the control group, experienced an increase of more than 10% in the documentation of pain intensity, pain quality, pain duration, numeric rating scale used, pain behavior, factors that increase pain, vital signs, sedation level, cognitive status, social interaction, and mood from before the program to 6 months after the program. Across all sites, documentation of assessment, treatment, and treatment outcome data was infrequent and inconsistent. Calculation of documentation of 4 items that constituted a focused assessment of postoperative pain on the surgical floor revealed a significant program effect for assessment of pain quality and pain intensity. A postprogram survey of participants in the educational program revealed an increase in discussion of postoperative pain management with other practitioners and an increase in use of a 0 to 10 scale to rate pain. More documentation of patient pain history, clinical problems, treatment, and follow-up action is needed to improve practice and research.
Clinical Competence↗
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.
Adult↗
Pharmacology and therapeutic use of trastuzumab in breast cancer.
The development, pharmacology, safety, efficacy, and dosage and administration of trastuzumab are reviewed. The discovery of HER2 gene amplification in up to 30% of women with breast cancer led to the development of trastuzumab, a humanized recombinant monoclonal antibody directed against the HER2-receptor protein on breast cancer cells. In large, multicenter trials of trastuzumab as a single agent or in combination with chemotherapy as first-line or second-line therapy for metastatic breast cancer (MBC), response rates have ranged from 12% to 23% for single-agent trastuzumab and from 25% to 62% for trastuzumab plus chemotherapy. Trastuzumab increased time to disease progression and survival time when administered in combination with chemotherapy. The National Comprehensive Cancer Network guidelines for the treatment of breast cancer now include trastuzumab and paclitaxel as an option for patients with MBC or recurrent breast cancer in which the HER2-receptor protein is overexpressed. Trastuzumab is administered weekly, with an initial i.v. dose of 4 mg/kg followed by weekly doses of 2 mg/kg. Most clinical trials continued treatment until disease progression occurred. Adverse effects include infusion-related reactions manifested by fever and chills, exacerbation of chemotherapy-induced gastrointestinal toxicity and myelosuppression, and cardiotoxicity. Trastuzumab, either as a single agent or in combination with chemotherapy, can be an effective therapeutic option for MBC patients who overexpress the HER2-receptor protein and has changed the standard of care.
Antibodies, Monoclonal↗
Oral serotonin type 3-receptor antagonists for prevention of chemotherapy-induced emesis.
The theoretical basis for and clinical experience with using oral serotonin type 3 (5-HT3)-receptor antagonists for preventing chemotherapy-induced emesis are discussed. Evidence supports the idea that antineoplastic drugs and irradiation can initiate emesis by releasing serotonin from enterochromaffin cells in the gut mucosa, which activates peripheral vagal afferent nerves. In view of the GI site of serotonin release and vagal afferent activation, the proximity of neuronal 5-HT3 receptors, and the pharmacologic properties of 5-HT3-receptor antagonists, the oral use of these agents is rational. Oral granisetron 2 mg once daily or 1 mg twice daily has been evaluated in more than 4500 patients receiving highly or moderately emetogenic chemotherapy. Rates of total control of emesis ranged from 44% to 60%, and complete-response rates ranged from 70% to 94%. Oral ondansetron 8 mg three times daily has proven effective in patients receiving antineoplastics with moderate or moderately high emetogenic potential. Two double-blind studies demonstrated the efficacy of a single 24-mg oral dose of ondansetron administered approximately 30 minutes before cisplatin-based chemotherapy. Patients randomized to oral ondansetron had higher total-control and complete-response rates than patients receiving intravenous granisetron or ondansetron. Oral dolasetron 100 or 200 mg once daily also prevented emesis. Oral administration of 5-HT3-receptor antagonists for the prevention of acute emesis associated with chemotherapy is rational and appears to be effective.
Administration, Oral↗
Clinical economics: calculating the cost of acute postoperative pain medication.
Few data are available that address the cost of postoperative pain management, although such knowledge would enhance our understanding of caregiver choices related to direct medical costs, such as type, frequency, and route of medication. This article describes the cost of postoperative pain medications before and after an educational program provided to nurses, pharmacists, and physicians in six community hospitals. Medication costs were calculated by averaging across all brands the average wholesale price of the most common dose administered in the sample for each medication. The median cost of postoperative pain medication across all days, all surgeries, was $9.46. Calculating the cost of acute postoperative pain medication suggested that cost over stay is highly influenced by the use of a few expensive medications. The relationship of medication cost to length of stay (LOS), function, and pain intensity is discussed.
Acute Disease↗
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.
Administration, Oral↗
Anagrelide: a novel agent for the treatment of myeloproliferative disorders.
