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Background and Purpose: Radiotherapy plays a pivotal role in lung cancer treatment. Selection of patients for new (radio)therapeutic options aiming at improving outcomes requires reliable and validated prediction models. We present the implementation of a prospective platform for evaluation and development of lung radiotherapy (proPED-LUNG) as an instrument enabling multidimensional predictive modelling., Materials and Methods: ProPED-LUNG was designed to comprise relevant baseline and follow up data of patients receiving pulmonary radiotherapy with curative intent. Patient characteristics, diagnostic and staging information, treatment parameters including full dose-volume-histograms, tumour control, survival, and toxicity are scored. Besides physician-rated data, a range of patient-rated data regarding symptoms and health-related quality-of-life are collected., Results: After 18 months of accrual, 315 patients have been included (accrual rate, 18 per month). Of the first hundred patients included, 70 received conformal (chemo)radiotherapy and 30 underwent stereotactic radiotherapy. Compliance at 3 and 6 months follow-up was 96-100% for patient-rated, and 81-94% for physician-rated assessments. For data collection, 0.4 FTE were allocated in a 183 FTE department (0.2%)., Conclusions: ProPED-LUNG is feasible with high compliance rates and yields a large amount of high quality prospective disease-related, treatment-related, patient- and physician-rated data which can be used to evaluate new developments in pulmonary radiotherapy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Stage III unresectable non-small cell lung cancer (NSCLC) is preferably treated with concurrent schedules of chemoradiotherapy, but none is clearly superior Gemcitabine is a radiosensitizing cytotoxic drug that has been studied in phase 1 and 2 studies in this setting. The aim of this study was to describe outcome and toxicity of low-dose weekly gemcitabine combined with concurrent 3-dimensional conformal radiotherapy (3D-CRT)., Patients & Methods: Treatment consisted of two cycles of a cisplatin and gemcitabine followed by weekly gemcitabine 300 mg/m2 during 5 weeks of 3D-CRT, 60 Gy in 5 weeks (hypofractionated-accelerated). Overall survival (OS), progression-free survival (PFS), and treatment related toxicity according to Common Toxicity Criteria of Adverse Events (CTCAE) version 3.0 were assessed., Results: Between February 2002 and August 2008, 318 patients were treated. Median age was 64 years (range 36-86); 72% were male, WHO PS 0/1/2 was 44/53/3%. Median PFS was 15.5 months (95% confidence interval [CI], 12.9-18.1) and median OS was 24.6 months (95% CI., 21.0-28.1). Main toxicity (CTCAE grade ≥3) was dysphagia (12.6%), esophagitis (9.6%), followed by radiation pneumonitis (3.0%). There were five treatment related deaths (1.6%), two due to esophagitis and three due to radiation pneumonitis., Conclusion: Concurrent low-dose gemcitabine and 3D-CRT provides a comparable survival and toxicity profile to other available treatment schemes for unresectable stage III.

Introduction: In randomly assigned studies with EGFR TKI only a minor proportion of patients with NSCLC have genetically profiled biopsies. Guidelines provide evidence to perform EGFR and KRAS mutation analysis in non-squamous NSCLC. We explored tumor biopsy quality offered for mutation testing, different mutations distribution, and outcome with EGFR TKI., Patient and Methods: Clinical data from 8 regional hospitals were studied for patient and tumor characteristics, treatment and overall survival. Biopsies sent to the central laboratory were evaluated for DNA quality and subsequently analyzed for mutations in exons 18-21 of EGFR and exon 2 of KRAS by bidirectional sequence analysis., Results: Tumors from 442 subsequent patients were analyzed. For 74 patients (17%) tumors were unsuitable for mutation analysis. Thirty-eight patients (10.9%) had EGFR mutations with 79% known activating mutations. One hundred eight patients (30%) had functional KRAS mutations. The mutation spectrum was comparable to the Cosmic database. Following treatment in the first or second line with EGFR TKI median overall survival for patients with EGFR (n = 14), KRAS (n = 14) mutations and wild type EGFR/KRAS (n = 31) was not reached, 20 and 9 months, respectively., Conclusion: One out of every 6 tumor samples was inadequate for mutation analysis. Patients with EGFR activating mutations treated with EGFR-TKI have the longest survival.

Small-cell lung cancer (SCLC) is characterized by rapid growth and early metastasis. Despite its sensitivity to cytotoxic treatment, until now treatments have failed to control or cure this disease in most patients. Here, we describe a patient with SCLC in which symptoms caused by iris metastasis were the only sign of relapse after multimodality treatment.

