Quality of care and variability in lung cancer management across Belgian hospitals: a population-based study using routinely available data.

OBJECTIVE: To evaluate the quality of care for all patients diagnosed with lung cancer in Belgium based on a set of evidence-based quality indicators and to study the variability of care between hospitals. DESIGN, SETTING, PARTICIPANTS: A retrospective study based on linked data from the cancer registry, insurance claims and vital status for all patients diagnosed with lung cancer between 2010 and 2011. Evidence-based quality indicators were identified from a systematic literature search. A specific algorithm to attribute patients to a centre was developed, and funnel plots were used to assess variability of care between centres. INTERVENTION: None. MAIN OUTCOME MEASURE: The proportion of patients who received appropriate care as defined by the indicator. Secondary outcome included the variability of care between centres. RESULTS: Twenty indicators were measured for a total of 12 839 patients. Good results were achieved for 60-day post-surgical mortality (3.9%), histopathological confirmation of diagnosis (93%) and for the use of PET-CT before treatment with curative intent (94%). Areas to be improved include the reporting of staging information to the Belgian Cancer Registry (80%), the use of brain imaging for clinical stage III patients eligible for curative treatment (79%), and the time between diagnosis and start of first active treatment (median 20 days). High variability between centres was observed for several indicators. Twenty-three indicators were found relevant but could not be measured. CONCLUSION: This study highlights the feasibility to develop a multidisciplinary set of quality indicators using population-based data. The main advantage of this approach is that not additional registration is required, but the non-measurability of many relevant indicators is a hamper. It allows however to easily point to areas of large variability in care.

Immunotherapy for non-small-cell lung cancer: the past 10 years.

ABSTRACT In the past decade, the approach to patients with metastatic non-small-cell lung cancer has relied on chemotherapy and on targeted agents for molecularly selected subgroups of patients. Recent work has introduced immunotherapy as another area of progress, and likely as a new treatment paradigm in the near future. While the large Phase III studies with cancer vaccination with the current technologies remain at present disappointing, the immunomodulation strategies with immune checkpoint inhibitors have delivered remarkable results in expanded Phase I studies and are now intensively studied in large Phase III studies. This review summarizes the past decade of immunotherapy for non-small-cell lung cancer, gives an updated overview of trials in this field, and the context of future development in this exciting field.

Rebound-associated vertebral fractures after denosumab discontinuation in a lung cancer patient with bone metastases.

Denosumab is a commonly used antiresorptive treatment in patients with osteoporosis or solid tumours with bone metastases. Upon denosumab discontinuation, a rebound phenomenon can occur that results in an increased (vertebral) fracture risk. This phenomenon is well-known in the setting of osteoporosis but rarely reported in cancer patients with bone metastases discontinuing denosumab. We present the case of a 43-year old women with lung cancer and bone metastases who suffered multiple vertebral fractures after discontinuation of denosumab.

Case report: BRAF A598-T599insV mutation as a potential resistance mechanism to alectinib in ALK-rearranged lung adenocarcinoma.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved the prognosis of advanced-stage non-small cell lung cancer (NSCLC) with ALK rearrangement, but resistance mechanisms limit their efficacy. We describe the case of a 63-year-old man with a stage cIVA ALK-rearranged lung adenocarcinoma who developed a BRAF A598-T599insV mutation as a potential resistance mechanism to alectinib, a second-generation ALK TKI. He was treated with an association of BRAF and MEK inhibitors but death occurred two months after treatment initiation in a context of tumor progression and toxicity. Based on this first report of BRAF A598-T599insV mutation occurring in lung cancer, we discuss resistance mechanisms to ALK TKIs, implications of BRAF mutation in NSCLC, and BRAF A598-T599insV mutation in other cancers.

Impact of FDG-PET-induced treatment choices on long-term outcome in non-small cell lung cancer.

