Christian von Plessen

Phase III Study by the Norwegian Lung Cancer Study Group: Pemetrexed Plus Carboplatin Compared With Gemcitabine Plus Carboplatin As First-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer

PURPOSE To compare pemetrexed/carboplatin with a standard regimen as first-line therapy in advanced non-small-cell lung cancer NSCLC. PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC and performance status of 0 to 2 were randomly assigned to receive pemetrexed 500 mg/m(2) plus carboplatin area under the curve (AUC) = 5 (Calverts formula) on day 1 or gemcitabine 1,000 mg/m(2) on days 1 and 8 plus carboplatin AUC = 5 on day 1 every 3 weeks for up to four cycles. The primary end point was health-related quality of life (HRQoL) defined as global quality of life, nausea/vomiting, dyspnea, and fatigue reported on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and the lung cancer-specific module LC13 during the first 20 weeks. Secondary end points were overall survival and toxicity. Results Four hundred thirty-six eligible patients were enrolled from April 2005 to July 2006. Patients who completed the baseline questionnaire were analyzed for HRQoL (n = 427), and those who received > or = one cycle of chemotherapy were analyzed for toxicity (n = 423). Compliance of HRQoL questionnaires was 87%. There were no significant differences for the primary HRQoL end points or in overall survival between the two treatment arms (pemetrexed/carboplatin, 7.3 months; gemcitabine/carboplatin, 7.0 months; P = .63). The patients who received gemcitabine/carboplatin had more grade 3 to 4 hematologic toxicity than patients who received pemetrexed/carboplatin, including leukopenia (46% v 23%, respectively; P < .001), neutropenia (51% v 40%, respectively; P = .024), and thrombocytopenia (56% v 24%, respectively; P < .001). More patients on the gemcitabine/carboplatin arm received transfusions of RBCs and platelets, whereas the frequencies of neutropenic infections and thrombocytopenic bleedings were similar on both arms. CONCLUSION Pemetrexed/carboplatin provides similar HRQoL and survival when compared with gemcitabine/carboplatin with less hematologic toxicity and less need for supportive care.

Influence of comorbidity on survival, toxicity and health-related quality of life in patients with advanced non-small-cell lung cancer receiving platinum-doublet chemotherapy.

AIM OF THE STUDY To investigate whether patients with severe comorbidity receiving platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC) have a shorter overall survival, experience more toxicity or more deterioration of health-related quality of life (HRQoL) than other patients during treatment. PATIENTS AND METHODS Patients enrolled onto a phase III trial comparing pemetrexed/carboplatin with gemcitabine/carboplatin as first-line therapy of stage IIIB/IV NSCLC were analysed. Eligible patients had performance status 0-2 and adequate kidney/liver/bone-marrow function. Comorbidity was assessed from hospital medical records using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Toxicity was graded using the CTCAE v3.0 and the patients reported HRQoL on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30/LC13. RESULTS Data from 402 of the 436 of the patients enrolled onto the phase III trial were analysed. The patients with severe comorbidity had similar survival as other patients (6.9 versus 8.1months; p=.34), similar frequency of neutropenia (48% versus 42%; p=.16), but experienced more neutropenic fevers (12% versus 5%; p=.012) and deaths from neutropenic infections (3% versus 0%; p=.027). They had more thrombocytopenia (46% versus 36%; p=.03), but not more thrombocytopenic bleedings (3% versus 4%; p=.65). In general, the patients with severe comorbidity reported poorer HRQoL, but not significantly more deterioration of HRQoL. CONCLUSIONS The results from our study suggest that patients with advanced NSCLC who have severe co-existing disorders benefit from and tolerate platinum-doublet chemotherapy as well as other patients. They do, however, appear to have a higher risk of acquiring infections when neutropenic.

Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data

BACKGROUND Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy. METHODS All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics. FINDINGS Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients-568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months [95% CI 8·98-10·69] in patients assigned to six cycles vs 8·68 months [8·03-9·54] in those assigned to fewer cycles; hazard ratio [HR] 0·94 [95% CI 0·83-1·07], p=0·33) with slight heterogeneity between trials (p=0·076; I(2)=56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82-6·87) in patients assigned to six cycles and 5·33 months (4·90-5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68-0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia. INTERPRETATION Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients. FUNDING None.

Sustainability of healthcare improvement: what can we learn from learning theory?

