Overall survival and risk of second malignancies with cancer chemotherapy and G-CSF support.

Background: The use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently recommended by several clinical practice guidelines. However, in a previous meta-analysis, G-CSF prophylaxis was associated with an increased risk of secondary malignancies while reducing long-term mortality. We present here an updated systematic review and meta-analysis. Materials and methods: A systematic literature search was carried out to identify randomized controlled trials of cancer patients receiving conventional-dose chemotherapy, assigned to primary G-CSF support or a control group without initial G-CSF, with at least 2 years of follow-up. Studies were categorized into one of the four groups, based on the chemotherapy regimen and study design. An updated meta-analysis was carried out; relative risk (RR) and 95% confidence intervals (CIs) for all-cause mortality and secondary malignancies were calculated. Results: Of 2604 articles screened, 14 eligible studies were identified and combined with studies identified in the previous systematic literature searches. The updated meta-analysis included a total of 68 studies presenting 71 separate comparisons. Survival was significantly improved in patients receiving primary G-CSF support, compared with patients without primary G-CSF support (mortality RR=0.92; 95% CI 0.90-0.95; ARD=-3.3%; 95% CI -4.2--2.4; P < 0.0001). The largest improvement in survival was observed with dose-dense chemotherapy regimens with G-CSF support, compared with controls receiving no G-CSF support (mortality RR=0.86; 95% CI 0.80-0.92; P < 0.0001). Patients who received primary G-CSF support experienced a significantly higher risk of secondary malignancies, compared with controls (RR=1.85; 95% CI 1.19-2.88; ARD=0.47; 95% CI 0.21-0.73; P < 0.01). Conclusions: Our findings demonstrate that overall survival is improved in patients receiving intensified chemotherapy with primary G-CSF support, compared with those receiving standard chemotherapy. Primary G-CSF support was also associated with a higher risk of developing secondary malignancies, including secondary acute myeloid leukemia and myelodysplastic syndrome.

The effect of filgrastim or pegfilgrastim on survival outcomes of patients with cancer receiving myelosuppressive chemotherapy.

BACKGROUND: Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is associated with higher chemotherapy relative dose intensity, which may lead to improved outcomes; however, the association between G-CSF primary prophylaxis and overall survival (OS) is not well characterized. This study assessed the effect of G-CSF primary prophylaxis on patient outcomes in randomized, controlled, registrational clinical trials of filgrastim and pegfilgrastim. PATIENTS AND METHODS: Three placebo-controlled and two non-inferiority clinical trials of filgrastim and/or pegfilgrastim in patients receiving myelosuppressive chemotherapy for lung, breast, or colorectal cancer were included. The median OS, 6- and 12-month survival rates, and hazard ratios [HRs; unadjusted Cox model with 95% confidence intervals (CIs)] were estimated for patients receiving ≥1 dose of filgrastim, pegfilgrastim, or placebo. Comparisons were based on a log-rank test. A fixed-effect meta-analysis assessed the effect of primary prophylaxis with filgrastim/pegfilgrastim on OS in the placebo-controlled trials. RESULTS: In patients with lung cancer receiving filgrastim versus placebo, the median OS was 14.1 versus 11.1 months (HR, 0.81; 95% CI 0.48-1.35; P = 0.412); in patients who crossed over to filgrastim from placebo after cycle 1, the median OS was 16.9 months (HR, 0.75; 95% CI 0.43-1.28; P = 0.286). The median OS was inestimable in at least one treatment arm in the other studies because of the small number of OS events. Where estimable, 6- and 12-month survival rates were generally greater among patients receiving filgrastim/pegfilgrastim versus placebo. In the meta-analysis of placebo-controlled studies comparing G-CSF primary prophylaxis with placebo in the as-treated analysis sets, the HR (95% CI) for OS was 0.77 (0.58-1.03). CONCLUSIONS: In this retrospective analysis, OS point estimates were greater among patients receiving filgrastim versus placebo, but the differences were not statistically significant. Further studies evaluating patient outcomes with G-CSF prophylaxis are warranted. CLINICAL TRIAL REGISTRATION: NCT00035594, NCT00094809.

The impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The granulocyte colony-stimulating factor (G-CSF) is utilized to reduce neutropenic complications in patients receiving cancer chemotherapy. This study represents a systematic review and evidence summary of the impact of G-CSF support on chemotherapy dose intensity and overall mortality. MATERIALS AND METHODS: All randomized controlled trials (RCTs) comparing chemotherapy with or without G-CSF support and reporting all-cause mortality with at least 2 years of follow-up were sought. Dual-blind data abstraction of disease, treatment, patient and outcome study results with conflict resolution by third party was carried out. RESULTS: The search revealed 61 randomized comparisons of chemotherapy with or without initial G-CSF support. Death was reported in 4251 patients randomized to G-CSFs and in 5188 controls. Relative risk (RR) with G-CSF support for all-cause mortality was 0.93 (95% confidence interval: 0.90-0.96; P < 0.001). RR for mortality varied by intended chemotherapy dose and schedule: same dose and schedule (RR = 0.96; P = 0.060), dose dense (RR = 0.89; P < 0.001), dose escalation (RR = 0.92; P = 0.019) and drug substitution or addition (RR = 0.94; P = 0.003). Greater RR reduction was observed among studies with longer follow-up (P = 0.02), where treatment was for curative intent (RR = 0.91; P < 0.001), and where survival was the primary outcome (RR = 0.91; P < 0.001). CONCLUSIONS: All-cause mortality is reduced in patients receiving chemotherapy with primary G-CSF support. The greatest impact was observed in RCTs in patients receiving dose-dense schedules.

Supportive care in patients with cancer during the COVID-19 pandemic.

Cancer care has been profoundly impacted by the global pandemic of severe acute respiratory syndrome coronavirus 2 disease (coronavirus disease 2019, COVID-19), resulting in unprecedented challenges. Supportive care is an essential component of cancer treatment, seeking to prevent and manage chemotherapy complications such as febrile neutropenia, anaemia, thrombocytopenia/bleeding, thromboembolic events and nausea/vomiting, all of which are common causes of hospitalisation. These adverse events are an essential consideration under routine patient management, but particularly so during a pandemic, a setting in which clinicians aim to minimise patients' risk of infection and need for hospital visits. Professional medical oncology societies have been providing updated guidelines to support health care professionals with the management, treatment and supportive care needs of their patients with cancer under the threat of COVID-19. This paper aims to review the recommendations made by the most prominent medical oncology societies for devising and modifying supportive care strategies during the pandemic.

Clinical prediction rules for mortality in patients with pulmonary embolism and cancer to guide outpatient management: a meta-analysis.

Essentials Clinical prediction rules (CPRs) can stratify patients with pulmonary embolism (PE) and cancer. A meta-analysis was done to assess prognostic accuracy in CPRs for mortality in these patients. Eight studies evaluating ten CPRs were included in this study. CPRs should continue to be used with other patient factors for mortality risk stratification. SUMMARY: Background Cancer treatment is commonly complicated by pulmonary embolism (PE), which remains a leading cause of morbidity and mortality in these patients. Some guidelines recommend the use of clinical prediction rules (CPRs) to help clinicians identify patients at low risk of mortality and therefore guide care. Objective To determine and compare the accuracy of available CPRs for identifying cancer patients with PE at low risk of mortality. Methods A literature search of Medline and Scopus (January 2000 to August 2017) was performed. Studies deriving/validating ≥ 1 CPR for early post-PE all-cause mortality were included. A bivariate, random-effects model was used to pool sensitivity and specificity estimates for each CPR. Traditional random-effects meta-analysis was performed to estimate the weighted proportion of patients deemed at low risk of early mortality, mortality in low risk patients and odds ratios for death compared with higher-risk patients. Results Eight studies evaluating 10 CPRs were included. The highest sensitivities were observed with Hestia (98.1%, 95% confidence interval [CI] = 75.6-99.9%) and the EPIPHANY index (97.4%, 95% CI = 93.2-99.0%); sensitivities of remaining rules ranged from 59.9 to 96.6%. Of the six CPRs with sensitivities ≥ 95%, none had specificities > 33%. Random-effects meta-analysis suggested that 6.6-51.6% of cancer patients with PE were at low risk of mortality, 0-14.3% of low-risk patients died and low-risk patients had a 43-94% lower odds of death compared with those at higher risk. Conclusions Because of the limited total body of evidence regarding CPRs, their results, in conjunction with other pertinent patient-specific clinical factors, should continue to be used in identifying appropriate management for PE in patients with cancer.

EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours.

Chemotherapy-induced neutropenia is not only a major risk factor for infection-related morbidity and mortality, but is also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact on the success of treatment, particularly when treatment intent is either curative or to prolong survival. The incidence of severe or FN can be reduced by prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim, lenograstim or pegfilgrastim. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. While several academic groups have produced evidence-based clinical practice guidelines in an effort to standardise and optimise the management of FN, there remains a need for generally applicable, European-focused guidelines. To this end, we undertook a systematic literature review and formulated recommendations for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. We recommend that patient-related adverse risk factors such as elderly age (>or=65 years), be evaluated in the overall assessment of FN risk prior to administering each cycle of chemotherapy. In addition, when using a chemotherapy regimen associated with FN in >20% patients, prophylactic G-CSF is recommended. When using a chemotherapy regimen associated with FN in 10-20% patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Finally, studies have shown that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications, where indicated.

Randomized clinical trials for hematopoietic stem cell transplantation: lessons to be learned from the European experience.

We evaluated the number and characteristics of randomized controlled trials (RCTs) addressing hematopoietic stem cell transplantation (HSCT) for patients with hematological malignancies, comparing the productivity of US and Europe. A MEDLINE search was conducted to identify all published RCTs for the management of adult patients with hematological malignancies from January 1992 to December 2003. Eighty-three of the 306 trials identified included HSCT as one of the treatment arms. The US produced 25, Europe 54, and all other countries four. Four European countries, France, Italy, Germany, and UK (FIGU), produced 32 out of the 54 European studies. Significant differences emerged when focus of the study and accrual numbers were analyzed. Trials comparing HSCT to standard dose therapy represented 34.9% of the 83 trials and 59.4% of FIGU trials, but only 4% of US studies (P = 0.001). US trials accrued a mean of 110.2 patients per study, as compared to 222.6 in FIGU studies (P = 0.006) and 205.3 when all non-US countries are considered (P = 0.01). Our conclusions are that US transplant RCT have focused on issues other than the comparison of HSCT to standard therapies. There is serious paucity of US trials defining the role of HSCT in the management of hematological malignancies.

Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy.

BACKGROUND: Hematopoietic growth factors (HGFs) have been shown to reduce the incidence of neutropenia and fever in patients receiving cancer chemotherapy. PURPOSE: This cost analysis was designed to determine the conditions in which use of HGFs in patients receiving cancer chemotherapy is cost-effective. METHODS: We used a standard model based on decision theory; the model assumes that all patients experiencing neutropenia and fever will be hospitalized and treated with intravenous antibiotics. Data from a prospective, randomized clinical trial of granulocyte colony-stimulating factor in small-cell lung cancer treated with combination chemotherapy were used to determine baseline probabilities for control hospitalization risk and survival; proportional hospitalization risk with prophylactic HGF; and median durations of hospitalization and prophylactic HGF use. The model was analyzed by one-way and multivariate sensitivity analyses, with estimation of threshold values at which the expected cost is the same for either of two treatment options. One or more of the specific costs and durations and the probability for each group of threshold curves were varied in a sensitivity analysis that generated variable thresholds. Use of Monte Carlo analysis based on the available distributions of the main variables provided 90% confidence limits and an inference method for comparing decision options. RESULTS: The expected excess cost per treatment cycle, based on hospitalization for neutropenic fever and/or HGF administration, was $5500 for no HGF, $4750 for prophylactic HGF, and $6875 for therapeutic HGF. Sensitivity analysis provided the following thresholds for no HGF versus prophylactic HGF: control risk of hospitalization, 0.40; risk of hospitalization with HGF as a proportion of control, 0.64; total daily cost of hospitalization, $727; total daily cost of HGF, $344; duration of hospitalization, 7.3 days; and duration of HGF use, 11.0 days. Multivariate analysis revealed that conditions favoring the use of HGF on a cost basis become greater (a) as risk of hospitalization, total daily hospital cost, and duration of hospitalization increase and (b) as the proportional risk of hospitalization with HGF, daily cost of HGF, and duration of HGF treatment decrease. CONCLUSIONS: The major determinants of total excess cost were the control risk of hospitalization, the proportional reduction in risk with HGF, and the average daily hospital cost. IMPLICATIONS: Use of HGFs should be based on the risk of hospitalization for neutropenic fever and consideration of the patient population and institutional costs.