BACKGROUND: The TNM staging reflects the anatomic extent of lung cancer and estimates the survival expectation. Addition of FDG-PET to conventional staging (CS) improves accuracy, but few data have described the impact of this on long-term survival in relation to treatment. OBJECTIVES: To study the influence of FDG-PET on long-term outcome. METHODS: Long-term outcome data of patients were retrieved out of previously published PET studies of the Leuven Lung Cancer Group. All patients had a potential for radical treatment, and at least 5-year follow-up data. Patients were dichotomized in early (I-IIIA) versus late (IIIB-IV) stages. RESULTS: A first analysis - comparison of the 2 staging algorithms, CS alone versus CS+PET - confirmed the better staging capabilities of the latter. A second analysis, focusing on discordant findings and interaction of both staging algorithms, demonstrated that patients with early stage on PET did well, while those with late stage on PET did poorly, irrespective of findings on CS. The third analysis focused on the relation between treatment choices at the multidisciplinary board and outcome, which is especially relevant in patients with discordant finding on CS and CS+PET. From all radically treated patients, only those with early stage on CS+PET had a good outcome, but not those with early stage on CS and an unexplained late stage finding on PET. CONCLUSION: This long-term follow-up analysis confirms that addition of PET to CS results in better stage designation and prognosis. Additionally, discordant findings between CS and CS+PET should be considered relevant, with need for cytological/histological examination.

Association between surgical volume and post-operative mortality and survival after surgical resection in lung cancer in Belgium: A population-based study.

OBJECTIVES: The existence of a relationship between hospital surgical volume and outcome after lung cancer surgery remains an ongoing debate. We aimed to evaluate the association between volume and 60-day mortality, 1- and 3-year observed survival (OS) in non-small cell lung cancer (NSCLC) patients in Belgium. METHODS: Patients diagnosed with NSCLC in 2010-2011 were identified in the database of the Belgian Cancer Registry, excluding patients with multiple tumours. Regression models were applied to assess the relationship between hospital surgical volume, 60-day mortality and 1- and 3-year OS, adjusting for different patient and tumour characteristics. Surgical volume was taken into account as a continuous variable in the models. RESULTS: In 2010-2011 a total of 9,817 patients with NSCLC were diagnosed in Belgium and 2,084 of them underwent surgery. After adjusting for patient and tumour characteristics, a relationship between hospital surgical volume and patients' outcome was found. Postoperative mortality and survival improved with increasing annual surgical volume up to 10 interventions. However, no further gain in outcome has been observed above 10. While the 60-day postoperative mortality is 3.5% for hospitals with an annual volume larger than 10, the predicted mortality rate for a hospital with an annual volume of only 5 interventions is 6.5%. Similar results were observed for 1- and 3-year OS. CONCLUSION: In Belgium, a higher hospital surgical volume is associated with improved outcome in NSCLC patients after surgical resection. Minimally 10 surgical interventions per year seem to be required to achieve an optimal performance.

The challenge of molecular testing for clinical trials in advanced non-small cell lung cancer patients: Analysis of a prospective database.

OBJECTIVES: Molecular testing has become important in the biomarker program of clinical trials for advanced non-small lung cancer (NSCLC). These tissue samples often have to be analyzed in a central laboratory. We evaluated the turnaround time and possible delay in start of therapy in this process and how often testing resulted in inclusion in a clinical trial. METHODS: We reviewed our prospective database on all molecular testing cases for clinical trial suitability in patients with advanced NSCLC between March 1, 2011 and October 31, 2014. RESULTS: 250 patients were considered for biomarker-driven trials. Twenty-three cases did not have further analysis and 20 patients had failure of central biomarker analysis. Results were obtained for 207 (83%) patients. In 91 of 227 (40%) samples sent, a biomarker of interest was documented. This led to 34 (15%) clinical trial inclusions. The mean waiting time between informed consent and request for tissue sections from the pathology lab and receipt of biomarker result from central lab was 24.4 (SD 13.7) calendar days. CONCLUSION: While molecular biomarker testing is crucial in many NSCLC trials, our results show that waiting times for central laboratory analysis can cause an important delay in treatment initiation, and even ineligibility for the trial(s) under consideration. Start of therapy based on properly validated local testing, with a posteriori central biomarker testing to guarantee the integrity of the trial, would be more rewarding for quite some patients.

Melanoma-associated antigen-A3 vaccination in the treatment of non-small-cell lung cancer.

