Palonosetron: a unique 5-HT3 receptor antagonist indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting.

Despite the advance in supportive care that occurred with the introduction of selective serotonin subtype 3 (5-HT3) receptor antagonists, control of chemotherapy-induced nausea and vomiting (CINV) with first-generation agents (ondansetron, dolasetron, and granisetron) is less than ideal. Palonosetron is a unique 5-HT3 receptor antagonist whose distinctive pharmacologic characteristics (ie, high 5-HT3 receptor binding affinity, prolonged half-life) result in superior clinical benefit. Superiority of palonosetron over ondansetron and dolasetron in the prevention of both acute and delayed CINV has been observed in each phase III trial conducted. Of note, such evidence of superiority has never been seen in US Food and Drug Administration (FDA) registration trials of other approved agents in this class. Recently approved by the FDA, palonosetron 0.25 mg intravenously is indicated for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy. Unlike other 5-HT3 receptor antagonists, palonosetron is also indicated for prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. Palonosetron exhibits an excellent tolerability profile, with frequency, severity, and duration of adverse reactions similar to that of comparator agents. Unlike older agents that are considered therapeutically interchangeable at equipotent doses, palonosetron should be considered a clinically distinct and superior treatment for the prevention of CINV.

Evidence-based guidelines for managing mucositis.

OBJECTIVES: To discuss implementation of evidence-based clinical practice guidelines for mucositis. DATA SOURCE: Published articles, book chapters, web sources, clinical experience, unpublished manuscripts. CONCLUSION: Nurses can implement evidence-based guidelines but must include an evaluation component to determine effect on clinical outcomes. IMPLICATIONS FOR NURSING PRACTICE: Nurses have an integral role implementing and evaluating evidence-based practice guidelines for managing mucositis. When evidence is lacking and guidelines have gaps, nurses can play important roles in research to overcome these gaps.

Palonosetron triggers 5-HT(3) receptor internalization and causes prolonged inhibition of receptor function.

Palonosetron is a 5-HT(3) receptor antagonist that has demonstrated superiority in preventing both acute and delayed emesis when compared to older first generation 5-HT(3) receptor antagonists. The objective of this work was to determine if palonosetron exhibits unique molecular interactions with the 5-HT(3) receptor that could provide a scientific rationale for observed clinical efficacy differences. Previously, we showed that palonosetron exhibits allosteric binding and positive cooperativity to the 5-HT(3) receptor in contrast to ondansetron and granisetron which exhibit simple bimolecular binding. The present work shows, through several independent experiments, that palonosetron uniquely triggers 5-HT(3) receptor internalization and induces prolonged inhibition of receptor function. After 24h incubation followed by dissociation conditions, [(3)H]palonosetron remained associated with whole cells but not to cell-free membranes (P<0.001). [(3)H]Palonosetron's binding to cells was resistant to both protease and acid treatments designed to denature cell surface proteins suggesting that the receptor complex was inside the cells rather than at the surface. Cells pretreated with unlabeled palonosetron subsequently exhibited reduced cell surface 5-HT(3) receptor binding. Palonosetron-triggered receptor internalization was visualized by confocal fluorescence microscopy using cells transfected with 5-HT(3) receptor fused to enhanced cyan fluorescent protein. In contrast, granisetron and ondansetron showed minimal to no effect on receptor internalization or prolonged inhibition of receptor function. These experiments may provide a pharmacological basis for differences noted in published clinical trials comparing palonosetron to other 5-HT(3) receptor antagonists.

New approaches to chemotherapy-induced nausea and vomiting: from neuropharmacology to clinical investigations.

