Three palonosetron regimens to prevent CINV in myeloma patients receiving multiple-day high-dose melphalan and hematopoietic stem cell transplantation.

BACKGROUND: Explore safety and efficacy of three palonosetron-containing regimens for emesis prevention over 7 days in multiple myeloma (MM) patients receiving melphalan (100 mg/m(2)) and hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: Randomized, double-blind pilot study in MM patients (n=73) receiving 1, 2, or 3 days of 0.25 mg palonosetron (30-s i.v. bolus) 30 min before melphalan (days -2 and -1) and HSCT (day 0). Patients received dexamethasone (20 mg i.v., days -2 and -1) immediately before or after study drug/placebo. Daily diaries recorded emesis, rescue medication, nausea duration, and adverse events (AEs). RESULTS: Seven-day complete protection (no emesis) occurred in 41.7% [95% confidence interval (CI) 22.1% to 63.4%], 41.7% (95% CI 22.1% to 63.4%), and 44.0% (95% CI 24.2% to 65.1%) of patients receiving 1, 2, or 3 days of palonosetron, respectively (P=0.43). Complete response (emesis free without rescue medication) occurred in 8.3%, 20.8%, and 20.0% (P=0.14). Common AEs (≥10%) were mild-to-moderate diarrhea, constipation, headache, insomnia, and flatulence. No serious AEs occurred. CONCLUSIONS: Palonosetron with dexamethasone was safe and effective in preventing emesis in MM patients receiving melphalan and HSCT. This pilot study with a limited number of patients suggests that multiple doses of palonosetron could be more effective than a single dose in making patients emesis free without need for rescue medication. However, even multiple doses of palonosetron resulted in only 20% of patients being emesis free without rescue medication, suggesting that further improvement will require development of more effective combination antiemetic therapy.

Incidence, cost, and outcomes of bleeding and chemotherapy dose modification among solid tumor patients with chemotherapy-induced thrombocytopenia.

PURPOSE: To describe the incidence and outcomes of bleeding and chemotherapy dose modifications associated with chemotherapy-induced thrombocytopenia (platelets < 50,000/microL). PATIENTS AND METHODS: Six hundred nine patients with solid tumors or lymphoma were followed-up during 1,262 chemotherapy cycles complicated by thrombocytopenia for development of bleeding, delay or dose reduction of the subsequent cycle, survival, and resource utilization. The association between survival and bleeding or dose modification was examined using the Cox proportional hazards model. Predisposing factors were identified by logistic regression. RESULTS: Bleeding occurred during 9% of cycles among patients with previous bleeding episodes (P <.0001), baseline platelets less than 75,000/microL (P <.0001), bone marrow metastases (P =.001), poor performance status (P =.03), and cisplatin, carboplatin, carmustine or lomustine administration (P =.0002). Major bleeding episodes resulted in shorter survival and higher resource utilization (P <.0001). Chemotherapy delays occurred during 6% of cycles among patients with more than five previous cycles (P =.003), radiotherapy (P =.03), and disseminated disease (P =.04). They experienced similar clinical outcomes but used significantly more resources. Dose reductions occurred during 15% of cycles but were not associated with poor clinical outcomes or excess resource utilization. Significantly shorter survival and higher resource utilization were observed among the 20% of patients who failed to achieve an adequate response to platelet transfusion. CONCLUSION: The incidence of bleeding is low among solid tumor patients overall but exceeds 20% in some subgroups. These subgroups are easily identifiable using routinely available clinical information. A clinical prediction rule is being developed. Poor response to platelet transfusion is a clinically and financially significant downstream effect of thrombocytopenia and warrants further investigation.

Identifying risk factors for imminent death in cancer patients with acute dyspnea.

A substantial proportion of cancer patients presenting to an emergency center (EC) or clinic with acute dyspnea survives fewer than 2 weeks. If these patients could be identified at the time of admission, physicians and patients would have additional information on which to base decisions to continue therapy to extend life or to refocus treatment efforts on palliation and/or hospice care alone. The purpose of this study was to identify risk factors for imminent death (survival

Colony stimulating factors in patients with fever and neutropenia.

