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Background: Improving survival in non-small cell lung cancer (NSCLC) will require new strategies or new drugs. Sequential administration of conventional non-cross-resistant cytotoxic drugs offers an opportunity to increase drug diversity while maintaining dose intensity. This Phase II trial was designed to assess the efficacy and feasibility of such a regimen in advanced NSCLC., Methods: Patients with NSCLC stage IIIB or IV received as first-line treatment four cycles of carboplatin (AUC 5) (day 1) plus gemcitabine 1000 mg/m(2) (days 1 and 8) every 3 weeks. Thereafter, treatment continued with 12 weekly cycles of paclitaxel 80 mg/m(2)., Results: In total, 46 patients were included. Median age was 59.6 years (range 41.3-74.3 years) and 93.5 % (n = 43) had Eastern Cooperative Oncology Group performance score of 0 or 1. All but 6 had stage IV disease, and 13 (28.3 %) had squamous cell carcinomas. Thirty-six (78 %) patients completed 4 cycles of carboplatin-gemcitabine and 35 patients received at least 1 cycle of paclitaxel, of whom 16 (46 % of total) patients completed 12 cycles of paclitaxel. The overall objective response rate was 49 %. Sixteen (37 %) patients had a response to carboplatin-gemcitabine, increasing to 21 (49 %) patients after administration of paclitaxel. Of the 13 assessable patients who showed a partial response (PR) on carboplatin-gemcitabine, 12 (92 %) patients showed also a PR on paclitaxel. Of 19 assessable patients with stable disease (SD) on carboplatin-gemcitabine, 4 (21 %) had a PR and 13 (68 %) SD on paclitaxel. Toxicity was moderate: 24 % stopped because of toxicity., Conclusion: Sequential chemotherapy with carboplatin-gemcitabine and weekly paclitaxel is active and feasible in advanced NSCLC patients.

Introduction: In early stage non-small cell lung cancer (NSCLC), presence of lymphatic micrometastases and isolated tumor cells, primarily detected by immunohistochemistry, is suggested to be a prognostic factor. However, there is no consensus whether immunohistochemistry should be used routinely in lymph node assessment.The goal of our study was to determine whether recurrent disease is associated with the presence of lymphatic micrometastases and/or isolated tumor cells, at the time of the lung resection., Methods: We retrospectively analyzed the prevalence of lymphatic micrometastases and/or isolated tumor cells in two groups of patients, who underwent a curative resection for early stage NSCLC. Group I had a follow-up of 5 years without recurrent disease. Group II consisted of a matched group of patients with recurrent disease. Patients were originally classified as having negative mediastinal lymph nodes.All lymph nodes obtained by mediastinoscopy and thoracotomy were re-examined by serial sectioning and immunohistochemistry., Results: Micrometastases and/or isolated tumor cells were found in one of 16 patients in group I, which was significantly different from six of 16 patients in group II. (Fisher exact test, 4.6; p, 0.04; risk ratio, 2.4).Serial sectioning and immunohistochemistry did not change N-stage for the single patient in group I, in contrast to all six patients in group II., Conclusion: Presence of lymphatic micrometastases and/or isolated tumor cells is associated with distant recurrence in patients with early stage NSCLC. We recommend the routine use of serial sectioning and immunohistochemistry in lymph node assessment to improve the accuracy of staging.

In advanced non-small cell lung cancer (NSCLC) the clinical benefit of a platinum-based doublet is only modest, therefore, attenuated dosed three-drug combinations are investigated. We hypothesized that with adequate support a full dosed chemotherapy triplet is feasible. The study was designed as a dose finding study of paclitaxel in chemotherapy-naive patients. Paclitaxel was given as a 3-h infusion on day 1, followed by fixed doses of teniposide (or etoposide) 100mg/m(2) days 1, 3, 5 and cisplatin 80 mg/m(2) day 1 every 3 weeks. As myelotoxicity was expected to be the dose-limiting toxicity, prophylactic G-CSF and antibiotic support was evaluated. Indeed, paclitaxel 120 mg/m(2) resulted in dose-limiting neutropenia, despite G-CSF support. Teniposide/etoposide day 1, 3, 5 was less myelotoxic compared to day 1, 2, 3. G-CSF support allowed paclitaxel dose-escalation to 250 mg/m(2). The addition of prophylactic antibiotics enabled dose-escalation to 275 mg/m(2) without reaching MTD. In conclusion, G-CSF and antibiotics prophylaxis enables the delivery of a full dosed chemotherapy triplet in previously untreated NSCLC patients.

