Capecitabine-induced cardiotoxicity: more evidence or clinical approaches to protect the patients' heart?

Fluoropyrimidines, such as capecitabine and 5-fluorouracil, may cause cardiac toxicity. In recent years, the incidence of this side effect has increased and it is expected to further rise due to the population aging and the disproportionate incidence of breast and gastrointestinal cancers in older individuals. The spectrum of cardiac manifestations includes different signs and symptoms and the diagnosis may be difficult. Here, we report the case of a 43-year-old woman with advanced breast cancer who was rechallenged with a capecitabine-based regimen after experiencing a cardiac adverse event during the first fluoropyrimidine exposure. This real-practice case serves as a springboard for discussion about the current evidence on differential diagnosis of capecitabine-related cardiac toxicity, its risk factors, and the underpinning mechanisms of early onset. Moreover, we discussed whether a rechallenge with fluoropyrimidines could be safe in patients who had experienced a previous cardiac adverse event.

Chemotherapy prescribing errors: an observational study on the role of information technology and computerized physician order entry systems.

BACKGROUND: Chemotherapy administration is a high-risk process. Aim of this study was to evaluate the frequency, type, preventability, as well as potential and actual severity of outpatient chemotherapy prescribing errors in an Oncology Department where electronic prescribing is used. METHODS: Up to three electronic prescriptions per patient record were selected from the clinical records of consecutive patients who received cytotoxic chemotherapy between January 2007 and December 2008. Wrong prescriptions were classified as incomplete, incorrect or inappropriate. Error preventability was classified using a four-point scale. Severity was defined according to the Healthcare Failure Mode and Effect Analysis Severity Scale. RESULTS: Eight hundred and thirty-five prescriptions were eligible. The overall error rate was 20%. Excluding systematic errors (i.e. errors due to an initially faulty implementation of chemotherapy protocols into computerized dictionaries) from the analysis, the error rate decreased to 8%. Incomplete prescriptions were the majority. Most errors were deemed definitely preventable. According to error presumptive potential for damage, 72% were classified as minor; only 3% had the potential to produce major or catastrophic injury. Sixty-eight percent were classified as near misses; adverse drug events had no or little effect on clinical outcome. CONCLUSIONS: Chemotherapy prescribing errors may arise even using electronic prescribing. Although periodic audits may be useful to detect common errors and guide corrective actions, it is crucial to get the computerized physician order entry system and set-ups correct before implementation.

Adopting integrated care pathways in non-small-cell lung cancer: from theory to practice.

INTRODUCTION: Integrated care pathways (ICPs) have been proposed as effective strategies for quality improvement. To date, limited data are available that detail the methodology to design an optimal care pathway for patients with non-small-cell lung cancer (NSCLC). The main aim of this study was to assess the quality of health care delivered to lung cancer patients referred to a hub university hospital. METHODS: All professionals involved with the management of NSCLC patients, in cooperation with health care researchers, identified 11 quality indicators and associated benchmarks. These were used to estimate the quality and efficiency of health care delivered to a cohort of 175 NSCLC patients. RESULTS: The gap between "desired" and "actual" performance has been measured by benchmarking current practice against key quality indicators. Diagnostic workup, multidisciplinary team care and medical treatment of advanced disease have emerged as areas of good performance. Conversely, the management of early-stage disease offers room for improvement, in terms of both accuracy of nodal staging and surgical timeliness. CONCLUSIONS: Analyzing the process of caring for NSCLC patients is feasible and offers room for improvement. Acquired knowledge may be shared with hospital administrators, guide the revision of ICPs, and enable the delivery of consistent, high-quality clinical standards.

A model to estimate human resource needs for the treatment of outpatients with cancer.