Colony stimulating factors (CSFs), are essential for the regulation of the hematopoietic system and were developed by the pharmaceutical biotechnology industry in the early 1990s for the prevention of serious neutropenic complication after myelosuppressive chemotherapy. Both G-CSF and GM-CSF consistently lead to an increase in circulating white blood cells and a reduction in the incidence of fever and neutropenia after myelosuppressive chemotherapy in patients with solid tumors, hematologic malignancies, and those undergoing stem-cell transplantation. Their role in improving response rates to chemotherapy and overall survival is less clear.

Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care.

PURPOSE: To determine whether antibiotic regimens with similar rates of response differ significantly in the speed of response and to estimate the impact of this difference on the cost of febrile neutropenia. METHODS: The time point of clinical response was defined by comparing the sensitivity, specificity, and predictive values of alternative objective and subjective definitions. Data from 488 episodes of febrile neutropenia, treated with either of two commonly used antibiotics (coded A or B) during six clinical trials, were pooled to compare the median time to clinical response, days of antibiotic therapy and hospitalization, and estimated costs. RESULTS: Response rates were similar; however, the median time to clinical response was significantly shorter with A-based regimens (5 days) compared with B-based regimens (7 days; P =.003). After 72 hours of therapy, 33% of patients who received A but only 18% of those who received B had responded (P =.01). These differences resulted in fewer days of antibiotic therapy and hospitalization with A-based regimens (7 and 9 days) compared with B-based regimens (9 and 12 days, respectively; P <.04) and in significantly lower estimated median costs ($8,491 v $11,133 per episode; P =.03). Early discharge at the time of clinical response should reduce the median cost from $10,752 to $8,162 (P <.001). CONCLUSION: Despite virtually identical rates of response, time to clinical response and estimated cost of care varied significantly among regimens. An early discharge strategy based on our definition of the time point of clinical response may further reduce the cost of treating non-low-risk patients with febrile neutropenia.

The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients.

PURPOSE: Febrile neutropenia remains a potentially life-threatening complication of anticancer chemotherapy, but some patients are at low risk for serious medical complications. The purpose of this study was to develop an internationally validated scoring system to identify these patients. MATERIALS AND METHODS: Febrile neutropenic cancer patients were observed in a prospective multinational study. Independent factors assessable at fever onset, predicting low risk of complications, on a randomly selected derivation set, were assigned integer weights to develop a risk-index score, which was subsequently tested on a validation set. RESULTS: On the derivation set (756 patients), predictive factors were a burden of illness indicating absence of symptoms or mild symptoms (weight, 5; odds ratio [OR], 8.21; 95% confidence interval [CI], 4.15 to 16.38) or moderate symptoms (weight, 3; OR, 3.70; 95% CI, 2.18 to 6.29); absence of hypotension (weight, 5; OR, 7.62; 95% CI, 2.91 to 19.89); absence of chronic obstructive pulmonary disease (weight, 4; OR, 5. 35; 95% CI, 1.86 to 15.46); presence of solid tumor or absence of previous fungal infection in patients with hematologic malignancies (weight, 4; OR, 5.07; 95% CI, 1.97 to 12.95); outpatient status (weight, 3; OR, 3.51; 95% CI, 2.02 to 6.04); absence of dehydration (weight, 3; OR, 3.81; 95% CI, 1.89 to 7.73); and age less than 60 years (weight, 2; OR, 2.45; 95% CI, 1.51 to 4.01). On the validation set, a Multinational Association for Supportive Care in Cancer risk-index score >/= 21 identified low-risk patients with a positive predictive value of 91%, specificity of 68%, and sensitivity of 71%. CONCLUSION: The risk index accurately identifies patients at low risk for complications and may be used to select patients for testing therapeutic strategies that may be more convenient or cost-effective.