Nausea and vomiting are considered to be among the most distressing consequences of cytotoxic chemotherapies. Currently, there are several novel 5-HT(3) receptor antagonists for the treatment of chemotherapy-induced nausea and vomiting (CINV), including ondansetron, granisetron, and dolasetron. These agents provide significant improvement in the management of acute emesis but are ineffective at preventing delayed emesis. In 2003, a new 5-HT(3) receptor antagonist, palonosetron HCL (Aloxi), was introduced to the U.S. market. Palonosetron was found to be effective in preventing delayed CINV. Indeed, palonosetron was the first and only 5-HT(3) receptor antagonist approved by the FDA for the prevention of both acute and delayed CINV. More recently, studies on the role of substance P in the emetic process led to the development of aprepitant (Emend) for the prevention of delayed emesis in combination with 5-HT(3) receptor antagonists. Despite these major advances, CINV remains uncontrolled in some patients. Current efforts are focused on treating refractory emesis and include both the clinical evaluation of compounds marketed for other indications and the preclinical evaluation of novel molecules targeting other transmitters in the emetic pathway. Ongoing work in pharmacogenomics has postulated several candidate genes that could be involved in emetic sensitivity and responsiveness to antiemetic therapy. Investigations into the pharmacogenomics of CINV may someday be able to aid in the identification of high risk patients and patients unlikely to respond to conventional therapies.

Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer.

GOALS OF WORK: Although many patients with ovarian cancer achieve favorable responses to primary chemotherapy, the majority of women will experience recurrence of their cancer. Selection of second- or third-line chemotherapy ultimately depends on patient preferences for different side effects. To better understand this process, we evaluated preferences and symptom distress in patients with ovarian cancer. PATIENTS AND METHODS: A total of 70 women with ovarian cancer who had previously received at least three cycles of platinum-based chemotherapy and currently undergoing chemotherapy for newly diagnosed or recurrent disease were interviewed in an outpatient chemotherapy clinic. The patients were asked to rank order 27 health states using a modified visual analog scale and to complete the Memorial Symptom Assessment Scale (MSAS). MAIN RESULTS: Most favorable health states included perfect health, clinical remission and complete control of chemotherapy-induced nausea and vomiting (CINV). Least favorable health states included more severe CINV health states and death. Patients on first-line chemotherapy had less symptom distress, and rated sexual dysfunction, fatigue and memory loss more favorably than patients on second- or third-line chemotherapy (P<0.05). Married patients generally had less symptom distress compared to patients who were not married, but married patients indicated more distress with sexual dysfunction (P=0.04). Married patients rated alopecia less favorably than unmarried patients (P=0.03), but married patients viewed certain CINV health states more favorably (P=0.02-0.04). CONCLUSIONS: CINV remains one of the most dreaded side effects of chemotherapy. Separate preference profiles exist for patients with newly diagnosed and recurrent disease, as well as for married versus unmarried patients. While MSAS scores and VAS rankings showed consistency across some health states, this was not true for CINV, suggesting that current symptom status may only influence patient preferences for selected side effects.

Measuring chemotherapy-induced nausea and emesis.

BACKGROUND: Chemotherapy-induced nausea and emesis (CINE) is one of the most dreaded side effects of cancer therapy. To investigate the influence of these symptoms on a patient's quality of life (QOL), a validated tool measuring many domains is needed. METHODS: A QOL questionnaire consisting of scales from the European Organization for Research and Treatment of Cancer QLQ-C30, the Morrow Assessment of Nausea and Emesis, the Osoba Nausea and Emesis Module, and new items specific to nausea, emesis, and retching was constructed and administered daily for 7-9 days to outpatients receiving emetogenic chemotherapy. RESULTS: Test-retest and internal consistency reliabilities ranged from 0.44 to 0.84 and from 0.59 to 0.85, respectively. Item and scale correlations indicated good convergent and discriminant validity. Scales and items measuring similar factors (e.g., severity of emesis and severity of nausea) had strong correlations than did scales measuring dissimilar factors (e.g., cognitive functioning and physical functioning). The validity of known groups was demonstrated by significant differences (P < 0.01) in patients' QOL scores between days with no episodes of nausea, emesis, or retching, days with 1 or 2 episodes, and days with more than 3 episodes. Patients' QOL significantly decreased as the number of episodes per day increased (P < 0.001). CONCLUSIONS: A CINE QOL questionnaire that successfully measures the short-term impact of nausea, emesis, and retching on patients receiving emetogenic chemotherapy has been developed, largely as a battery of preexisting questionnaires. The psychometric properties of the new questionnaire show adequate reliability and validity to warrant its use in clinical trials and outcomes studies. CINE adversely affects many domains within a patient's QOL.