INTRODUCTION: Lung cancer is a common health problem with a bad prognosis, despite recent advances in its treatment. Antigen-specific immunotherapy implies the administration of tumor-specific antigens with an immunostimulant to induce a powerful antitumor immune response, which has shown to be capable of eliminating tumor cells. Melanoma-associated antigen (MAGE) A3 is a good antigen to use in antigen-specific immunotherapy, since it is aberrantly expressed in cancer cells, but not expressed in normal tissue, except in germline and placental cells. AREAS COVERED: Trials have been performed with the MAGE-A3 vaccine in the adjuvant setting after resection of non-small-cell lung cancer. They have shown that the MAGE-A3 vaccine is safe and well tolerated, with promising signs of clinical benefit, especially in patients expressing a specific gene signature. Outcome data are currently expected of a large Phase III randomized controlled trial in the same setting. EXPERT OPINION: The future is hopeful for antigen-specific immunotherapy in general and MAGE-A3 vaccine in specific. Further research needs to identify new tumor-specific antigens, more potent adjuvants and genetic profiles suggestive of a better response toward antigen-specific immunotherapy. The MAGE-A3 vaccine has to be investigated in other settings than the adjuvant one and in other tumor types expressing MAGE-A3.

Performance of standard procedures in detection of EGFR mutations in daily practice in advanced NSCLC patients selected according to the ESMO guideline: a large Caucasian cohort study.

BACKGROUND: ESMO consensus recommends EGFR mutation testing in never/former light smokers (<15 pack-years) or patients with non-squamous NSCLC. The aim of this work was to determine the frequency and clinical predictors of EGFR mutations, and the role of specimen sampling tests, in Caucasian standard practice setting. METHODS: We screened 297 patients according to this consensus. Mutational analysis of EGFR was performed using the Therascreen EGFR RGQ PCR mutation kit. Clinical and pathological correlative data were collected. RESULTS: An EGFR activating mutation was found in 32 patients (11%), twelve exon 19 deletions, two exon 18 and eighteen exon 21 point mutations. Most were in females, but half were in smokers. Negative TTF-1 staining had a very strong negative predictive value (all except one patient had TTF-1 positive adenocarcinoma). Both biopsies as well as cytology specimens (mainly EBUS-TBNA) did well: 24 mutations in 213 biopsy samples (11.2%) and 8 in 84 cytology samples (9.5%), respectively. The Therascreen acted as a sensitive test in all types of samples: 7 activating mutations were found in samples rated to have <5% of tumour cells, and there were only 4 test failures in the whole series. CONCLUSION: In this Caucasian standard practice NSCLC cohort, tested according to the ESMO consensus, activating EGFR mutation occurred in 11% of the patients. Half of these were in former/current smokers. With our sampling technique and use of the Therascreen kit, EBUS-TBNA cell blocks performed as good as biopsies.

Chemotherapy-induced anemia: the story of darbepoetin alfa.

BACKGROUND: Prior to the approval of the first erythropoiesis-stimulating agent (ESA) in the early 1990s, red blood cell transfusions were the primary means of treating severe chemotherapy-induced anemia (CIA), with little recourse for those with more mild forms of the condition. The introduction of the ESAs allowed treatment of mild-to-moderate CIA in patients with cancer. It has been a decade since darbepoetin alfa (DA), a second-generation ESA with a longer half-life, became available to patients with CIA. OBJECTIVE AND METHODS: We present a review of studies on DA in CIA, from its development through to the present day. Medline was searched for randomized clinical trials on DA. Additional trials and meta-analyses on ESAs were incorporated into this review when relevant. RESULTS: The first publications on DA generally focused on optimal dosing, efficacy and tolerability. In these, it was shown that DA is an effective and well tolerated treatment option to achieve hematopoietic response, regardless of dosing interval. Subsequently, the focus shifted towards meta-analyses on survival data of all ESAs. These reported conflicting results regarding mortality and/or disease progression. However, guidelines for ESA use were updated and, when followed, these make ESAs a well tolerated and effective tool for managing CIA. CONCLUSIONS: As the past decade has broadened our knowledge on the benefits and risks of CIA management, continued high-quality studies will help to optimize treatment with ESAs in order to maximize quality of life for these patients. The limitation of a literature review of this nature is the complete reliance on previously published research and the availability of these studies using the methodology outlined above.

Darbepoetin alfa in the treatment of anemia in cancer patients undergoing chemotherapy.