Anagrelide hydrochloride (Agrylin, Roberts Pharmaceutical Corp.) is an oral imidazoquinazoline agent that has been shown to reduce elevated platelet counts and the risk of thrombosis in patients with thrombocythaemia in various myeloproliferative disorders (MPD). It is currently approved by the FDA as oral treatment for essential thrombocythaemia (ET) and thrombocythaemia associated with polycythaemia vera (PV). Anagrelide selectively suppresses bone marrow megakaryocytes by interfering with the maturation process and decreasing platelet production without affecting the erythroid and myeloid progenitor cells. Other medications indicated for the treatment of thrombocythaemia, including interferon alpha (IFN-alpha), alkylating agents and hydroxyurea, suppress all cell lines. Anagrelide is known to inhibit platelet cyclic adenosine monophosphate (cAMP) phosphodiesterase at concentrations that exceed those achieved at doses used to treat ET. Anagrelide is extensively metabolised in the liver and its metabolites are primarily excreted in the urine. Adverse effects associated with the use of anagrelide are primarily caused by the drugs' direct vasodilating and positive inotropic effects. These include headache, hypotension and diarrhoea. It has also been known to cause fluid retention, tachycardia, nausea, abdominal pain and arrhythmias. The starting dose of anagrelide ranges from 0.5 mg q.i.d. to 1 mg b.i.d. with a maximum dose of 2.5 mg q.i.d. Adequate responses have been maintained with a median dose of 2-2.5 mg/day. Platelet counts begin to decrease in 7-10 days, however, they return to pre-treatment levels within 4-8 days if therapy is stopped. Anagrelide 2 mg/day for one year costs approximately US$6439, and treatment must continue indefinitely [1].
Clinical Trials as Topic↗
Changing acute pain management to improve patient outcomes: an educational approach.
The United States Agency for Health Care Policy and Research (AHCPR) Acute Pain Management Guidelines were written to provide a scientific basis for practice. Educational programs designed to promote use of the guidelines may change practice in community hospitals. This article describes the development and implementation of an education program for nurses, physicians, and pharmacists in six community hospitals. Program content addressing the use of continuous quality improvement (CQI) teams, detailed pain histories, application of algorithms and dose calculation is described; direct and indirect outcome measures are reviewed. Six months after the program, all three experimental sites reported use of the AHCPR Guidelines in practice. Nurses reported that assessment and documentation of patients' duration of pain were perceived to be the most important caregiver behaviors providing benefit to patients: Across all respondents' reports of regularly performed activities, the activity performed by the largest proportion was assessing and documenting pain using a 0-10 rating scale.
Acute Disease↗
Organization of hospital-based acute pain management programs.
BACKGROUND: The management of acute pain is an aspect of hospital-based practice that has been neglected. Control of pain is important for ethical reasons, for compliance with new guidelines and standards, and for optimizing patient satisfaction and outcomes. METHODS: Be review the rationale for establishing priority to the control of acute pain, the importance of an institutional approach to improve pain management, and specific steps in the establishment and conduct of an acute pain program. RESULTS: Improvement in pain control depends on an institutional approach to facilitate changes in attitude and prioritization. Pain management programs should provide for patient and staff education, adequate documentation of care, institutional standards for pain control, quality assurance/continuous quality improvement (CQI) activities, and periodic review of practice and policy. CONCLUSIONS: Effective pain management can set the stage for a rehabilitational approach to postoperative care, which should lead to earlier recovery and improved outcomes.
Acute Disease↗
Cyclic AMP can decrease expression of genes subject to catabolite repression in Saccharomyces cerevisiae.
External cyclic AMP (cAMP) hindered the derepression of gluconeogenic enzymes in a pde2 mutant of Saccharomyces cerevisiae, but it did not prevent invertase derepression. cAMP reduced nearly 20-fold the transcription driven by upstream activation sequence (UAS1FBP1) from FBP1, encoding fructose-1,6-bisphosphatase; it decreased 2-fold the activation of transcription by UAS2FBP1. Nuclear extracts from cells derepressed in the presence of cAMP were impaired in the formation of specific UASFBP1-protein complexes in band shift experiments. cAMP does not appear to act through the repressing protein Mig1. Control of FBP1 transcription through cAMP is redundant with other regulatory mechanisms.
Carboxy-Lyases↗
American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants.
PURPOSE: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration-approved agents that have potential chemotherapy- and radiotherapy-protectant activity-dexrazoxane, mesna, and amifostine-and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials. METHODS: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m(2)/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplantation setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m(2) or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m(2) of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemoth
Adult↗
Quality of life and preferences for treatment following systemic adjuvant therapy for early-stage breast cancer.