PURPOSE: Although personnel costs significantly affect cancer health care expenditures, little is known about the relationship between workload, human resource requirements, and associated costs. An empirical model to forecast staffing demand is described according to the yearly caseload of outpatients with cancer beginning active treatment and the number of personnel working hours. METHODS: The oncology department at the University Hospital of Udine (Udine, Italy) is a computerized unit taking care of approximately 1,300 patients per year. Each clinical episode is centrally recorded. We queried the database for the total number of consultations per patient beginning treatment during 2006. With predefined bonds (ie, time limit set for each visit type and annual working hours per employee), we sought to estimate yearly per-patient hours of care and the number of personnel needed. RESULTS: In 2006, each outpatient with cancer beginning active treatment generated an average of 16 clinical evaluations, which in turn translated into 8 and 16 hours of physician and nurse working time, respectively. Assuming an average of 1,672 annual working hours, a need for one physician and three nurses for every 600 patients could be estimated for every 200 novel patients. In the next year, the same caseload induced 4.5 consultations on average; using a similar approach, the demand for additional time and resources was calculated. CONCLUSION: By means of a simple model combining predefined conditions with a centralized record of clinical episodes, we were able to provide a reasonable estimate of human resource requirements and a tool to forecast the staff expenditures of a cancer unit.

A randomised phase II study of docetaxel/oxaliplatin and docetaxel in patients with previously treated non-small cell lung cancer: an Alpe-Adria Thoracic Oncology Multidisciplinary group trial (ATOM 019).

INTRODUCTION: To date, no combination regimen has proven superior to single agent chemotherapy as a second-line treatment for non-small cell lung cancer (NSCLC). METHODS: This multicenter, non-comparative randomised phase II trial evaluated the activity of docetaxel (75 mg/m(2) on day 1) with oxaliplatin (70 mg/m(2) on day 2) every 3 weeks in previously treated NSCLC patients; the reference arm was single-agent docetaxel (75 mg/m(2) on day 1 every 3 weeks). It was designed as a one-stage, three-outcome phase II trial; 21 evaluable patients were required in each arm. The primary end-point was response rate; secondary end-points were toxicity, progression free survival (PFS) and overall survival. RESULTS: Fifty patients were enrolled. Patient characteristics included male/female, 76/24%; median age 62 years; ECOG PS 0/1, 36/64%; previous platinum-based chemotherapy, 98%. Partial response was seen in 20% and 8%, stable disease in 52% and 32%, of patients treated with docetaxel/oxaliplatin and docetaxel, respectively. Main grade 3-4 toxicities were neutropenia 56% and 64%; febrile neutropenia 4% and 8%; diarrhoea 12% and 4% for docetaxel/oxaliplatin and docetaxel, respectively. Median PFS was 5.0 and 1.7 months, median survival 11.0 and 7.1 months, and 1-year survival 44% and 32% for docetaxel/oxaliplatin and docetaxel, respectively. CONCLUSIONS: The study met its pre-defined study end-point; docetaxel/oxaliplatin and more generally platinum-containing doublets warrant further evaluation as second-line therapy for patients with NSCLC.

Future scenarios for the treatment of advanced non-small cell lung cancer: focus on taxane-containing regimens.

Despite recent progress in the development of new molecularly targeted agents, the chemotherapy regimens considered standard at the end of the last century--that is, two-drug combinations consisting of either cisplatin or carboplatin plus a third-generation agent (docetaxel, paclitaxel, gemcitabine, or vinorelbine)--remain the primary treatment option for advanced non-small cell lung cancer (NSCLC) patients. Most recently, the existing standard of care has been amended to reflect the significant survival advantage of cisplatin-pemetrexed over cisplatin-gemcitabine as first-line treatment of nonsquamous NSCLC. The addition of a biological drug (bevacizumab, cetuximab) or the use of a single-agent epidermal growth factor receptor inhibitor may further improve outcomes in selected patients. It has become increasingly clear, primarily through recent meta-analyses, that although the therapeutic equivalence of any combination of a platinum agent plus either gemcitabine, vinorelbine, docetaxel, or paclitaxel has been long accepted, each regimen has different side effects and therapeutic outcomes that allow clinicians to select the most appropriate treatment for chemotherapy-naïve patients with stage IIIB/IV NSCLC. In this review, we evaluate the available evidence and explore the role and importance of various modern chemotherapy regimens, with the aim of optimizing treatment selection and combination with biological agents. Emphasis is placed on the role of taxanes (docetaxel versus paclitaxel) in this changing landscape.

