Jim M. Koeller

Recommendations for the Use of Antiemetics: Evidence-Based, Clinical Practice Guidelines

THE GOAL OF ANTIEMETIC therapy is to prevent nausea and vomiting completely. This goal is achieved for many patients receiving chemotherapy or radiation therapy, and is based on clinical and basic research that has steadily improved the control of emesis over the last 20 years. As therapy has become more effective, it has also become safer, with few side effects associated with the most commonly used regimens. These regimens are convenient for patients to receive and for health care professionals to administer. However, despite improvements, a significant number of patients still experience emesis, and efforts to reduce this side effect of treatment must continue. As antiemetic usage has grown, the classes of agents available for antiemetic treatment, the number of agents, and the indications for antiemetics have all increased as well. The prevention of delayed emesis and anticipatory emesis is equal in importance to the need to prevent acute chemotherapyand radiation-induced emesis. Additionally, managing special and difficult emetic problems and selecting the proper antiemetic approach necessitate identification of the patient’s emetic risk. Although the neuropharmacologic basis of emesis is still incompletely understood, the selection of an appropriate antiemetic regimen is possible and can have an impact on several aspects of clinical care. Goals related to the complete control of emesis, ie, no vomiting, include providing care that is convenient for the patient, treatment that reduces hospitalization and time in the ambulatory setting, and therapy that enhances the patient’s quality of life. Additionally, practitioners need to be mindful of reducing costs of treatment while achieving these goals. 1-3

A phase I trial of taxol given by a 6-hour intravenous infusion.

Taxol is a unique mitotic inhibitor that has entered phase II investigation. Phase I studies demonstrated hypersensitivity reactions that were related to the cremophor vehicle and to the rate of drug infusion. As a result, the time span of intravenous (IV) infusion of taxol was routinely prolonged to 6 hours or beyond, and premedication with diphenhydramine, dexamethasone, and cimetidine was initiated. Early studies showed antitumor activity, especially against malignant melanoma and ovarian carcinoma. This phase I trial was performed giving taxol, as a 6-hour IV infusion every 21 days, without premedication. The purpose was to study the necessity of premedication and its impact on toxicity and pharmacokinetics. Thirty-one patients received 64 assessable courses of taxol. One patient had a hypersensitivity reaction, which was easily controlled using routine measures. Myelosuppression was dose-limiting, but sporadic, with two fatalities due to sepsis. Nonhematologic toxicity was of grade 1 and 2 except for one patient with grade 3 mucositis and two patients with grade 3 neuropathy. The neuropathy consisted of reversible painful paresthesias, requiring discontinuation of drug in two patients. Four partial responses were seen (three in patients with non-small-cell lung cancer, one in a patient with adenocarcinoma of unknown primary). Pharmacokinetic values were consistent with those previously reported. The occurrence of myelosuppression or neurotoxicity appeared to be associated with the area under the concentration x time curve (AUC) of taxol. The recommended phase II starting dose on this schedule is 225 mg/m2. Taxol merits broad investigation at the phase II level.

Consensus proposals for the prevention of acute and delayed vomiting and nausea following high-emetic-risk chemotherapy

This paper uses an evidence-based approach whenever possible to formulate recommendations, emphasizing the results of controlled trials concerning the best use of antiemetic agents. We address issues of dose, schedule, and route of administration of five selective 5-HT3 antagonists. We conclude that for each of these five drugs, there is a plateau in therapeutic efficacy above which further dose escalation does not improve outcome. Furthermore, for all classes of antiemetic agents, a single dose is as effective as multiple doses or a continuous infusion. The oral route is as efficacious as the intravenous route of administration, even with chemotherapy of high emetic risk. Selective antagonists of the type 3 serotonin receptor (5-HT3) in combination with dexamethasone and aprepitant are the standard of care for the prevention of emesis following chemotherapy of high emetic risk.

Acute emesis: moderately emetogenic chemotherapy

This paper is a review of the recommendations for the prophylaxis of acute emesis induced by moderately emetogenic chemotherapy as concluded at the Perugia Consensus Conference, which took place at the end of March 2004. The review focuses on new studies appearing since the last consensus conference in 1997. The following issues are addressed: dose and schedule of antiemetics, different groups of antiemetics such as corticosteroids, serotonin (5-HT3)-receptor antagonists, dopamine D2 receptor antagonists, and neurokinin (NK1) receptor antagonists. Antiemetic prophylaxis in patients receiving multiple cycles of moderately emetogenic chemotherapy is also reviewed. Consensus statements are given, including optimal dose and schedule of 5-HT3-receptor antagonists and of dexamethasone. The new 5-HT3-receptor antagonist, palonosetron, is a reasonable alternative to the well-established agents of this class—ondansetron, granisetron, tropisetron and dolasetron. It is concluded that the best prophylaxis in patients receiving moderately emetogenic chemotherapy is still the combination of one of the 5-HT3-receptor antagonists and dexamethasone. The results of studies adding a NK1-receptor antagonist to this combination are awaited and might change future recommendations.

Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for Elderly Advanced Colorectal Cancer Patients in the Community Oncology Setting

BACKGROUND The clinical trials on which the treatment of advanced colorectal (CRC) is based enroll few elderly patients. Furthermore, few investigations have determined the use and outcomes of the treatment of advanced CRC in practice. This study evaluated the treatment of advanced CRC in community oncology practices, focusing on age-related differences in treatment and outcome. METHODS A national, retrospective chart review was conducted to evaluate the management of advanced CRC in 10 community practices across the U.S. All medical records of patients diagnosed with advanced CRC initiating chemotherapy treatment after January 1, 2003 through 2006 were included. The primary aim was to compare the proportion receiving doublet chemotherapy (irinotecan or oxaliplatin with a fluoropyrimidine) as initial therapy in young (age <or=65 years) and elderly (age >65 years) patients. Additional aims included age-based comparisons of the addition of bevacizumab to chemotherapy, overall chemotherapy use, all-cause mortality, and toxicity-related events. RESULTS Overall, 520 patients (56% elderly) received 6,253 cycles of chemotherapy. Of the younger patients, 84% received doublet chemotherapy first-line, compared with 58% of elderly patients (p < .001). The use of each of the medications--irinotecan, oxaliplatin, and bevacizumab--was lower in elderly patients (p < .001). Independent predictors of a higher risk for mortality were age >65 (adjusted hazards ratio [HR],1.19; 95% confidence interval [CI], 1.02-1.39) and performance status score >or=2 (HR, 1.65; 95% CI, 1.41-1.91). CONCLUSION Elderly patients are less likely to receive first-line doublet chemotherapy than younger patients. Age and performance status are independent predictors of treatment and overall survival.

Treatment failure and costs in patients with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections: A south Texas ambulatory research network (STARNet) study

Objective: To measure the incidence of treatment failure and associated costs in patients with methicillin-resistant Staphylococcus aureus skin and soft tissue infections (SSTIs). Methods: This was a prospective, observational study in 13 primary care clinics. Primary care providers collected clinical data, wound swabs, and 90-day follow-up information. Patients were considered to have “moderate or complicated” SSTIs if they had a lesion ≥5 cm in diameter or diabetes mellitus. Treatment failure was evaluated within 90 days of the initial visit. Cost estimates were obtained from federal sources. Results: Overall, treatment failure occurred in 21% of patients (21 of 98) at a mean additional cost of

Antiemetic therapy for multiple-day chemotherapy and high-dose chemotherapy with stem cell transplant: review and consensus statement

1,933.71 per patient. In a subgroup analysis of patients who received incision and drainage, those with moderate or complicated SSTIs had higher rates of treatment failure than those with mild or uncomplicated SSTIs (36% vs. 10%; P=.04). Conclusions: One in 5 patients presenting to a primary care clinic for a methicillin-resistant S. aureus SSTI will likely require additional interventions at an associated cost of almost

Recombinant Interleukin-2

2,000 per patient. Baseline risk stratification and new treatment approaches are needed to reduce treatment failures and costs in the primary care setting.

Impact of Atypical Coverage for Patients with Community-Acquired Pneumonia Managed on the Medical Ward: Results from the United States Community-Acquired Pneumonia Project

The objective of this paper is to evaluate the efficacy of modern antiemetic therapy for chemotherapy-induced nausea and vomiting for patients receiving multiple-day or high-dose chemotherapy. Published phase II and phase III studies as well as their personal experiences were evaluated by the authors to develop this consensus statement. The largest published experience with multiple-day chemotherapy is with 5-day cisplatin combination chemotherapy. The introduction of 5-HT3 antagonists greatly improved emetic control. However, day 4–5 nausea as well as delayed nausea and vomiting remains a clinical problem despite the inclusion of dexamethasone. A 5-HT3 antagonist plus dexamethasone is the preferred current option for patients receiving high-dose chemotherapy with stem cell transplant. However, the results do not appear as successful as for highly emetic standard-dose chemotherapy.

Chemotherapy-induced nausea and vomiting: contemporary approaches to optimal management

Recombinant interleukin (IL)‐2 is a newly approved immunoregulatory protein produced by lymphocytes that exhibits a wide range of immunologic effects. It is a true biologic response modifier in that is has no known direct antitumor activity, but mediates its cytotoxicity through activation of effector cells including T cells, natural killer cells, and lymphokine‐activated killer cells. Recombinant IL‐2 has demonstrated activity in patients with renal cell carcinoma and melanoma, with objective response rates of approximately 15–20%. The median duration of response in renal cell carcinoma is 23 months. Toxicity experienced with high‐dose IL‐2 can be significant. The most common dose‐limiting toxicities are hypertension, weight gain, oliguria, respiratory insufficiency, and neurotoxicity. These effects are generally manageable and reversible on discontinuation of therapy. Administration of low‐dose IL‐2 has emerged as a means of substantially reducing toxicity. At least in renal cell carcinoma, it appears that the response rate to low‐dose IL‐2 is comparable to that with higher dosages.