Influence of data display formats on physician investigators' decisions to stop clinical trials: prospective trial with repeated measures.

OBJECTIVE: To examine the effect of the method of data display on physician investigators' decisions to stop hypothetical clinical trials for an unplanned statistical analysis. DESIGN: Prospective, mixed model design with variables between subjects and within subjects (repeated measures). SETTING: Comprehensive cancer centre. PARTICIPANTS: 34 physicians, stratified by academic rank, who were conducting clinical trials. INTERVENTIONS: PARTICIPANTS were shown tables, pie charts, bar graphs, and icon displays containing hypothetical data from a clinical trial and were asked to decide whether to continue the trial or stop for an unplanned statistical analysis. MAIN OUTCOME MEASURE: Percentage of accurate decisions with each type of display. RESULTS: Accuracy of decisions was affected by the type of data display and positive or negative framing of the data. More correct decisions were made with icon displays than with tables, pie charts, and bar graphs (82% v 68%, 56%, and 43%, respectively; P=0.03) and when data were negatively framed rather than positively framed in tables (93% v 47%; P=0.004). CONCLUSIONS: Clinical investigators' decisions can be affected by factors unrelated to the actual data. In the design of clinical trials information systems, careful consideration should be given to the method by which data are framed and displayed in order to reduce the impact of these extraneous factors.

Evaluating cost-effectiveness in outpatient management of medical complications in cancer patients.

It has been estimated that 85% to 90% of all cancer patient care occurs in the outpatient setting, and the vast majority of chemotherapy is administered in the outpatient setting either in physician offices or hospital clinics. With the introduction of white blood cell growth factors in the early 1990s, dose-intensive regimens either for curative or palliative therapy became more common. Since that time, major dose-limiting toxicities have become gastrointestinal mucositis and chemotherapy-induced thrombocytopenia. Patient-reported symptoms have also become important as the changing financing and reimbursement for health care shifts the focus to a patient-centered, value-oriented approach in hematology and medical oncology. This paper will examine advances in the management of three common complications of antineoplastic therapy, mucositis, thrombocytopenia, and fatigue, with a particular emphasis on cost-effectiveness as it relates to value in health care.

Costs of blood transfusion: a process-flow analysis.

PURPOSE: To determine the cost of transfusing 2 units (U) of packed RBCs at a comprehensive cancer center. METHODS: We performed a process-flow analysis to identify all costs of transfusing 2 U of allogeneic packed RBCs on an outpatient basis to patients with either (1) solid tumor who did not undergo bone marrow transplantation (BMT), (2) solid tumor who underwent BMT, (3) hematologic malignancy who did not undergo BMT, (4) hematologic malignancy who underwent allogeneic BMT, or (5) hematologic malignancy who underwent autologous BMT. We conducted structured interviews to determine the personnel time used and physical resources necessary at all steps of the transfusion process. RESULTS: The mean cost of a 2-U transfusion of allogeneic packed RBCs was $548, $565, $569, $569, and $566 for patients with non-BMT solid tumor, BMT solid tumor, non-BMT hematologic malignancy, allogeneic BMT hematologic malignancy, and autologous BMT hematologic malignancy, respectively. Sensitivity analysis showed that total transfusion costs were sensitive to variations in the amount of clinician compensation and overhead costs, but were relatively insensitive to reasonable variations in the direct costs of blood tests and the blood itself, or the probability or extent of transfusion reaction. CONCLUSION: The costs of the transfusion of packed RBCs are greater than previously analyzed, particularly in the cancer care setting.

Ambulatory management of varicella-zoster virus infection in immunocompromised cancer patients.

