Celeste Lindley

Proposal for classifying the acute emetogenicity of cancer chemotherapy.

PURPOSE To propose a classification of the acute emetogenicity of antineoplastic chemotherapy agents, and to develop an algorithm to define the emetogenicity of combination chemotherapy regimens. METHODS A Medline search was conducted to identify (1) clinical trials that used chemotherapy as single-agent therapy, and (2) major reviews of antiemetic therapy. The search was limited to patients who received commonly used doses of chemotherapy agents, primarily by short (< 3 hours) intravenous infusions. Based on review of this information and our collective clinical experience, we assigned chemotherapy agents to one of five emetogenic levels by consensus. A preliminary algorithm to determine the emetogenicity of combination chemotherapy regimens was then designed by consensus. A final algorithm was developed after we analyzed a data base composed of patients treated on the placebo arms of four randomized antiemetic trials. RESULTS Chemotherapy agents were divided into five levels: level 1 (< 10% of patients experience acute [< or = 24 hours after chemotherapy] emesis without antiemetic prophylaxis); level 2 (10% to 30%); level 3 (30% to 60%); level 4 (60% to 90%); and level 5 (> 90%). For combinations, the emetogenic level was determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents. The following rules apply: (1) level 1 agents do not contribute to the emetogenic level of a combination; (2) adding > or = one level 2 agent increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination; and (3) adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent. CONCLUSION The proposed classification schema provides a practical means to determine the emetogenic potential of individual chemotherapy agents and combination regimens during the 24 hours after administration. This system can serve as a framework for the development of antiemetic guidelines.

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

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.

Pharmacokinetics and pharmacodynamics of recombinant factor VIIa

To evaluate the pharmacokinetics and pharmacodynamics of recombinant activated factor VII (rFVIIa).

Incidence and duration of chemotherapy-induced nausea and vomiting in the outpatient oncology population.

Nausea and vomiting are commonly recognized side effects of chemotherapy. However, the incidence and duration of these effects have not been systematically studied in a large outpatient oncology population. This survey was conducted over two consecutive 6-week periods in the adult oncology clinics of two university teaching hospitals. The objectives were: (1) to document the incidence and duration of chemotherapy-induced nausea and vomiting; (2) to identify variables that influence nausea and vomiting; and (3) to describe patterns of antiemetic prescribing and compliance. One hundred thirty-eight completed patient-maintained diaries were returned (70% response rate). Anticipatory nausea and vomiting were reported by 9.4% and 6.5% of patients, respectively. Fifty percent and 27% of patients reported nausea and vomiting, respectively, on the day chemotherapy was administered (day 1: acute nausea and vomiting phase). Percentages fell to 22% and 11% by day three and 14% and 2.5% on day 5. Of patients who reported nausea and vomiting during the five-day period, 52% and 33% experienced nausea and vomiting, respectively, during the delayed period only (days 2 through 5: delayed emesis phase). Emetogenicity of chemotherapy significantly influenced incidence and duration of those symptoms. Sixty-seven percent of patients reported taking antiemetics on one or more days during the survey period. Of patients who reported antiemetic use, 92% reported antiemetics on day 1, 51% on day 3, and 31% on day 5. At-home antiemetic use was related to the emetogenicity of chemotherapy received. Patients who receive moderate to strong emetogens as defined in this report should receive antiemetic therapy for a minimum of three days. Increasing the dose of antiemetic prescribed both in the clinic and at home may be of benefit.

Lopinavir/ritonavir Reduces Bupropion Plasma Concentrations in Healthy Subjects

Limited data are available about the effect of steady‐state lopinavir and ritonavir (LPV/r) on bupropion pharmacokinetics. As patients may benefit by using these two agents in combination, this study determined the extent and direction of this drug–drug interaction. Twelve healthy volunteers received a single 100 mg dose of sustained‐release bupropion before and after 2 weeks of treatment with LPV/r 400 mg/100 mg twice daily. Pharmacokinetics profiles were determined on days 1 and 30 for bupropion and hydroxybupropion and days 29 and 30 for LPV/r. LPV/r administration significantly decreased bupropion maximum plasma concentration (Cmax) by 57% (90% confidence interval (CI), 38–76% P<0.01) and area under the curve (AUC)∞ by 57% (90% CI, 32–83% P<0.01). Hydroxybupropion Cmax and AUC∞ decreased by 31% (90% CI, 7–55% P<0.01) and by 50% (90% CI, 34–65% P<0.01), respectively. No significant changes in the pharmacokinetics of LPV/r were found following administration of a single dose of bupropion. Concurrent use of LPV/r and bupropion resulted in decreased exposure to bupropion and its active metabolite hydroxybupropion that may necessitate as much as a 100% dose increase of bupropion. A probable mechanism for this interaction is the concurrent induction of cytochrome P450 2B6 and UDP‐glucuronosyltransferase enzymes. LPV/r exposure is unaffected by a single dose of bupropion.

Aprepitant – a novel NK1-receptor antagonist

Recently, a new class of agents, the substance P antagonists, has heralded a novel approach for the control of emesis. Aprepitant (Emend®, Merck & Co., Inc.), the first of this class, was recently approved by the FDA for the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). Of interest is the vast array of processes in which substance P is involved such as pain, anxiety, depression and inflammation and the potential wide applicability of substance P antagonists to a number of medical conditions outside of the nausea and vomiting realm. The following review provides an overview of aprepitant including pharmacokinetics, pharmacology and clinical evidence for its use in CINV. A brief discussion of other possible indications for aprepitant will also be presented.

Is patient satisfaction a legitimate outcome of pain management

Though many studies have measured patient satisfaction with pain management using the American Pain Society (APS) Satisfaction Survey or its variants, little is known about the relationship among the survey items, or whether items relate to satisfaction at all. In an effort to refine the measurement of patient satisfaction, a modified version of the APS survey, which was given to 787 patients as part of a study of postoperative pain management in six community hospitals, was subjected to principal components analysis to determine the surveys empirical structure. Correlations among the five components found were low; a weak relationship (r = -0.24) was discovered between pain intensity and satisfaction. A heuristic model estimated by structural equations analysis yielded additional insights. Though many items thought to influence patient satisfaction were not closely related to patient-reported satisfaction, they indicate important clinical factors relevant to quality of care, and thus, to continuing quality improvement (CQI) efforts. Results suggest that satisfaction was influenced by effectiveness of medication, independent of pain intensity, and by communication. Pain severity ratings near the time satisfaction was measured were more influential than earlier ratings.

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:DXin 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 (a = 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.

Quality of life in patients surviving at least 12 months following high dose chemotherapy with autologous bone marrow support

Over the past decade, high dose chemotherapy with autologous bone marrow (HDC‐ABMT) support has been used increasingly in the treatment of patients with breast cancer. In evaluating the results of HDC‐ABMT in patients with breast cancer, an assessment of quality of life can add to the traditional endpoints (toxicity, and disease‐free and overall survival) that are routinely assessed in clinical trials.