PURPOSE: To evaluate the quality of life (QOL) of breast cancer patients who survived 2 to 5 years following initiation of adjuvant cytotoxic and/or hormonal therapy and to characterize relationships between QOL and patient physical symptoms, sexual function, and preferences regarding adjuvant treatment. PATIENTS AND METHODS: Eighty-six patients who had completed systemic adjuvant therapy for early-stage breast cancer between 1988 and 1991 were surveyed by written questionnaire and telephone interview. Sociodemographic information was obtained for each patient, and patients were asked to complete the Functional Living Index-Cancer (FLIC), the Symptom Distress Scale (SDS), the Medical Outcomes Study (MOS) Short Form 36 (SF-36), a series of questions regarding sexual function, and a survey about preferences for adjuvant therapy in relation to possible benefit. RESULTS: The mean FLIC score among all patients was 138.3 (+/- 12.2), which suggests a high level of QOL. The reported frequency of moderate to severe symptoms was generally low (ie, < 15%), with fatigue (31.4%), insomnia (23.3%), and local numbness at the site of surgery (22.1%) occurring with greatest frequency. Patients reported a wide range of sexual difficulties. Preference assessment showed that more than 65% of patients were willing to undergo 6 months of chemotherapy for a 5% increase in likelihood of cancer cure. CONCLUSION: Self-rated QOL in breast cancer patients 2 to 5 years following adjuvant therapy was generally favorable. Less than one third of patients reported moderate to severe symptoms. Selected aspects of sexual function appeared to be compromised. The majority of patients indicated a willingness to accept 6 months of chemotherapy for small to modest potential benefit.
Adult↗
Appropriateness of maximum-dose guidelines for vincristine.
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Antineoplastic Agents, Phytogenic↗
Antiemetic therapy in managed care oncology: roundtable discussion.
Few diagnoses are feared more by patients than cancer. In addition to the life-threatening nature of many cancers, the spectre of very difficult the treatment provides patients with little or no level of comfort. However, recent advances in the treatment of the side effects of cancer chemotherapy are helping to change these attitudes. On April 4, 1996, a panel of experts was convened to discuss these issues and how they affect MCOs.
Antiemetics↗
Vinorelbine: a novel vinca alkaloid.
The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of vinorelbine are reviewed. Vinorelbine is a semisynthetic vinca alkaloid with a broader spectrum of antitumor activity in vitro than naturally occurring vinca alkaloids have. Vinorelbine shows selective activity against mitotic microtubules. Higher concentrations of vinorelbine relative to vinblastine and vincristine are required to affect axonal microtubules; presumably this accounts for the decreased neurotoxicity of vinorelbine. Vinorelbine is lipophilic and is rapidly distributed into peripheral tissues. It is highly bound to blood components. Vinorelbine is excreted slowly by the fecal route and rapidly by the urinary route. Disposition is characterized by a three-compartment model, high systemic clearance, and a long terminal-phase elimination half-life. In clinical studies, vinorelbine has shown antitumor activity both as a single agent and in combination with cisplatin in patients with non-small-cell lung cancer (NSCLC). Vinorelbine plus cisplatin produces a higher response rate and longer survival than vindesine plus cisplatin, a combination previously found to be superior to best supportive care. Encouraging results for vinorelbine in the treatment of advanced breast cancer, advanced ovarian epithelial cancer, and other tumors have also been observed. The dose-limiting adverse effect of vinorelbine is myelosuppression. Vinorelbine has FDA-approved labeling for use alone or in combination with cisplatin for the first-line treatment of unresectable, advanced NSCLC. The recommended dosage is 30 mg/sq m i.v. weekly administered by either slow i.v. push or i.v. infusion. Vinorelbine alone or in combination with other antineoplastics has shown activity against NSCLC, advanced breast cancer, and other malignancies. More study is needed to determine whether vinorelbine is superior to best supportive care in patients with NSCLC.
Antineoplastic Agents↗
Overview of current development in patient-controlled analgesia.
Over the past two decades, numerous trials have assessed the safety and efficacy of patient-controlled analgesia (PCA). Advantages over conventional parenteral narcotics reported from these trials include equivalent to superior pain relief, superior patient satisfaction, decreased sedation and anxiety, faster return to normal functional status, and reduction in nursing time and hospitalization. The majority of these trials have been conducted in the postoperative patient population. In the mid to late 1980s, interest arose in applying PCA technology to the management of cancer pain. Factors that served as an impetus for the use of PCA in cancer pain included favorable reports from the postoperative setting and the often-cited statistics regarding the magnitude of the cancer pain problem. Advances in PCA technology coupled with advances in vascular access technology that allow the placement of long-term ports and catheters to facilitate intravenous, epidural, or intrathecal administration of opioid analgesics have made the applicability of PCA in ambulatory cancer patients an attractive option. The greatest breakthrough in PCA technology came with the introduction of devices making it possible to choose between intermittent (demand bolus) and continuous administration (continuous infusion) or both intermittent and continuous modes. A comparison of these types of PCA devices is described. The limitations of the literature involving PCA therapy in cancer patients make it difficult to identify optimal patient selection criteria, PCA administration schedules, drug selection and dosing, and optimal route of administration. The current status and pertinent issues related to these topics are addressed.
Analgesia, Patient-Controlled↗