Immunocompromised patients with varicella-zoster virus (VZV) infection are at greater risk for dissemination and the development of complications than immunocompetent individuals. Consequently, they are generally hospitalized in strict isolation rooms and treated with parenterally administered acyclovir. Although effective, this approach is expensive and creates logistic difficulties in the hospital. We treated 38 immunosuppressed cancer patients presenting to our ambulatory treatment center with VZV infections with intravenous acyclovir (500 mg/m2 8-hourly) in an ambulatory/home setting. Patients were monitored for success or failure of therapy, progression of infection, development of complications or drug toxicity, and satisfaction/compliance with therapy. Most patients (33, or 87%) responded to therapy. Among the failures, 2 patients had progressive VZV infection, 2 were hospitalized due to renal toxicity, and 1 developed a superinfection. All patients eventually responded and there were no deaths on this study. Two patients relapsed within 1 month of initial response. Both responded to retreatment with acyclovir, without hospitalization. The median duration of parenteral therapy with acyclovir was 7.5 days. Seven patients (18%) had to be switched to oral acyclovir (800 mg, 5 times a day) before complete response, owing to problems with venous access. All 7 completed therapy successfully. Overall, patients expressed a high level of satisfaction with outpatient therapy, and there were no instances of noncompliance or patient requests for withdrawal from study. The results of this study indicate that VZV infections in clinically stable immunosuppressed cancer patients are relatively benign and do not require hospitalization. Parenterally administered acyclovir in an ambulatory setting is effective therapy for such infections.

Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice.

BACKGROUND: Discrepancies between the severity of toxicities reported in early clinical trials and recent clinical experience with vancomycin have led to confusion regarding the need for routine serum vancomycin level monitoring and discontinuation of vancomycin when toxicities occur. Therefore, the authors examined the incidence, outcomes, and predictive factors of vancomycin-associated toxicities in general oncology practice with the goal of developing clinically relevant prediction rules and guidelines. METHODS: All 742 consecutive cancer patients who received vancomycin at a comprehensive cancer center during a 3-month period were followed prospectively for the development and outcome of phlebitis, rash, ototoxicity, and nephrotoxicity. Logistic regression was used to derive a multiple variable model of the risk of nephrotoxicity. A clinical prediction rule, the Nephrotoxicity Risk Score, was developed from the risk model and validated prospectively. RESULTS: Phlebitis occurred in 3% of patients (95% confidence interval [95% CI], 2-4%), predominantly those with recently inserted central venous catheters. Rashes occurred in 11% of patients (95% CI, 9-13%); however, all but 4 patients also were receiving beta-lactam antibiotics. Clinical evidence of ototoxicity developed in 6% of patients (95% CI, 4-9%) who were receiving vancomycin plus other ototoxic agents and only 3% of patients (95% CI, 2-5%) not receiving other ototoxic agents (P = 0.08). Nephrotoxicity occurred in 17% of patients (95% CI, 15-20%). Logistic regression revealed that factors associated with an increased risk of nephrotoxicity included administration of other mild to moderate (P = 0.01) or severely nephrotoxic agents (P < 0.001) or an acute physiology and chronic health evaluation (APACHE) score > 40 (P = 0.002). Elevated serum vancomycin peak levels did not reliably predict subsequent nephrotoxicity. CONCLUSIONS: Vancomycin-associated toxicities usually are mild and self-limiting. Some patients are at a significantly higher risk of nephrotoxicity but the authors believe these individuals can be identified reliably with the Nephrotoxicity Risk Index using information available at vancomycin initiation. Further testing of the Nephrotoxicity Risk Index is ongoing.

Incorporating new modalities into practice guidelines: platelet growth factors.