Prognostic stratification of stage IIIA pN2 non-small cell lung cancer by hierarchical clustering analysis of tissue microarray immunostaining data: an Alpe Adria Thoracic Oncology Multidisciplinary Group study (ATOM 014).

INTRODUCTION: Stage IIIA non-small cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node metastases (N2) is a heterogeneous disease with differing prognoses. In this study, we retrospectively investigated the prognostic value of the expression of 10 molecular markers in 87 patients with stage IIIA pN2 NSCLC treated with radical surgery. METHODS: Primary tumor tissue microarrays (TMAs) were constructed and sections used for immunohistochemical analysis of epidermal growth factor receptor, ErbB-2, c-kit, cyclooxygenase-2, survivin, bcl-2, cyclin D1, cyclin B1, metalloproteinase (MMP)-2, and MMP-9. Univariate and multivariate analyses and unsupervised hierarchical clustering analysis of clinical pathologic and immunostaining data were performed. RESULTS: Bcl-2 (p < 0.0001) and cyclin D1 (p = 0.015) were more highly expressed in squamous cell carcinoma (SCC), whereas MMP-2 (p = 0.009), MMP-9 (p = 0.005), and survivin (p = 0.032) had increased expression in other histologic subtypes. In univariate analysis, SCC histology and cyclin D1 expressions were favorable prognostic factors (p = 0.015 and p < 0.0001, respectively); by contrast, MMP-9 expression was associated with worse prognosis (p = 0.042). In multivariate analysis, cyclin D1 was the only positive prognostic factor (p < 0.0001). Unsupervised hierarchical clustering analysis of TMA immunostaining data identified five distinct clusters. They formed two subsets of patients with better (clusters 1 and 2) and worse (clusters 3, 4, and 5) prognoses, and median survival of 51 and 10 months, respectively (p < 0.0001). The better prognosis subset mainly comprised patients with SCC (80%). CONCLUSIONS: Hierarchical clustering of TMA immunostaining data using a limited set of markers identifies patients with stage IIIA pN2 NSCLC at high risk of recurrence, who may benefit from more aggressive treatment.

Impact of third-generation drugs on the activity of first-line chemotherapy in advanced non-small cell lung cancer: a meta-analytical approach.

BACKGROUND: The therapeutic equivalence of different third-generation agents in the first-line treatment of advanced non-small cell lung cancer (NSCLC) has long been accepted, although recent studies seem to suggest some superiority of gemcitabine- or docetaxel-containing regimens over other third-generation doublets. OBJECTIVE: To assess the relative impact of different third-generation drugs on the activity of first-line chemotherapy in advanced non-small cell lung cancer by considering both response and progressive disease (PD) rates as outcome measures. METHODS: Published and unpublished data were collected from randomized trials comparing a gemcitabine-, docetaxel-, vinorelbine- or paclitaxel-containing regimen with one or more gemcitabine-, docetaxel-, vinorelbine- or paclitaxel-free combinations. For each study, 2 x 2 tables were constructed for both response and immediate progression. Pooled odds ratios were calculated using a general variance-based method. RESULTS: Forty-five trials (11,867 patients) were eligible. The odds of obtaining an objective response to treatment were similar across different regimens. Gemcitabine-based chemotherapy was associated with a 14% lower risk for immediate progression, whereas patients receiving paclitaxel showed a 22% higher risk for having PD as the best response. Docetaxel treatment provided a nonsignificant 9% lower odds for progression. CONCLUSIONS: These data demonstrate that different third-generation regimens have comparable activity in chemotherapy-naïve patients with advanced NSCLC. Gemcitabine-based chemotherapy provides better disease control, whereas the risk for immediate progression is significantly higher when paclitaxel-containing regimens are used.

Targeting the VEGF pathway: antiangiogenic strategies in the treatment of non-small cell lung cancer.