BackgroundChanges that improve the quality of health care should be sustained. Falling back to old, unsatisfactory ways of working is a waste of resources and can in the worst case increase resistance to later initiatives to improve care. Quality improvement relies on changing the clinical system yet factors that influence the sustainability of quality improvements are poorly understood. Theoretical frameworks can guide further research on the sustainability of quality improvements. Theories of organizational learning have contributed to a better understanding of organizational change in other contexts. To identify factors contributing to sustainability of improvements, we use learning theory to explore a case that had displayed sustained improvement.MethodsFørde Hospital redesigned the pathway for elective surgery and achieved sustained reduction of cancellation rates. We used a qualitative case study design informed by theory to explore factors that contributed to sustain the improvements at Førde Hospital. The model Evidence in the Learning Organization describes how organizational learning contributes to change in healthcare institutions. This model constituted the framework for data collection and analysis. We interviewed a strategic sample of 20 employees. The in-depth interviews covered themes identified through our theoretical framework. Through a process of coding and condensing, we identified common themes that were interpreted in relation to our theoretical framework.ResultsClinicians and leaders shared information about their everyday work and related this knowledge to how the entire clinical pathway could be improved. In this way they developed a revised and deeper understanding of their clinical system and its interdependencies. They became increasingly aware of how different elements needed to interact to enhance the performance and how their own efforts could contribute.ConclusionsThe improved understanding of the clinical system represented a change in mental models of employees that influenced how the organization changed its performance. By applying the framework of organizational learning, we learned that changes originating from a new mental model represent double-loop learning. In double-loop learning, deeper system properties are changed, and consequently changes are more likely to be sustained.

A new pathway for elective surgery to reduce cancellation rates

BackgroundThe cancellation of planned surgeries causes prolonged wait times, harm to patients, and is a waste of scarce resources. To reduce high cancellation rates in a Norwegian general hospital, the pathway for elective surgery was redesigned. The changes included earlier clinical assessment of patients, better planning and documentation systems, and increased involvement of patients in the scheduling of surgeries. This study evaluated the outcomes of this new pathway for elective surgery and explored which factors affected the outcomes.MethodsWe collected the number of planned operations, performed operations, and cancellations per month from the hospital’s patient administrative system. We then used Students t-test to analyze differences in cancellation rates (CRs) before and after interventions and a u-chart to analyze whether the improvements were sustained. We also conducted semi-structured interviews with employees of the hospital to explore the changes in the surgical pathway and the factors that facilitated these changes.ResultsThe mean CR was reduced from 8.5% to 4.9% (95% CI for mean reduction 2.6-4.5, p < 0.001). The reduction in the CR was sustained over a period of 26 months after the interventions. The median number of operations performed per month increased by 17% (p = 0.04). A clear improvement strategy, involvement of frontline clinicians, introduction of an electronic scheduling system, and engagement of middle managers were important factors for the success of the interventions.ConclusionThe redesign of the old clinical pathway contributed to a sustained reduction in cancellations and an increased number of performed operations.

Experiences with global trigger tool reviews in five Danish hospitals: an implementation study

Objectives To describe experiences with the implementation of global trigger tool (GTT) reviews in five Danish hospitals and to suggest ways to improve the performance of GTT review teams. Design Retrospective observational study. Setting The measurement and monitoring of harms are crucial to campaigns to improve the safety of patients. Increasingly, teams use the GTT to review patient records and measure harms in English and non-English-speaking countries. Meanwhile, it is not clear as to how the method performs in such diverse settings. Participants Review teams from five Danish pilot hospitals of the national Danish Safer Hospital Programme. Primary and secondary outcome measures We collected harm rates, background and anecdotal information and reported patient safety incidents (PSIs) from five pilot hospitals currently participating in the Danish Safer Hospital Programme. Experienced reviewers categorised harms by type. We plotted harm rates as run-charts and applied rules for the detection of patterns of non-random variation. Results The hospitals differed in size but had similar patient populations and activity. PSIs varied between 3 and 12 per 1000 patient-days. The average harm rate for all hospitals was 60 per 1000 patient-days ranging from 34 to 84. The percentage of harmed patients was 25 and ranged from 18 to 33. Overall, 96% of harms were temporary. Infections, pressure ulcers procedure-related and gastrointestinal problems were common. Teams reported differences in training and review procedures such as the role of the secondary reviewer. Conclusions We found substantial variation in harm rates. Differences in training, review procedures and documentation in patient records probably contributed to these variations. Training reviewers as teams, specifying the roles of the different reviewers, training records and a database for findings of reviews may improve the application of the GTT.

Treatment outcome in performance status 2 advanced NSCLC patients administered platinum-based combination chemotherapy.