The outcomes of thrombocytopenia are clinically serious (hemorrhage), costly to prevent and treat (platelet transfusions and hospitalization), and may result in delay of the subsequent cycle of chemotherapy. Oprelvekin, the first commercially available platelet growth factor, has been shown to be safe and effective in reducing the need for platelet transfusions. In placebo-controlled trials of patients with solid tumors receiving dose-intensive chemotherapy, 68% of oprelvekin recipients escaped transfusion altogether, compared with only 41% of those who received a placebo. Side effects are generally mild, reversible, and related to fluid retention. Although clinical trials provide evidence about how many patients, on average, can be expected to benefit from agents such as oprelvekin, the trials provide little information about which patients in the general oncology population will benefit. Guidelines based on clinical trial data are limited by this approach. An alternative approach is to develop a clinical profile or model of patients at high risk of developing serious clinical outcomes and target platelet growth factors to these patients through the use of guidelines. Other important components of the guideline development process include a thorough evaluation of the costs of treatments and side effects as well as a careful evaluation of patient's preferences for alternative treatment strategies. Guidelines limiting growth factor use to only those patients who are most likely to benefit provide an opportunity to use expensive new agents in a cost-effective, evidence-based fashion.

Controversies in new antibiotic therapy for ambulatory patients.

The care of the febrile neutropenic patient has undergone a shift in the last 10 years with the realization that neutropenic patients presenting with fever do not constitute a homogeneous group. Strategies of risk assessment have allowed the testing of novel therapies including outpatient treatment with oral and intravenous antibiotics, either in combination regimens or as monotherapy; the addition of growth factors to hasten the return of the absolute neutrophil count; and the possibility of self-initiation of antibiotics by cancer patients when they develop fever. The clinical trials data regarding these new approaches will be reviewed, and areas requiring further research will be discussed.

Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials.

The prognostic significance of major organ and tissue infection was examined in 909 episodes of bacteremia that were selected from 10 consecutive, randomized clinical trials of antibiotic therapy for infection in patients with cancer and neutropenia. Extensive tissue infection significantly compromised response to initial therapy (38% vs. 74%; P < .0001), ultimate outcome of infection (73% vs. 94%; P < .0001), median time to normalization of temperature (5.3 days vs. 2.5 days; P < .0001), and survival (P < .0001). Other poor prognostic factors revealed by logistic regression included shock (P < .0001) and bacteremia caused by Pseudomonas species (P = .03), Clostridium species (P = .006), or a pathogen resistant to antibiotics used for initial therapy (P < .0001). Recovery of the granulocyte count predicted a superior response (P < .0001). Although the overall mortality rate was not significantly increased when patients with bacteremia due to gram-negative organisms initially received monotherapy or when patients with bacteremia due to gram-positive organisms received delayed vancomycin therapy, these strategies increased the duration of therapy by 25%. Patients with bacteremia due to alpha-hemolytic streptococcus died more often when vancomycin was not included in the initial empirical regimen (P = .004). Because of the prognostic significance of extensive tissue or major organ infection, this factor should be considered in decisions concerning modification of therapy and use of colony-stimulating factors. The cost-effectiveness of initial monotherapy and delayed vancomycin therapy remains to be demonstrated.

Medical futility and appropriate medical care in patients whose death is thought to be imminent.

Often it is very difficult to make decisions involving the termination of aggressive cancer care in the case of patients who are no longer benefiting. Among these patients, our ability to "do everything possible" to continue life is in conflict with "doing the right thing"; the greatest benefit to these patients derives from delivering excellent supportive care and assisting them in understanding and accepting end-of-life issues. Furthermore, in a cost-conscious environment with limited resources, all patients and, indeed, all of society, benefit when aggressive and often costly cancer care is limited to those patients who are likely to benefit. However, these issues are complex, blending treatment science and ethics, and thus, the physician frequently has no objective reference point on which to base the decisions. This paper integrates the principles of ethics (respect for autonomy, beneficence, nonmaleficence, and justice) and three difficult issues encountered by physicians in clinical decision-making in terminal cancer patients in the American healthcare system. These issues include: medical futility and appropriate care, applications of outcomes research in clinical decision-making, and impact of cost, particularly in a managed care environment, on treatment choice. These topics are illustrated with reference to patients presenting to our emergency center with stage IV lung cancer and dyspnea, and the application of an outcomes model under development to predict imminent death in these patients is discussed. Outcomes models may provide patients, their families, and their physicians with objective data on which to base end-of-life decision-making. Minimizing aggressive treatment of terminally ill patients may provide better life quality and will reduce costs during the patients' end of life. Ethics plays a crucial role in integrating medical science, patient choice, and cost in making appropriate decisions.