Background: Endoscopic ultrasonography (EUS) is a novel method for staging of the mediastinum in lung cancer patients. The recent development of linear scanners enables safe and accurate fine-needle aspiration (FNA) of mediastinal and upper abdominal structures under real-time ultrasound guidance. However, various methods and equipment for mediastinal EUS-FNA are being used throughout the world, and a detailed description of the procedures is lacking. A thorough description of linear EUS-FNA is needed., Methods: A step-by-step description of the linear EUS-FNA procedure as performed in our hospital will be provided. Ultrasonographic landmarks will be shown on images. The procedure will be related to published literature, with a systematic literature search., Results: EUS-FNA is an outpatient procedure under conscious sedation. The typical linear EUS-FNA procedure starts with examination of the retroperitoneal area. After this, systematic scanning of the mediastinum is performed at intervals of 1-2cm. Abnormalities are noted, and FNA of the abnormalities can be performed. Specimens are assessed for cellularity on-site. The entire procedure takes 45-60 min., Conclusions: EUS-FNA is minimally invasive, accurate, and fast. Anatomical areas can be reached that are inaccessible for cervical mediastinoscopy. EUS-FNA is useful for the staging of lung cancer or the assessment and diagnosis of abnormalities in the posterior mediastinum.

A 48-year-old woman with exanthema, pruritus and eosinophilia was found upon further examination to have a small-cell bronchus carcinoma; after chemotherapy and radiotherapy there was an almost complete response and the skin symptoms disappeared. A 70-year-old man who was recently treated due to primary malignant fibrous histiocytoma associated with eosinophilia became cachectic and anaemic. He was found to have a metastased leiomyosarcoma and died shortly afterwards. Worldwide the most common cause of eosinophilia is a parasitic infection, whereas in Western Europe the most common causes are allergic reactions and medicine use. Paraneoplastic symptoms are present in 7-10% of adults with cancer. However, the frequency of eosinophilia as a paraneoplastic phenomenon is unknown. It is important to recognise this phenomenon of paraneoplastic eosinophilia for the timely diagnosis and treatment of the underlying disease.

Aim of this study was to evaluate activity and toxicity of docetaxel and carboplatin as second-line treatment in advanced non-small-cell lung cancer (NSCLC) patients who failed or relapsed after previous chemotherapy. Patients had to have unresectable stage IIIb or IV NSCLC, previous chemotherapy, a performance status < or = 2, a normal bone marrow reserve, and an adequate renal and liver function. Treatment consisted of docetaxel 75 mg/m2 and carboplatin AUC 6 mg/ml min administered every 3 weeks for a maximum of 5 cycles. Fifty-seven patients with a median age of 57 years were included. Prior treatment consisted of gemcitabine alone (n = 2) or gemcitabine in combination with cisplatin (n = 26) or epirubicin (n = 29). Median number of cycles for carboplatin and docetaxel was 4. Granulocytopenia and thrombocytopenia common toxicity criteria (CTC) grades 3 and 4 occurred in 79 and 30% of patients, respectively. Febrile neutropenia occurred in eight patients (14%), of whom two patients died. Fatigue grades 2 and 3 occurred in 42% of patients. Other non-haematological toxicity was mild. Tumour response rate was 37%, irrespective of the previous regimen. Median survival was 31 weeks, 1-year survival was 32%. In conclusion, the combination of docetaxel and carboplatin is active as second-line treatment in platinum and non-platinum pre-treated patients.

Background: Positron emission tomography (PET) is accurate for mediastinal staging of lung cancer but has a moderate positive predictive value, necessitating pathological verification. Endoscopic ultrasonography with fine needle aspiration (EUS-FNA) is a technique for tissue verification of mediastinal and upper retroperitoneal abnormalities. The use of EUS-FNA may decrease the number of surgical procedures and thereby staging costs., Methods: EUS-FNA was used prospectively for the cytological assessment of mediastinal and/or upper retroperitoneal PET hot spots in patients with suspected lung cancer. Only if EUS-FNA was positive for malignancy was subsequent mediastinoscopy or exploratory thoracotomy cancelled. The cost effectiveness of EUS-FNA was determined., Results: Of 488 consecutive patients with suspected lung cancer, 81 were enrolled with mediastinal and/or upper retroperitoneal PET hot spots. EUS-FNA was positive in 50 (62%) patients, negative in six, and inconclusive in 25. Of the 31 negative or inconclusive patients, 26 underwent surgical staging (resulting in 14 patients with and 12 without mediastinal malignancy), while five patients had mediastinal metastases during follow up. No EUS-FNA related morbidity or mortality was encountered. The accuracy of the decision to proceed to surgery (or not) on the basis of EUS-FNA was 77% (95% CI 68 to 86). EUS-FNA detected more mediastinal abnormalities than PET except for the upper mediastinal region. Addition of EUS-FNA to conventional lung cancer staging reduced staging costs by 40% per patient, mainly due to a decrease in surgical staging procedures., Conclusion: EUS-FNA can replace more than half of the surgical staging procedures in lung cancer patients with mediastinal and/or upper retroperitoneal PET hot spots, thereby saving 40% of staging costs.