Environmental tobacco smoke and lung cancer risk in nonsmoking women.

BACKGROUND: Exposure to environmental tobacco smoke (passive smoking) has been suggested to be a cause of lung cancer, although early epidemiologic studies have produced inconsistent results. PURPOSE: We conducted an epidemiologic case-control study to assess the relationship between exposure to environmental tobacco smoke and lung cancer risk among women who have never smoked (i.e., having smoked for a total of less than 6 months or having smoked less than 100 cigarettes in their lifetimes). METHODS: Case patients (n = 210) were women with histologically confirmed primary carcinomas of the lung who were lifetime nonsmokers. They were identified through hospital tumor registries and the Florida Cancer Data System of the Statewide Cancer Registry. Community-based control women (n = 301) were also lifetime nonsmokers and were identified through random-digit dialing. Details on childhood and adulthood exposures to environmental tobacco smoke were ascertained through interviews with the study participants themselves or with surrogate respondents. Risks were calculated in terms of smoke-years, defined as the sum of the reported years of exposure to cigarette smoke from each smoker in the household. RESULTS: The risk of lung cancer more than doubled for women who reported 40 or more smoke-years of household exposure during adulthood (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.1-5.3) or 22 or more smoke-years of exposure during childhood and adolescence (OR = 2.4; 95% CI = 1.1-5.4). Risks were highest for non-adenocarcinoma lung cancers, although modest elevations in risk were also observed for adenocarcinomas. When a surrogate respondent other than the patient's husband provided information on exposure, the risk estimates were considerably lower. CONCLUSION: These findings suggest that long-term exposure to environmental tobacco smoke increases the risk of lung cancer in women who have never smoked.

Phospholipid membrane stabilization by dimethylsulfoxide and other inducers of Friend leukemic cell differentiation.

A large number of low molecular weight polar cryoprotective agents have recently been found to induce erythroid differentiation of Friend leukemic cells in vitro. The effect of these agents on membrane fluidity in phospholipid vesicles was studied by determining the solid-to-liquid crystalline phase transition using differential scanning calorimetry. Some of the inducing agents studies were found to raise the normal transition temperature (Tc) by a few degrees. All of these agents were found to produce a separate transition at a much higher temperature. Changes in the head group of the phospholipid, the pH, the presence of divalent cations, and the addition of other membrane-active compounds were found to significantly influence the inducing agent's effects on the Tc of phospholipid membranes. The ability of the different agents to produce a new transition at a high temperature was found to correlate well with their ability to induce Friend leukemic cell differentiation. The possible mechansims of action of the chemical inducers, and the significance of the observed membrane effects on differentiation and malignancy are discussed. It is concluded that inducing agents decrease the fluidity and stabilize phospholipid membranes, and that their effects in cell differentiation might be initiated by a similar change in the properties of cell membranes.

What threshold for adjuvant therapy in older breast cancer patients?