Background: In the current study, the authors focused on determinants influencing the quality of care and variations in the actual quality of integrated care for patients with nonsmall cell lung cancer (NSCLC) to estimate whether there is room for improvement., Methods: The authors tested the quality of integrated care for 276 NSCLC patients with 14 quality indicators of professional (4 indicators), organizational (3 indicators), and patient-oriented quality (7 indicators). Patient characteristics and actual care data were derived from medical record data, patient-oriented care was derived from patient questionnaires, and professional and hospital characteristics were derived from questionnaires for professionals. The performance measure was the proportion of patients to whom the indicator applied who had positive scores on the indicator. Multilevel logistic regression analysis determined the influence of patient, professional, and hospital characteristics on care., Results: With regard to professional quality, the proportions of patients who underwent fluorodeoxyglucose-positron emission tomography or cervical mediastinoscopy according to the guideline criteria were 88% and 84%, respectively. Only 50% of the biopsies were adequately obtained during mediastinoscopy, and in 3% of the patients with clinical stage III disease (based on the TNM classification) there was a search for brain metastases before the initiation of combination therapy. With regard to organizational quality, the diagnostic route of 79% of the patients was completed within 21 days; 51% of patients began therapy within 35 days and 57% were discussed during multidisciplinary consultation. All but 1 patient-oriented quality indicator scored /=20% with regard to 11 of the 14 indicators. The patient-related determinants "stage of disease," "age," and "comorbidity" were found to influence the indicator scores the most., Conclusions: The quality of integrated care (especially patient-oriented care) for NSCLC patients needs improvement. Patient characteristics appear to influence performance more than professional or hospital characteristics.

Background: Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to thoracic radiotherapy as locoregional therapy., Methods: Selected patients with histologic or cytologic proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy. Responding patients were subsequently randomly assigned to surgical resection or radiotherapy. Survival curves were estimated using Kaplan-Meier analyses from time of randomization., Results: Induction chemotherapy resulted in a response rate of 61% (95% confidence interval [CI] = 57% to 65%) among the 579 eligible patients. A total of 167 patients were allocated to resection and 165 to radiotherapy. Of the 154 (92%) patients who underwent surgery, 14% had an exploratory thoracotomy, 50% a radical resection, 42% a pathologic downstaging, and 5% a pathologic complete response; 4% died after surgery. Postoperative radiotherapy was administered to 62 (40%) of patients in the surgery arm. Among the 154 (93%) irradiated patients, overall compliance to the radiotherapy prescription was 55%, and grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7%; one patient died of radiation pneumonitis. Median and 5-year overall survival for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio = 1.06, 95% CI = 0.84 to 1.35). Rates of progression-free survival were also similar in both groups., Conclusion: In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiotherapy. In view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these patients.

Background: While developing and distributing clinical practice guidelines are important in optimising clinical healthcare, insight into actual care is necessary to achieve successful implementation. Developing quality indicators may be the first step to becoming aware of actual care. The Dutch national practice guideline Non-small cell lung cancer: staging and treatment is one of the first clinical, multidisciplinary guidelines for oncology in the Netherlands for which quality indicators were developed systematically. We describe indicator development based on this guideline as a practical experience., Methods: To develop a set of indicators for diagnosis and treatment of patients with non-small cell lung cancer, we systematically achieved consensus on the basis of a national, multidisciplinary, evidence-based guideline and the opinions of professionals and patients. After the researchers extracted the recommendations from the guideline, we carried out a so-called Rand-modified-Delphi procedure. This consisted of three rounds: a national panel of professionals and representatives of the national patient organization scored all recommendations, the professionals had a consensus meeting, and the final set of indicators was e-mailed for a last check. Subsequently, some clinimetric characteristics of this final set were assessed in a practice test., Results: Thirty-two of 83 recommendations were selected in the first round. After the consensus meeting, 8 recommendations met the final criteria and were incorporated into 15 indicators, which were tested in practice. The most successful indicators for quality improvement are indicators that are measurable, have potential for improvement, have a broad range between practices and are applicable to a large part of the population., Conclusions: For successful implementation of evidence-based guidelines, each new guideline should be developed and tested with a set of indicators based on the guideline. The procedure we describe can serve as an example for other new guidelines.