Pharmacoeconomic analysis of oprelvekin (recombinant human interleukin-11) for secondary prophylaxis of thrombocytopenia in solid tumor patients receiving chemotherapy.

BACKGROUND: Previous research has shown oprelvekin (recombinant human interleukin-11 [rhIL-11]) to be effective in reducing the requirements for platelet transfusions after myelosuppressive chemotherapy in patients who have previously experienced thrombocytopenia. The economic consequences of the routine use of this platelet growth factor and the usual standard of platelet transfusions for prophylaxis of severe chemotherapy-induced thrombocytopenia have not been compared. METHODS: The authors constructed a decision-analytic model to compare the alternatives of rhIL-11 versus usual care using probability, outcome, and cost data from previously published clinical trials and their own institutional sources. They incorporated the costs of platelet transfusions and adverse events from rhIL-11 into the analysis. Quality-of-life outcomes were not considered. The pharmacoeconomic analysis was based on the criterion of cost minimization from the payer's perspective. RESULTS: The expected cost of the usual care strategy for prophylaxis of severe thrombocytopenia (transfusion when platelets < 20000 microL(-1)) was US dollars 3495 for a 3-week cycle of chemotherapy. The prophylactic rhIL-11 strategy was more expensive, with an expected cost of US dollars 5328 over the same time period. Nonetheless, it was associated with fewer platelet transfusions, avoiding an average of 6.7 U compared with usual care. The savings from avoidance of platelet transfusion and adverse reactions to transfusion from the use of rhIL-11 were not offset by the substantial cost of the pharmaceutical. The greater expected costs from the rhIL-11 strategy were relatively insensitive to the unit price and efficacy of rhIL-11 and the costs of platelet transfusions and monitoring. CONCLUSIONS: From the payer's perspective, rhIL-11 cannot be considered a cost-saving clinical strategy compared with routine platelet transfusions for patients with severe chemotherapy-induced thrombocytopenia.

The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis.

BACKGROUND: Mucositis is a common but poorly studied problem among patients with solid tumors. The authors examined the clinical and economic outcomes of oral and gastrointestinal (GI) mucositis among patients receiving myelosuppressive chemotherapy. METHODS: A retrospective, random sample of 599 patients who developed chemotherapy-induced myelosuppression was followed for development of oral or GI mucositis and for development of subsequent episodes of bleeding or infection. Multilevel regression models of the risk of bleeding and infection were fit with chemotherapy cycles nested within patients. RESULTS: Mucositis developed during 37% of 1236 cycles of chemotherapy. Episodes of bleeding were significantly more common during cycles with GI mucositis than during cycles without GI mucositis (13% vs. 8%; P = 0.04). Episodes of infection were significantly more common during cycles with mucositis (especially GI mucositis) than during cycles without mucositis (73% vs. 36%; P < 0.0001). The mean durations of hospitalization were 4 days, 6 days, and 12 days during cycles with no mucositis, oral mucositis, and GI mucositis, respectively. After accounting for the depth and duration of myelosuppression and for other predictive factors, GI mucositis was associated with both bleeding (odds ratio [OR], 2.0; P = 0.01) and infection (OR, 2.24; P < 0.0001), whereas oral mucositis was associated with infection only (OR, 2.4; P < 0.0001). CONCLUSIONS: Mucositis was clinically and economically significant among patients with solid tumors who were receiving myelosuppressive chemotherapy. New preventive and therapeutic agents are needed.

Incidence of chemotherapy-induced nausea and emesis after modern antiemetics.