PURPOSE: To consider the question of when to prescribe adjuvant treatment for elderly breast cancer patients, particularly when comorbidities are present. Knowledge of the threshold relapse risks above which adjuvant treatment is worth prescribing would enhance decision making. PATIENTS AND METHODS: A Markov analysis of data from the medical literature was conducted. Patients aged 65 to 85 years were considered, along with three levels of comorbidity. The threshold risk of relapse at 10 years (RR10), at which time treatment provides absolute reduction or reduction of an absolute 1% in relapse or mortality, was evaluated. RESULTS: The threshold RR10 for an absolute reduction in mortality risk by adjuvant treatment was low through the age of 85 years. However, for an absolute 1% reduction, the effect of treatment on relapse and the effect of treatment on mortality increasingly diverged. The threshold RR10 for an absolute 1% reduction in relapse risk remained fairly low (5% to 6% for tamoxifen, 12% to 19% for chemotherapy). The threshold RR10 for an absolute 1% reduction in mortality risk, although starting close to the RR10 for an absolute 1% reduction in relapse risk, rose sharply. For tamoxifen, the difference between the two was 4% for an average 65-year-old, 6% at the age of 75 years, and 15% at the age of 85 years. For chemotherapy, the differences were 6%, 12%, and 30%, respectively. Similarly, thresholds increased with increasing comorbidity. In older and sicker patients, the maximum benefit was reached after 5 years rather than 10 years. CONCLUSION: Older breast cancer patients can expect a reduction in relapse that is fairly similar to that of younger patients. However, the effect on mortality diverges markedly, and attention should be paid to this difference in clinical decision making. Comorbidity should be considered in recommendations for adjuvant treatment, including clinical practice guidelines.

Sudden death in cancer patients receiving lithium.

Lithium carbonate may attenuate the incidence and severity of infection associated with cancer chemotherapy but does not appear to improve patient survival. Of 100 patients with small-cell lung cancer receiving an identical regimen of cyclophosphamide, doxorubicin, and vincristine, 40 were assigned to treatment with lithium concurrently. To date, 60 patients have died, including 14 who died suddenly of apparent cardiovascular causes without evident progression of neoplastic disease or concurrent illness. Thirteen of the 14 sudden deaths were among 50 patients with clinical or electrocardiographic evidence of cardiovascular abnormalities before study entry. Among patients with pretreatment cardiovascular abnormalities, lithium administration was associated with a greater risk of sudden death and shorter survival. A strong interaction for risk of death was evident between lithium treatment and the use of bronchodilators. In multivariate analysis, the major predictors of patient survival were the quality of tumor response and treatment with lithium with or without bronchodilators. Lithium treatment is a major risk factor for sudden death in cancer patients with pretreatment cardiovascular changes receiving combination chemotherapy including an anthracycline antibiotic.

Comorbidity and functional status are independent in older cancer patients.

PURPOSE: Comorbidity is a frequent and often therapeutically limiting problem in older cancer patients. However, to date, there is no standard measure of the comorbidity burden available for these patients. We tested the performance of two comorbidity scales and their relationship with functional status. PATIENTS AND METHODS: The Cumulative Illness Rating Scale-Geriatric (CIRS-G) was compared with the Charlson scale in 203 patients who received a comprehensive geriatric assessment (CGA) in our Senior Adult Oncology Program (SAOP). Study end points were variability, reliability, correlation with Eastern Cooperative Oncology Group (ECOG) performance status (PS), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL). The relative weight of comorbidity versus tumor stage in the correlations with functional status was assessed. RESULTS: Median age was 75 years (range, 63 to 91). Sixty-four percent of patients scored 0 on the Charlson scale versus 6% on the CIRS-G. The correlation between the Charlson and CIRS-G was fair (p = 0.25 to 0.39). CIRS-G grade 3/4 had a fair correlation with ADL (p = 0.27). Otherwise, there was low or no correlation between comorbidity and functional status across the measures. Tumor stage was not correlated with functional status either. Correlation of ECOG PS with ADL (p = 0.51)c and IADL (p = 0.61) was moderate. Interrater and test-retest correlations were good or very good for both the Charlson and CIRS-G. CONCLUSION: Comorbidity needs to be assessed independently from functional status. Both the Charlson and CIRS-G scales are reliable tools for use in trials of older cancer patients. Both can be tested in further studies as predictors of outcomes such as toxicity of treatment, changes in functional status, or survival.

Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer.

PURPOSE: Clinical reports suggest that many breast cancer patients experience persistent fatigue as a long-term side effect of adjuvant chemotherapy treatment. To investigate this issue further, we examined the characteristics and correlates of fatigue in women who had completed adjuvant chemotherapy for breast cancer and in a comparison group of women with no history of cancer. PATIENTS AND METHODS: Participants were 61 women with breast cancer who had completed chemotherapy an average of 471 days previously and 59 women with no history of cancer. All participants completed standardized self-report measures of fatigue, sleep quality, menopausal symptoms, and coping and were administered a structured clinical interview to identify current and past psychiatric disorder. RESULTS: Compared with women with no history of cancer, former adjuvant chemotherapy patients reported more severe fatigue (P < .01) and worse quality of life because of fatigue (P < .05). More severe fatigue among patients was significantly (P < .05) related to poorer sleep quality, more menopausal symptoms, greater use of catastrophizing as a coping strategy, and current presence of a psychiatric disorder. CONCLUSION: These findings support the view that many breast cancer patients experienced heightened fatigue after completion of adjuvant chemotherapy treatment. Results yield a profile of women who are at increased risk for heightened fatigue after chemotherapy and suggest ways to intervene clinically to prevent or reduce fatigue in this patient population.

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

Quality of life after coronary angioplasty or continued medical treatment for angina: three-year follow-up in the RITA-2 trial. Randomized Intervention Treatment of Angina.

OBJECTIVES: We sought to evaluate the impact of percutaneous transluminal coronary angioplasty (PTCA) and medical treatment on self-perceived quality of life among patients with angina. BACKGROUND: The second Randomized Intervention Treatment of Angina trial (RITA-2) implemented initial policies of PTCA or continued medical treatment in patients with angina, allowing assessment of long-term health consequences. METHODS: A total of 1,018 patients were randomly assigned (504 to PTCA and 514 to medical treatment). The short form 36 (SF-36) self-administered quality-of-life questionnaire was completed at randomization and three months, one year and three years later. To date, 98% of patients reached one year and 67% reached three years. RESULTS: The PTCA group had significantly greater improvements in physical functioning, vitality and general health at both three months and one year, but not at three years. These quality-of-life scores were strongly related to breathlessness, angina grade and treadmill exercise time both at baseline and at one year. The treatment differences in quality of life are explained by the PTCA group's improvements in breathlessness, angina and exercise time. The attenuation of treatment difference at three years is partly attributed to 27% of medically treated patients receiving nonrandomized interventions in the interim. For both groups, there were also improvements in ratings of physical role functioning, emotional role functioning, social functioning, pain and mental health, but for these the superiority of PTCA over medical treatment was less pronounced. After one year, 33% and 22% of the PTCA and medical groups, respectively, rated their health much better. CONCLUSIONS: Coronary angioplasty substantially improves patient-perceived quality of life, especially physical functioning and vitality, as compared with continued medical treatment. These differences are attributed to alleviation of cardiac symptoms (specifically, breathlessness and angina), but must be balanced against the small procedure-related risks of PTCA.

The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia.