The management of advanced non-small cell lung cancer (NSCLC) has evolved considerably in recent years, due to a progressive understanding of tumour biology and the identification of promising molecular targets. Several agents have been developed so far inhibiting vascular endothelial growth factor (VEGF) - a key protein in tumour neoangiogenesis, growth and dissemination - or its receptor signalling system. The finding in study E4599 of a survival benefit for carboplatin-paclitaxel plus bevacizumab - a humanised anti-VEGF monoclonal antibody - over chemotherapy (CT) alone led the U.S. Food and Drug Administration (FDA) to approve the novel combination for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. In a randomised phase III trial presented at the American Society of Clinical Oncology (ASCO) 2007 Annual Meeting, patients receiving cisplatin-gemcitabine plus bevacizumab experienced a significantly longer progression-free survival (PFS) compared to the standard arm. Based on these data, the European Medicines Agency (EMEA) has granted marketing authorisation for bevacizumab in addition to any platinum-based CT for first-line treatment of advanced NSCLC other than predominantly squamous histology. Aim of this report is to provide an overview on bevacizumab in NSCLC, with special emphasis on clinical results presented at ASCO last meeting. Multitargeted tyrosine kinase inhibitors (TKIs), sharing a focus on both the angiogenesis process and additional cell-surface receptors, and VEGF Trap, a novel fusion protein with markedly higher affinity for VEGF than bevacizumab, will be briefly discussed as well.

Drug waste minimisation and cost-containment in Medical Oncology: two-year results of a feasibility study.

BACKGROUND: Cost-containment strategies are required to face the challenge of rising drug expenditures in Oncology. Drug wastage leads to economic loss, but little is known about the size of the problem in this field. METHODS: Starting January 2005 we introduced a day-to-day monitoring of drug wastage and an accurate assessment of its costs. An internal protocol for waste minimisation was developed, consisting of four corrective measures: 1. A rational, per pathology distribution of chemotherapy sessions over the week. 2. The use of multi-dose vials. 3. A reasonable rounding of drug dosages. 4. The selection of the most convenient vial size, depending on drug unit pricing. RESULTS: Baseline analysis focused on 29 drugs over one year. Considering their unit price and waste amount, a major impact on expense was found to be attributable to six drugs: cetuximab, docetaxel, gemcitabine, oxaliplatin, pemetrexed and trastuzumab. The economic loss due to their waste equaled 4.8% of the annual drug expenditure. After the study protocol was started, the expense due to unused drugs showed a meaningful 45% reduction throughout 2006. CONCLUSION: Our experience confirms the economic relevance of waste minimisation and may represent a feasible model in addressing this issue.A centralised unit of drug processing, the availability of a computerised physician order entry system and an active involvement of the staff play a key role in allowing waste reduction and a consequent, substantial cost-saving.

Identifying an optimum treatment strategy for patients with advanced non-small cell lung cancer.

Owing to the slow but sustained progress made in lung cancer treatment over the last 20 years, several therapeutic options are now available in the first-line setting as well as for patients who have progressed after one or more previous lines of treatment. Considering the growing array of choices currently confronting clinicians involved in the treatment of advanced non-small cell lung cancer (NSCLC), an effort should be made to define the optimal treatment option in each disease setting and to identify a logical therapeutic strategy after initial disease progression. This is especially crucial in the management of young, fit patients, who may be suitable candidates for two or more lines of therapy. At present, a rational treatment strategy for advanced NSCLC may be designed on the basis of patient clinicopathological features and rely on evidence from large, well-conducted clinical trials. In a near future the results of prospective validation studies will provide more sophisticated approaches for the classification of lung cancer patients, allowing clinicians to make individualised treatment decisions based on tumour molecular profile and on novel, more refined predictive/prognostic factors.

Low-dose computed tomography screening for lung cancer and pleural mesothelioma in an asbestos-exposed population: baseline results of a prospective, nonrandomized feasibility trial--an Alpe-adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002).