Randomized, double blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy. Oral Dolasetron Dose-Response Study Group.

BACKGROUND: This double blind parallel group study assessed the acute antiemetic efficacy of four oral doses of dolasetron mesylate in cancer patients receiving their first course of intravenous chemotherapy with doxorubicin and/or cyclophosphamide. METHODS: Patients were randomized to receive 25, 50, 100, or 200 mg of dolasetron mesylate 30 minutes prior to chemotherapy and were monitored for nausea and emetic episodes for the next 24 hours. RESULTS: Three hundred and nineteen cancer patients at 32 sites completed the study. Most patients were female (81%); of this group, 69% had breast carcinoma. A highly statistically significant linear trend demonstrating improved response with higher doses was detected for complete response (no emetic episodes and no rescue medication) (P < 0.001), for complete plus major response (0-2 emetic episodes and no rescue medication) (P < 0.001), and for patient visual analog scale assessments of nausea (P = 0.001) and general satisfaction with antiemetic therapy (P = 0.001). No serious adverse events were noted. The most frequent adverse event was mild, self-limiting headache, which has been reported with other drugs in this class. CONCLUSIONS: Single oral doses of dolasetron mesylate were found to be effective in preventing acute emesis in cancer patients receiving moderately emetogenic chemotherapy.

Outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients with cancer.

Until recently, febrile neutropenic patients were treated with intravenous antibiotics in inpatient settings. Because of work completed in the last several years by various investigators, identification of a low-risk group of febrile, neutropenic patients has allowed successful treatment with both parenteral and oral antibiotics in an ambulatory environment. This accomplishment has been facilitated by advances in broad-spectrum antibiotics with long half-lives and stabilities, the introduction of the quinolones providing oral antipseudomonal activity, home health care, improvements in vascular access devices, and technically enhanced antibiotic delivery systems. This review focuses on the rationale of risk stratification and the progress made in treating low-risk febrile neutropenic patients as outpatients.

Dyspnea in cancer patients. Etiology, resource utilization, and survival-implications in a managed care world.

BACKGROUND: Dyspnea is the fourth most common symptom of patients who present to the emergency department (ED) at The University of Texas M. D. Anderson Cancer Center and may, in some patients with advanced cancer, represent a clinical marker for the terminal phase of their disease. This retrospective study describes the clinical characteristics of these patients, the resource utilization associated with the management of dyspnea, and the survival of patients with this symptom. METHODS: The authors randomly selected 122 of 1068 patients presenting with dyspnea for a retrospective analysis. The median age of the patients was 58 years (range, 23-90 years) and 53% were female. Underlying malignancies were breast cancer (30%), lung cancer (37%), and other cancers (34%). Approximately 94% of the patients had received prior cancer treatment and the majority (69%) had uncontrolled, progressive disease. RESULTS: The most common treatments administered in the ED were oxygen (31%), beta-2 agonists (14%), antibiotics (12%), and narcotics (11%). Approximately 60% of patients were admitted to the hospital from the ED for further treatment of dyspnea and the underlying malignancy, and the median length of stay was 9 days. The median overall survival after the ED visit for dyspnea was 12 weeks. Specific diagnoses were associated with different median survival rates: lung cancer patients: 4 weeks; breast cancer patients: 22 weeks (P = 0.0073, vs. lung cancer); and other cancer diagnoses: 27 weeks (P = 0.0027, vs. lung cancer). CONCLUSIONS: Lung cancer patients presenting to the ED with dyspnea have much shorter survival than patients with other malignancies. For some patients, the presence of dyspnea requiring emergency treatment may indicate a phase in their illness in which resources should be shifted from acute intervention with hospitalization to palliative and supportive care measures.