Purpose: Recently, a Dutch, randomized, phase III trial demonstrated that, in small-cell lung cancer patients at risk of chemotherapy-induced febrile neutropenia (FN), the addition of granulocyte colony-stimulating factor (GCSF) to prophylactic antibiotics significantly reduced the incidence of FN in cycle 1 (24% v 10%; P = .01). We hypothesized that selecting patients at risk of FN might increase the cost-effectiveness of GCSF prophylaxis., Methods: Economic analysis was conducted alongside the clinical trial and was focused on the health care perspective. Primary outcome was the difference in mean total costs per patient in cycle 1 between both prophylactic strategies. Cost-effectiveness was expressed as costs per percent-FN-prevented., Results: For the first cycle, the mean incremental costs of adding GCSF amounted to 681 euro (95% CI, -36 to 1,397 euro) per patient. For the entire treatment period, the mean incremental costs were substantial (5,123 euro; 95% CI, 3,908 to 6,337 euro), despite a significant reduction in the incidence of FN and related savings in medical care consumption. The incremental cost-effectiveness ratio was 50 euro per percent decrease of the probability of FN (95% CI, -2 to 433 euro) in cycle 1, and the acceptability for this willingness to pay was approximately 50%., Conclusion: Despite the selection of patients at risk of FN, the addition of GCSF to primary antibiotic prophylaxis did not result in cost savings. If policy makers are willing to pay 240 euro for each percent gain in effect (ie, 3,360 euro for a 14% reduction in FN), the addition of GCSF can be considered cost effective.

A national, evidence-based guideline on the staging and treatment of patients with non-small cell lung carcinoma (NSCLC) has been compiled by the various disciplines involved. The initial diagnostic measures in patients with suspected lung cancer include history taking, physical examination and chest x-ray. Additional examinations include CT scan of the chest and upper abdomen, bronchoscopy, and 18F-fluorodeoxyglucose-positron-emission-tomography(FDG-PET)-scintigraphy, if curative therapy is planned. Cervical mediastinoscopy or endoscopic echography with fine needle aspiration can be performed for mediastinal tissue staging. The preferred treatment in stage I, II or limited III is radical resection. Postoperative radiotherapy is recommended in cases of incomplete resection and can be considered in patients in whom mediastinal lymph-node metastases are unexpectedly encountered. Chemoradiotherapy is recommended in locally advanced NSCLC. In patients with NSCLC stage I-III and poor performance status, palliative radiotherapy may be the only feasible treatment. Some patients with NSCLC stage III and stage IV can be offered palliative chemotherapy and supportive care. In cases of doubt about operability, resectability, significant pulmonary or cardiac comorbidity or combined treatment, a specialist centre should be consulted. Diagnostics should be completed within 3-5 weeks. Ensuing surgery or radiotherapy should be carried out within 2 weeks. Follow-up of patients with NSCLC includes history taking, physical examination and an optional chest x-ray. In the first year after treatment patient visits are planned quarterly, in the second year half-yearly and then yearly for at least five years.