For years, the treatment of chemotherapy-induced anemia (CIA) consisted of red blood cell transfusions. Major disadvantages of transfusions are their temporary effect and limitation to treatment of severe anemia. In an extensive clinical trial program in patients with CIA, darbepoetin alfa (DA) - a long-acting recombinant human erythropoietin - was proven to be very effective in reducing transfusion needs in patients developing CIA. The administration is suitable with most chemotherapy schemes. Caution is needed in patients with a history of thrombo-embolic events, as a slightly higher incidence of these events is noted in patients treated with darbepoetin alfa or erythropoietin substitution agents (ESAs) in general. In recent years, concerns have been raised about a potential negative influence of these agents on survival. In this respect, it is important to make the distinction between studies on the treatment of existing CIA versus treatment with ESAs outside this indication. On the other hand, it has always been assumed that transfusions were a completely safe treatment, but concerns about a potential negative effect on survival have been raised for transfusions as well. The safety concerns with DA and ESAs in general led to a pharmacovigilance program and an adaptation of the guidelines for treatment of CIA, focusing on treatment of moderate CIA but no longer on mild CIA. Now that the most recent safety data of the pharmacovigilance program of ESAs is almost completed, the clinical impact of the shift to the treatment of only moderate anemia is discussed in this review, which provides a critical view on the indications of DA and the benefit-risk assessment, in order to provide good supportive care without harm to the patient.

Maintenance therapy for advanced non-small-cell lung cancer: ready for clinical practice?

The treatment paradigm for advanced non-small-cell lung cancer has changed in recent years with the importance of histological subtyping for the choice of chemotherapy, and the use of molecular markers to select patients for targeted therapy. Maintenance therapy (MT) is another focus of interest. The potential benefit of MT for the patient is that it prolongs tumor control reached with first-line chemotherapy in order to improve overall survival with little added toxicity. Historical studies have never reached this goal, as the agents used for MT were too poorly tolerated. We review the data of the two types of recent MT studies, 'continuation' and 'switch' or 'consolidation' MT. We comment on how the benefits demonstrated in these studies may change clinical practice and reflect on factors that may identify subgroups of patients who derive the greatest benefit from MT in general, as this will help in a rational use of MT.

Maintenance therapy for advanced non-small-cell lung cancer: a pilot study on patients' perceptions.

INTRODUCTION: Several randomized trials on maintenance therapy (MT) for metastatic non-small-cell lung cancer (NSCLC) have demonstrated benefit in progression-free survival. More recently, a study with pemetrexed and one with erlotinib also showed significant gains in overall survival (OS). Yet, in this palliative treatment setting, the benefit has to be weighed against the potential burden of treatment, and thus patients' preferences should be taken into account. METHODS: In the absence of data on this topic, we undertook a pilot survey with 10 questions covering the overall patient attitude toward MT, the benefit expected by patients, and the acceptance of side effects or modes of administration. Included patients had stage IV NSCLC and were planned to start first-line platinum-based doublet chemotherapy. The questionnaire was submitted at the start of and after two and four cycles of chemotherapy. RESULTS: Thirty patients were included. Overall, patients had a positive attitude toward MT. At baseline, it was considered worthwhile by 83%, 67%, and 43% of patients for an OS benefit of 6, 3, or 1 month, respectively, with some decrease over time. Effects on symptom control were crucial for about 90% of the patients. There was a slight preference for oral versus intravenous administration. Side effects were accepted by most patients as long as they were mild to moderate. CONCLUSION: Our pilot survey showed that metastatic NSCLC patients in general are in favor of MT. They expect either an OS benefit of at least several months, or better symptom control, in balance with mild-to-moderate side effects.

Erythropoiesis-stimulating agents in cancer patients: reflections on safety.

Chemotherapy-induced anemia (CIA) is a frequent problem in cancer patients with a negative impact on prognosis and quality of life. Erythropoiesis-stimulating agents (ESAs) have proven efficacy in improving hemoglobin levels and reducing red blood cell transfusion needs of these patients. In several randomized studies in settings other than CIA (such as patients not receiving any chemotherapy, or studies on preventive use of ESAs to keep high hemoglobin levels), safety signals that ESA therapy may result in worse cancer outcome were documented. We review the evidence for these safety concerns, the different hypotheses to explain effects on outcome, the implications of the more restrictive guidelines on ESA therapy on daily practice and possible alternative treatments to consider.

Darbepoetin alfa in the treatment of chemotherapy-induced anaemia.