BACKGROUND: The authors determined the incidence of acute and delayed chemotherapy-induced nausea and emesis (vomiting) (CINV) among patients receiving highly (HEC) or moderately (MEC) emetogenic chemotherapy. They also assessed whether physicians and nurses accurately recognized the incidence of acute and delayed CINV in their own practices. METHODS: A prospective, observational study of adult patients receiving HEC or MEC for the first time was performed. Before patient enrollment, medical oncologists and oncology nurses estimated the incidence of acute (Day 1) and delayed (Days 2-5) CINV after first administration of HEC and MEC in their own practices. Eligible patients from their practices then completed a 6-day diary including emetic episodes, nausea assessment, and antiemetic medication use. Observed incidence rates of acute and delayed CINV were compared with physician/nurse predictions. RESULTS: Twenty-four physicians and nurses and 298 eligible patients (67 receiving HEC and 231 receiving MEC) were recruited from 14 oncology practices in 6 countries. Greater than 35% of patients overall experienced acute nausea, whereas 13% experienced acute emesis. Delayed nausea and emesis were observed in 60% and 50% of HEC patients, respectively, and in 52% and 28% of MEC patients, respectively. Delayed symptoms appeared without acute symptoms after HEC (emesis, 38%; nausea, 33%) and MEC (emesis, 19%; nausea, 21%). Physicians and nurses accurately predicted the incidence of acute CINV but underestimated the incidence of delayed nausea and emesis after HEC by 21 and 28 percentage points, respectively, and delayed nausea after MEC by 28 percentage points. Greater than 75% of physicians and nurses underestimated the incidence of delayed CINV after both HEC and MEC. CONCLUSIONS: Physicians and nurses markedly underestimated the incidence of delayed nausea and emesis after both HEC and MEC. Delayed nausea and emesis, which may appear even in the absence of acute nausea and emesis, remain important targets for improved therapeutic intervention.

Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis.

BACKGROUND: Oral and gastrointestinal (GI) mucositis can affect up to 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation, 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary track mucositis increases mortality and morbidity and contributes to rising health care costs. Consequently, the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an expert panel to evaluate the literature and to create evidence-based guidelines for preventing, evaluating, and treating mucositis. METHODS: Thirty-six panelists reviewed literature published between January 1966 and May 2002. An initial meeting in January 2002 produced a preliminary draft of guidelines that was reviewed at a second meeting the same year. Thereafter, a writing committee produced a report on mucositis pathogenesis, epidemiology, and scoring (also included in this issue), as well as clinical practice guidelines. RESULTS: Panelists created recommendations from higher levels of evidence and suggestions when evidence was of a lower level and there was a consensus regarding the interpretation of the evidence by the panel. Panelists identified gaps in evidence that made it impossible to recommend or not recommend use of specific agents. CONCLUSIONS: Oral/GI mucositis is a common side effect of many anticancer therapies. Evidence-based clinical practice guidelines are presented as a benchmark for clinicians to use for routine care of appropriate patients and as a springboard to challenge clinical investigators to conduct high-quality trials geared toward areas in which data are either lacking or conflicting.

The Bleeding Risk Index: a clinical prediction rule to guide the prophylactic use of platelet transfusions in patients with lymphoma or solid tumors.