OBJECTIVE: To evaluate the feasibility of using low-dose computed tomography (LDCT) for the early diagnosis of lung cancer and malignant pleural mesothelioma in an asbestos-exposed population. METHODS: Between February 2002 and October 2003, 1,045 volunteers already enrolled in a surveillance program for asbestos-exposed workers and former workers were recruited. The main eligibility criteria were: written informed consent, definite exposure to asbestos, age 40-75, no prior cancer or severe concomitant conditions, no chest CT scan in the past 2 years. A smoking history was not required. After a structured interview, chest X-ray (CXR) and LDCT were performed. Participants with negative examinations were assigned to annual LDCT. Participants with positive findings received high-resolution CT and additional diagnostic workup as appropriate. RESULTS: Baseline characteristics of the screened population were: median asbestos exposure time, 30 years; median age, 58; median pack-years in smokers/former smokers, 18.5. Thirty-four percent had never smoked. On LDCT, 834 noncalcified nodules were identified in 44% of participants, versus 43 nodules in 4% on CXR. Pleural abnormalities were observed in 44% and 70% of participants by CXR and LDCT, respectively. Overall, LDCT identified nine cases of non-small cell lung cancer-eight stage I, one stage IIA-and one thymic carcinoid, corresponding to 1% of the enrolled population. All cases were radically treated. None had been detected by CXR. No pleural mesothelioma was diagnosed. There were 11 false-positive results. CONCLUSIONS: Our findings first suggest that LDCT may be at least as useful in asbestos workers as in heavy smokers for the early diagnosis of lung cancer; this benefit is evident even in a poor-risk population, with low rates of smoking prevalence and a previous history of radiological surveillance. The role of spiral tomography in screening for pleural mesothelioma remains uncertain.

Bevacizumab and non-small-cell lung cancer: starving the enemy to survive.

Although platinum-based chemotherapy remains a mainstay of non-small-cell lung cancer treatment, its efficacy has probably reached a plateau. Increased understanding of cancer biology has allowed the identification of a number of possible molecular targets, including the EGF receptor and the angiogenesis pathway. ECOG-E4599 has randomised chemonaive patients to receive paclitaxel--carboplatin with and without bevacizumab, a humanised monoclonal antibody targeting the VEGF. The study is the first to show a survival advantage of adding a biological agent to chemotherapy in this setting: in particular, for the first time the survival of lung cancer patients has been extended beyond 1 year. The aim of this review is to describe the biological and clinical properties of bevacizumab and to discuss the evidence that has supported its approval for the first-line treatment of advanced non-squamous non-small-cell lung cancer.

Sequential, alternating, and maintenance/consolidation chemotherapy in advanced non-small cell lung cancer: a review of the literature.

A platinum-based doublet with a third-generation agent (paclitaxel, vinorelbine, gemcitabine, docetaxel) represents the standard first-line treatment for advanced non-small cell lung cancer patients with good performance status (PS). Traditional chemotherapy provides response rates of 20%-40% and a median survival of 8-10 months. In an attempt to improve its outcome, alternative schedules have been proposed, namely sequential, alternating, and maintenance/consolidation therapy. Sequential chemotherapy with a platinum-based doublet followed by a single agent is feasible in patients with good PS; preliminary results from randomized phase III trials with combination chemotherapy as a comparator are promising, suggesting similar efficacy and a better toxicity profile for the sequential arm. The use of sequential single agents is an option for elderly and frail patients unsuitable for a platinum-based combination. Based on trials published so far, it is unlikely that an alternating chemotherapy strategy will be proven superior to standard chemotherapy in patients with good PS. However, sufficient evidence exists that it could be appropriate in the elderly or in unfit individuals. Consolidation/maintenance chemotherapy may provide additional benefit for patients achieving disease control after standard first-line chemotherapy. Better results are seen when maintenance consists of an agent that has proven active in the induction phase. Further evaluation of this strategy, as well as of consolidation/maintenance therapy with targeted agents, is warranted. In conclusion, these approaches may improve the outcome in selected patients with advanced non-small cell lung cancer, but further results from randomized trials are needed. In the meantime, sequential, alternating, and maintenance/consolidation therapy should still be considered investigational.

Dramatic tumour response to pemetrexed single-agent in an elderly patient with malignant peritoneal mesothelioma: a case report.

BACKGROUND: To date, there is no standard treatment for unresectable malignant peritoneal mesothelioma; either best supportive care or systemic chemotherapy with palliative intent are accepted options. CASE PRESENTATION: Here, we report the case of a 79-year old patient with malignant peritoneal mesothelioma who was treated with pemetrexed single-agent and obtained an impressive long-lasting response. CONCLUSION: Single-agent pemetrexed is a treatment option for malignant peritoneal mesothelioma in selected elderly patients or in patients with unpaired performance status.