Enlarged mediastinal lymph nodes in patients with previous extrathoracic malignancy require pathological verification. However, surgical procedures lead to morbidity and (rarely) mortality. Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) is a minimally invasive, outpatient procedure. We prospectively assessed its usefulness in patients with mediastinal abnormalities and previous extrathoracic malignancy. All patients underwent EUS-FNA prior to planned surgical procedures. Specimens were categorised as positive, negative, or inconclusive. Surgical procedures were cancelled after positive EUS-FNA. Twenty patients underwent EUS-FNA, being positive in eleven and providing an alternative diagnosis in one patient (a total of 60%). In 8 patients, EUS-FNA was negative or inconclusive, while surgery was positive in five and negative in three. Sensitivity and specificity of EUS-FNA were 69 and 100%, respectively. EUS-FNA is useful in the assessment of mediastinal abnormalities in patients with previous extrathoracic malignancy. Surgical diagnostic procedures were precluded in 60% of such patients.

Purpose: To determine the radiosensitizing effect of prolonged exposure of carboplatin in patients with locally unresectable non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with histologically proven NSCLC, performance score <2, weight loss <10%, and normal organ functions were randomized between carboplatin 840 mg/m2 administered continuously during 6 weeks of radiotherapy or thoracic radiotherapy alone (both 60 Gy). Toxicity was evaluated with National Cancer Institute Common Toxicity Criteria (NCI CTC) and the Radiation Therapy Oncology Group (RTOG) criteria. Quality of life was measured with European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/LC13 questionnaires., Results: One-hundred and sixty patients were included. Pathologically confirmed persistent tumor was present in 53% of patients in the combination arm versus 58% in the radiotherapy alone arm (P=0.5). Median survival in the combination arm was 11.8 [95% confidence interval (CI) 9.3-14.2] months and in the radiotherapy alone arm 11.7 (95% CI 8.1-15.5) months; progression-free survival was not different between arms [6.8 and 7.5 months, respectively (P=0.28)]. Acute toxicity was mild, late toxicity was radiation-induced cardiomyopathy (three patients) and pulmonary fibrosis (five patients). Quality of life was not different between arms, but in all measured patients cough and dyspnea improved, pain became less, and slight paresthesia developed 3 months after treatment., Conclusion: Addition of continuously administered carboplatin as radiosensitizer for locally unresectable NSCLC does not improve local tumor control or overall survival.

The purpose of our study was to compare progression-free survival and quality of life (QOL) after cisplatin-gemcitabine (CG) or epirubicin-gemcitabine (EG) in chemotherapy-naive patients with unresectable non-small-cell lung cancer. Patients (n=240) were randomised to receive gemcitabine 1125 mg x m(-2) (days 1 and 8) plus either cisplatin 80 mg x m(-2) (day 2) or epirubicin 100 mg x m(-2) (day 1) every 3 weeks for a maximum of five cycles. Eligible patients had normal organ functions and Eastern Cooperative Oncology Group performance status

Purpose: Gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) is a potent radiosensitizer. The mechanism of dFdC-mediated radiosensitization is yet poorly understood. We recently excluded inhibition of DNA double-strand break (DSB) repair by nonhomologous end-joining (NHEJ) as a means of radiosensitization. In the current study, we addressed the possibility that dFdC might affect homologous recombination (HR)-mediated DSB repair or base excision repair (BER)., Methods and Materials: DFdC-mediated radiosensitization in cell lines deficient in BER and in HR was compared with that in their BER-proficient and HR-proficient parental counterparts. Sensitization to mitomycin C (MMC) was also investigated in cell lines deficient and proficient in HR. Additionally, the effect of dFdC on Rad51 foci formation after irradiation was studied., Results: DFdC did induce radiosensitization in BER-deficient cells; however, the respective mutant cells deficient in HR did not show dFdC-mediated radiosensitization. In HR-proficient, but not in HR-deficient, cells dFdC also induced substantial enhancement of the cytotoxic effect of MMC. Finally, we found that dFdC interferes with Rad51 foci formation after irradiation., Conclusion: DFdC causes radiosensitization by specific interference with HR.