Background: In patients with lung cancer, positron emission tomography (PET) using fluor-18-fluorodesoxyglucose (FDG) may be used both to detect extrathoracic metastases (ETM) and for mediastinal lymph node staging (MLS), potentially reducing the need for mediastinoscopy. We assessed the added value of FDG-PET in detecting ETM and focused on the reliability of FDG-PET and mediastinoscopy for MLS., Patients and Methods: In 72 consecutive patients with non-small cell lung cancer, the impact of adding FDG-PET to full conventional clinical staging was prospectively analyzed. The predictive value of FDG-PET findings and tumor location for pathologic mediastinal lymph node status were assessed in a logistic regression analysis., Results: Unexpected extrathoracic metastases were detected by FDG-PET in 15% of patients. In MLS overall negative and positive predictive values were 71 and 83% for FDG-PET, and 92 and 100% for mediastinoscopy. However, the negative predictive value of FDG-PET was only 17% in case of FDG-PET positive N1 nodes and/or a centrally located primary tumor, whereas it was 96% in case of FDG-PET negative N1 nodes and a non-centrally located primary tumor., Conclusion: By incorporating FDG-PET in clinical staging, 15% of patients with lung cancer are upstaged due to unexpected extrathoracic metastases. In case of a negative mediastinal FDG-PET, mediastinoscopy can only be omitted in the presence of a non-centrally located primary tumor and without FDG-PET positive N1 nodes.

The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-naïve patients with NSCLC, median age of 60 years, stage IIIA N2 disease and the ability to tolerate a pneumonectomy received paclitaxel 200 mg/m2 as a 3-h infusion followed by carboplatin at an area under the concentration curve (AUC) of 6 every 3 weeks for three courses. Most patients received three courses. No grade 3/4 anaemia or thrombocytopenia was documented. Over all of the cycles, 6% (3 patients) experienced grade 3 leucopenia while 63% (32/51 patients) experienced grade 3-4 neutropenia. There was 1 patient (2%) with febrile neutropenia, no early or toxic deaths and no hypersensitivity reactions. Severe non-haematological toxicity was uncommon, with the exception of grade 3 alopecia in 39%, lethargy in 8% and myalgia in 6%. Of the eligible patients (n=52), there was one complete response (CR) and 32 partial responses (PR), resulting in a response rate of 64% (95% Confidence Interval (CI) 49%-76%). Of the 15 eligible patients randomised to surgery after induction chemotherapy, 3 patients did not receive surgery and 2 patients (n=12) had no tumour in the mediastinal nodes (17%). Resections were considered complete in 2 of the 12. Median survival for all eligible patients (n=52) was 20.5 months (95% CI 16.1-31.2), with an estimated 1-year survival rate of 68.5% (95% CI 55.2-81.7). In patients with N2 stage IIIA NSCLC, paclitaxel/carboplatin is an active and very well-tolerated induction regimen.

The purpose of this study was to gain insight into the treatment policy and survival of patients with non-small cell lung cancer (NSCLC) clinical stage IIIA in daily practice. We selected 212 patients, who had been diagnosed between 1989 and 1994 and registered by the Cancer Registry, Comprehensive Cancer Centre East (CCCE). Diagnostic tests comprised chest X-ray and bronchoscopy in all cases but one, computed tomography in 89%, mediastinoscopy in 55% and conventional tomography of the chest in 16%. NSCLC had been verified histologically in 88% and cytologically in 12%. The initial treatment for the primary tumor had been surgery alone in 13% of the patients, surgery plus radiotherapy in 8%, radiotherapy alone in 56%, chemotherapy in 1% (three patients, one in addition to surgery); 22% received none of these treatments. Median survival of the 212 patients was 9.4 months (95% confidence interval 8.3-11.0 months). Overall survival rates after 1, 2 and 3 years were 41, 17 and 8%, respectively. Three-year survival of the patients who had undergone surgery, surgery plus radiotherapy, radiotherapy alone and no treatment was 18, 19, 6 and 4%, respectively. Treatment was an independent prognostic factor (multivariate Cox's proportional hazards analysis adjusted for sub-stage, age, number of co-morbid diseases and hospital). In the same model, the Hazard rate ratio for one hospital relative to the five others was 1.9 (95% confidence interval 1.2-2.8). Surgery (whether or not in combination with radiotherapy) independently gave the best results. In conclusion, policies varied between hospitals, although the variation in overall survival was small except at one hospital. New regional management guidelines are in preparation. Physicians will be encouraged to follow these guidelines, both with regard to diagnostic tests and to treatment policies, as our study showed that differences in policy might lead to differences in survival.