BACKGROUND: The correlation between platelet count and bleeding has been well described, although no formal methods for applying this information to clinical decisions are available. The authors developed a clinical prediction rule to guide the prophylactic use of platelet transfusions among patients with lymphoma or solid tumors. METHODS: The Bleeding Risk Index (BRI) was developed from logistic regression analysis of a randomly selected 750-chemotherapy cycle derivation set using data from Day 1 of cycles. The sensitivity and specificity of a BRI-based prophylaxis strategy were compared in a 512-cycle validation set with two strategies based on initiation of prophylaxis when platelet counts fell below thresholds of 20,000 per microL or 10,000 per microL. RESULTS: Factors that were predictive of bleeding included any prior episode of bleeding (odds ratio [OR], 5.6; 95% confidence interval [95% CI], 2.2-14.0), treatment with a drug affecting platelet function (OR, 5.1; 95% CI, 2.0-12.6), bone marrow metastases (OR, 4.3; 95% CI, 1.7-10.8), a baseline platelet count < 75,000 per microL (OR, 3.5; 95% CI, 1.4-8.9), genitourinary or gynecologic malignancy (OR, 3.3; 95% CI, 1.3-8.2), a Zubrod performance status score > 2 (OR, 3.4; 95% CI, 1.4-8.5), and treatment with agents that were highly toxic to the bone marrow (OR, 2.2; 95% CI, 1.0-5.4). Compared with 20,000 and 10,000 platelet threshold strategies, the BRI-based strategy provided the best trade-off between sensitivity for major bleeding episodes (80%) and specificity for any bleeding (84%). CONCLUSIONS: Patients with lymphoma or solid tumors who are at high risk of bleeding can be identified reliably on Day 1 of a chemotherapy cycle. An individualized, BRI-based approach to bleeding prophylaxis provides a highly sensitive and specific alternative to traditional, nonindividualized platelet threshold strategies.

Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients.

BACKGROUND: A frequent complication of anticancer treatment, oral and gastrointestinal (GI) mucositis, threatens the effectiveness of therapy because it leads to dose reductions, increases healthcare costs, and impairs patients' quality of life. The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an international multidisciplinary panel of experts to create clinical practice guidelines for the prevention, evaluation, and treatment of mucositis. METHODS: The panelists examined medical literature published from January 1966 through May 2002, presented their findings at two separate conferences, and then created a writing committee that produced two articles: the current study and another that codifies the clinical implications of the panel's findings in practice guidelines. RESULTS: New evidence supports the view that oral mucositis is a complex process involving all the tissues and cellular elements of the mucosa. Other findings suggest that some aspects of mucositis risk may be determined genetically. GI proapoptotic and antiapoptotic gene levels change along the GI tract, perhaps explaining differences in the frequency with which mucositis occurs at different sites. Studies of mucositis incidence in clinical trials by quality and using meta-analysis techniques produced estimates of incidence that are presented herein for what to our knowledge may be a broader range of cancers than ever presented before. CONCLUSIONS: Understanding the pathobiology of mucositis, its incidence, and scoring are essential for progress in research and care directed at this common side-effect of anticancer therapies.

Patient preferences regarding side effects of chemotherapy for ovarian cancer: do they change over time?

OBJECTIVE: The goals of this study were to: (1) systematically evaluate patient preferences regarding side effects of high-dose chemotherapy with stem cell support for treatment of advanced ovarian cancer; and (2) assess whether patients' preferences changed over time. METHODS: Forty patients with stage III or IV disease were enrolled in this study. Patients' preferences regarding 12 health states (side effects) were assessed using visual analogue scale (VAS) and time trade-off (TTO) methods during mobilization chemotherapy (T(1)) and 6-7 weeks later after high-dose chemotherapy and stem cell transplant (T(2)). Each assessment involved a 45-min interview conducted at the patient's bedside. RESULTS: The three most preferred health states were no evidence of disease (NED), a chemotherapy with few or no side effects, and alopecia, while the least preferred health states were chemotherapy with multiple severe side effects, hepatotoxicity, and nausea and vomiting. These results were observed at both T(1) and T(2) using both preference assessment methods. Pancytopenia scores significantly increased from T(1) to T(2) using the VAS method (P < 0.05), but decreased using the TTO method. CONCLUSIONS: Chemotherapy-experienced women with ovarian cancer have consistent preferences for the best and worst health states associated with the side effects of chemotherapy. Patients are more averse to nausea and vomiting than many other symptoms. Women's perceptions of pancytopenia may be dependent upon the number of prior cycles of chemotherapy and site of care for anemia, thrombocytopenia, and febrile neutropenia.