BACKGROUND: Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA), with a longer half-life than previous recombinant human erythropoietins. After its initial development for anaemia due to renal insufficiency, an extensive clinical trial program has defined its role in cancer patients. OBJECTIVE/METHODS: Review of the initial registration studies, further development and recent progress, guidelines for use in clinical practice (EORTC, ASCO/ASH), and specific focus on recent safety concerns. RESULTS: Darbepoetin alfa significantly decreases the number of red blood cell transfusions in patients with chemotherapy-induced anaemia, and has been shown to improve health-related quality of life in several studies. The prolonged half-life allows a prolonged dosing interval. Administration every three weeks, a suitable schedule to synchronise with day 1 of many chemotherapy regimens, is as efficient as the initially registered weekly administration. Recent data strongly suggest that the addition of intravenous iron improves haemoglobin response rates. The use of these agents in clinical practice has to be according to the guidelines. Recent safety data reported a negative effect on survival when ESAs were used to treat anaemia that was either not chemotherapy related, or when used to maintain high levels of haemoglobin and prevent anaemia. All of these studies were not in accordance with existing guidelines, while safety data from clinical trials using ESAs according to the guidelines remain reassuring. CONCLUSION: Darbepoetin alfa has a well defined place in the treatment of chemotherapy-induced anaemia, and is safe when used in line with existing guidelines. Recent safety signals on cancer outcomes in studies not in accordance with these guidelines illustrate the need for further research into the complex interaction between anaemia and tumour hypoxia in cancer patients.

Darbepoetin alfa for chemotherapy-induced anemia: evolution to extended dosing intervals.

Anemia is a frequent problem in cancer patients, especially in those treated with chemotherapy, and has an important negative impact on quality of life. Red blood cell transfusions provide clear but rather temporary comfort. The development of erythropoietic stimulating agents (ESAs) led to a more durable anemia treatment. Darbepoetin alpha is a unique ESA with a long plasma half life, thereby suitable for administration with different dosing intervals. Apart from administration every week, darbepoetin alpha also proved to be efficient in reducing red blood cell transfusion rates and in improving health-related quality of life when administered at a dose of 500 microg once every 3 weeks. This is a convenient therapy schedule because it can be synchronized with the chemotherapy cycle in many patients. Recently, concerns have been raised about the long-term safety of ESAs, more specifically about their effect on survival. Available data must be interpreted with caution, but at present there is no clear evidence to support a negative effect on outcome with darbepoetin alpha therapy when used according to the guidelines for treatment of chemotherapy-induced anemia. Further studies focusing on survival as the primary end point are ongoing.

Flexible dosing with Darbepoetin alfa for the treatment of chemotherapy-induced anemia.

Anemia is frequent in cancer patients with chemotherapy, and has an important negative effect on health-related quality of life (QoL). Darbepoetin alfa belongs to a new class of erythropoietic proteins with a unique molecular structure and interesting properties compared with classic recombinant human erythropoietin. Darbepoetin alfa is effective for chemotherapy-induced anemia when administered once weekly at a dose of 2.25 mug/kg, as shown in two large phase III placebo-controlled trials in patients with solid tumors and hematological malignancies. Furthermore, it was safe and well tolerated. More recently attention has been focused on optimizing Darbepoetin alfa therapy. Front-loaded dosing was explored to accelerate the hemoglobin (Hb) response and effect on QoL, but this idea could not be confirmed in a large phase III study. Based on the prolonged half-life of Darbepoetin alfa, administration every 3 weeks was appealing. In a large phase III trial, noninferiority of administration of 500 mug every 3 weeks compared with the weekly dosing could be confirmed, both in terms of reduction of red blood cell transfusion, Hb parameters, and QoL. This schedule is very convenient for patients and caregivers as it allows synchronization of erythropoietic therapy and common chemotherapy schedules. Questions for future study are the optimal iron supplementation strategy and the effect of Darbepoetin alfa on outcome. This article reviews the clinical development of Darbepoetin alfa with emphasis on recent data.

The use of darbepoetin alfa for the treatment of chemotherapy-induced anaemia.

Chemotherapy-induced anaemia, with its important consequences on quality of life and social function of cancer patients, can be improved with erythropoietic therapy. Darbepoetin alfa is the first of a novel generation of erythropoietic proteins with a unique molecular structure and a circulating half-life that is threefold longer than that of the previous recombinant human erythropoietin. The efficacy and safety of weekly administration have been confirmed in different Phase II and III randomised trials. In order to optimise the efficacy profile of darbepoetin alfa, extended dosing intervals and front-loading regimens are evaluated, as well the optimal haemoglobin level to initiate therapy. Across all trials, darbepoetin alfa was shown to be a well-tolerated and safe therapy. The possible favourable effect on the outcome of cancer patients needs to be further elucidated.