BACKGROUND There is no consensus regarding chemotherapy to patients with advanced NSCLC (ANSCLC) and performance status (PS) 2. Using data from a national multicenter study comparing two third-generation carboplatin-based regimens in ANSCLC patients, we evaluated the outcome of PS 2 patients. PATIENTS AND METHODS The 123 PS 2 patients were compared to 309 PS 0/1 patients regarding survival, quality of life (QOL) and treatment toxicity. RESULTS PS 2 patients had lower haemoglobin, lower global QOL and more pain, nausea/vomiting and dyspnea at inclusion. 68% of PS 2 patients received three chemotherapy courses vs. 85% in the PS 0/1 group (P<0.01). Median and 1-year survival were lower in the PS 2 group, 4.5 vs. 8.9 months and 10% vs. 37% (P<.01). More PS 2 patients needed blood transfusions (P=0.03) and hospitalization (P<0.01). In contrast, PS 2 patients had better relief of pain and dyspnea, and tended to a better global QOL and did not experience more leucopoenia, infections or bleeding. CONCLUSIONS Despite shorter survival, treatment toxicity was acceptable and PS 2 patients achieved better improvement of pain and dyspnea and tended to better global QOL when compared to PS 0/1 patients.

Patient experiences with interventions to reduce surgery cancellations: a qualitative study

BackgroundThe cancellation of planned surgery harms patients, increases waiting times and wastes scarce health resources. Previous studies have evaluated interventions to reduce cancellations from medical and management perspectives; these have focused on cost, length of stay, improved efficiency, and reduced post-operative complications. In our case a hospital had experienced high cancellation rates and therefore redesigned their pathway for elective surgery to reduce cancelations. We studied how patients experienced interventions to reduce cancellations.MethodsWe conducted a comparative, qualitative case study by interviewing 8 patients who had experienced the redesigned pathway, and 8 patients who had experienced the original pathway. We performed a content analysis of the interviews using a theory-based coding scheme. Through a process of coding and condensing, we identified themes of patient experience.ResultsWe identified three common themes summarizing patients’ positive experiences with the effects of the interventions: the importance of being involved in scheduling time for surgery, individualized preparation before the hospital admission, and relationships with few clinicians during their hospital stay.ConclusionsPatients appreciated the effects of interventions to reduce cancellations, because they increased their autonomy. Unanticipated consequences were that the telephone reminder created a personalized dialogue and centralization of surgical preparation and discharge processes improved continuity of care. Thus apart from improving surgical logistics, the pathway became more patient-centered.

Chemotherapy and quality of life in NSCLC PS 2 patients

Introduction. Nearly 40% of patients with advanced NSCLC are in performance status (PS) 2. These patients have a shorter life expectancy than PS 0/1 patients and they are underrepresented in clinical trials. Data on how platinum-based combination chemotherapy affects Health Related Quality of Life (HRQOL) of patients with PS 2 are scarce and the treatment of this important group of patients is controversial. Methods. A national multicenter phase III study on platinum based chemotherapy to 432 advanced NSCLC patients included 123 patients with PS 2. To explore the treatment impact on HRQOL, the development of HRQOL during the first nine weeks were compared between PS 2 and PS 0/1 patients. We used the EORTC QLQ-C30 and QLQ-LC13 questionnaires. Standardized area under the curve for all HRQOL items, and HRQOL responses classified as better, stable or worse, were compared between the groups. Results. Whereas the demographic data at baseline were well balanced between the groups, the PS 2 patients had significantly worse function and more severe symptoms than the PS 0/1 patients. In response to combination chemotherapy, the PS 2 patients had a more profound improvement of global QOL, cognitive function, fatigue, dyspnea, sleeping problems and appetite loss in comparison to the PS 0/1 group. Conclusions. PS 2 NSCLC patients seem to achieve valuable HRQOL benefits from platinum-based combination therapy. Prospective clinical studies with predefined HRQOL outcomes in PS 2 patients are needed to confirm these findings.

Adverse events in hospitalised cancer patients: a comparison to a general hospital population

Abstract Background: Patients with cancer are often treated by many healthcare providers, receive complex and potentially toxic treatments that can increase the risk for iatrogenic harm. The aim of this study is to investigate whether hospitalised cancer patients are at higher risk of adverse events (AEs) compared to a general hospital population. Material and methods: A total of 6720 patient records were retrospectively reviewed comparing AEs in hospitalised cancer patients to a general hospital population in Norway, using the IHI Global Trigger Tool method. Results: 24.2 percent of admissions for cancer patients had an AE compared to 17.4% of admissions of other patients (p < .001, rr 1.39, 95% CI 1.19–1.62). However, cancer patients did not have a higher rate of AEs per 1000 patient days compared to other patients, 37.1 vs. 36.0 (p = .65, rr 0.94, 95% CI 0.90–1.18). No particular cancer category is at higher risk. The rate of AEs increases by 1.05 times for each day spent in hospital. For every year increase in age, the risk for AEs increases by 1.3%. Cancer patients more often have hospital-acquired infections, other surgical complications and AEs related to medications. Conclusions: Because of higher age, longer length of stay and surgical treatment, hospitalised cancer patients experience AEs more often than other patients.