Healthcare costs continue to rise with hospitalization representing the single largest component of direct medical costs associated with cancer care. Neutropenia and its complications including febrile neutropenia remain the major dose-limiting toxicity associated with systemic cancer chemotherapy. Febrile neutropenia often occurs early in the course of chemotherapy and is associated with substantial morbidity, mortality and cost. The colony-stimulating factors (CSFs) have been used effectively in a variety of clinical settings to prevent or treat febrile neutropenia and to assist patients receiving dose-intensive chemotherapy. A meta-analysis of the available randomized controlled trials (RCTs) has confirmed the efficacy of prophylactic CSFs. Economic models based on measures of resource utilization derived from RCTs have provided estimates of expected treatment costs along with febrile neutropenia risk threshold estimates for the cost saving use of the CSFs. Recent studies have demonstrated the potential value of targeting the CSFs toward patients at greatest risk based on accurate and valid predictive models.

A novel approach to maintain planned dose chemotherapy on time: a decision-making tool to improve patient care.

Studies of primary prophylaxis of febrile neutropenia with recombinant granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim), administered to all patients starting with the initial course of chemotherapy, have demonstrated an economic advantage over a wide range of settings. In these analyses, the threshold risk for febrile neutropenia at which a cost saving is realised is inversely related to the direct medical costs of hospitalisation. Clinical practice guidelines for the use of filgrastim have been developed based on these observations. Recent studies incorporating indirect institutional costs have demonstrated that cost savings can be achieved at substantially lower febrile neutropenia risk thresholds than previously estimated. Despite the demonstrated efficacy of filgrastim in primary prophylaxis, its value may be further enhanced through the appropriate selection of patients for such therapy and a better understanding of the importance of sustaining dose intensity in specific malignancies. Clinical prediction models capable of identifying individuals at high risk for neutropenic complications yield further reductions in febrile neutropenia risk thresholds and treatment costs in patients receiving cancer chemotherapy. Prediction models can also be used to evaluate the cost-effectiveness or cost-efficiency of filgrastim use. Such a model has recently been developed and validated and is described here which incorporates both baseline clinical characteristics as well as the results of the first cycle of chemotherapy in patients with early-stage breast cancer. A cost-effectiveness ratio of US$ 34297 (Euro 32002)dagger per year of life saved (YLS) was calculated based on dose-response assumptions derived from a previously reported adjuvant breast cancer trial studying the impact of dose reduction on disease-free survival. This figure is comparable with accepted cost-effectiveness ratios for other interventions, e.g. US$ 45000/LYS (Euro 41989) for renal dialysis for patients with end-stage renal disease. The cost-effectiveness of filgrastim was evident over a wide range of clinical and cost assumptions. Clinical prediction models permit rational and cost-effective selection of patients for filgrastim support. Current guidelines should be re-evaluated in light of new information available on both the total cost of febrile neutropenia, as well as the cost-effectiveness of these agents in specific clinical situations.

The economics of febrile neutropenia: implications for the use of colony-stimulating factors.

The occurrence of fever and neutropenia following cancer chemotherapy generally prompts hospitalisation for evaluation and treatment. Colony-stimulating factors (CSFs) have been shown to reduce the risk of febrile neutropenia (FN) and the need for hospitalisation in such patients. This study was undertaken to obtain estimates of the actual institutional costs associated with FN and the impact of these costs on threshold estimates for the appropriate use of CSFs. Total hospital expenditures for patients admitted with FN over a 2 year period were studied. A cost allocation function was utilised to allocate all direct costs for non-revenue-generating support centres to revenue-generating service centres as indirect costs. A cost accounting function was then utilised to allocate direct and indirect costs for each service centre to the charge code level. Two groups of patients were defined based on diagnostic codes to represent the spectrum of patients with FN. Total hospital costs were estimated and incorporated into a cost model for the use of CSFs. Variation in the total cost of hospitalisation for FN relates primarily to differences in the average length of stay. The daily cost of hospitalisation was comparable in the groups studied, averaging between US$1675 and US$1892. Incorporation of these cost estimates into the cost model yielded FN risk threshold projections for CSF use in the range of 20-25%. Preliminary studies suggest that incorporation of non-medical, indirect and intangible costs into the CSF decision models will further decrease FN risk threshold projections. Total hospitalisation cost estimates for managing patients with FN are greater than those previously reported, reducing projected FN risk thresholds for CSF use.