Purpose: Our goal was to find the maximum tolerated dose of gemcitabine administered concurrently with thoracic radiotherapy in locally advanced non-small cell lung cancer (NSCLC)., Patients and Methods: Patients with stage III NSCLC and a radiation planning volume less than 2000 cm(3) were included. Treatment consisted of 6 weeks of thoracic radiation, 2 Gy daily for 5 days a week for a total dose of 60 Gy. Planning with multiple field arrangements and three-dimensional conformal technique was used. Patients were treated with gemcitabine, starting with a dose of 300 mg/m(2) in the 1st week of radiation. In subsequent cohorts, the weekly dosing frequency of gemcitabine was increased until weekly administration was reached. Thereafter, the doses of weekly gemcitabine were increased. Toxicity was measured using Common Toxicity of the National Cancer Institute (CTC), acute Radiation Therapy Oncology Group (RTOG), and late RTOG/European Organization for Research and Treatment of Cancer (EORTC) rating scales., Results: Twenty-seven patients were included, of whom 14 had stage IIIa and 13 had stage IIIb. Dose-limiting toxicity was grade 3 esophagitis and grade 3 radiation pneumonitis in the patient cohort receiving gemcitabine 450 mg/m(2) once weekly. The mean actual treated radiation volume was 760 cm(3) (range, 289-1718 cm(3))., Conclusions: The maximum tolerated dose and frequency of gemcitabine in locally advanced NSCLC is 300 mg/m(2) once weekly during 6 weeks of thoracic radiotherapy, as long as the treatment volume does not exceed 2000 cm(3).

In two patients, women aged 73 and 46 years, gastrointestinal symptoms were initially not recognised as a paraneoplastic syndrome due to small-cell lung cancer. This led to redundant diagnostics as well as a delay in final diagnosis. The anti-Hu syndrome is characterised by the presence of anti-Hu antibodies and neurological symptoms. About a quarter of the patients with the anti-Hu syndrome will develop gastrointestinal motility disorders in the course of their illness. The primary tumour is usually a small-cell lung cancer. Whereas the presence of anti-Hu antibodies appears to be beneficial for the oncological prognosis, the neurological outcome is less favourable.

Unlabelled: PET with (18)F-FDG is used for detection and staging of thoracic cancer; however, more specific PET radiopharmaceuticals would be welcome. (11)C-labeled choline (CHOL) is a new radiopharmaceutical potentially useful for tumor imaging, since it is incorporated into cell membranes as phosphatidylcholine. The aim of this study was to investigate whether (11)C-CHOL PET has advantages over (18)F-FDG PET in patients with thoracic cancer., Methods: We evaluated 17 patients with thoracic cancer both with (11)C-CHOL PET and (18)F-FDG PET. After transmission scanning, (11)C-CHOL was injected intravenously, and whole-body scanning was started after 5 min. Immediately thereafter, (18)F-FDG was injected intravenously, followed after 90 min by interleaved attenuation-corrected whole-body scanning. Scans were performed from crown to femur. Visual and quantitative (standardized uptake value) analyses of (11)C-CHOL PET and (18)F-FDG PET were performed and compared with results of traditional staging and follow-up., Results: The most prominent features of normal (11)C-CHOL distribution were high uptake in liver, renal cortex, and salivary glands. Except for some uptake in choroid plexus and pituitary gland, brain uptake was negligible. All primary thoracic tumors were detected with (11)C-CHOL PET and (18)F-FDG PET. Both (11)C-CHOL PET and (18)F-FDG PET correctly identified all 16 patients with lymph node involvement. However, in a lesion-to-lesion analysis, (11)C-CHOL PET detected only 29 of 43 metastatic lymph nodes, whereas (18)F-FDG PET detected 41 of 43. (11)C-CHOL PET detected fewer intrapulmonary and pleural metastases than (18)F-FDG PET (27/47 vs. 46/47). More brain metastases were detected with (11)C-CHOL PET (23/23) than with (18)F-FDG PET (3/23). For primary tumors, the median (range) standard uptake values of (11)C-CHOL and (18)F-FDG were 1.68 (0.98-3.22) and 4.22 (1.40-8.26), respectively (P = 0.001)., Conclusion: (11)C-CHOL PET can be used to visualize thoracic cancers. Although detection of lymph node metastases with (11)C-CHOL PET was inferior compared with (18)F-FDG PET, the detection of brain metastases was superior.

The aim of the study was to evaluate activity, toxicity and health-related quality of life (HRQL) with gemcitabine as second-line treatment after previous chemo- or radiotherapy in non-small-cell lung cancer (NSCLC). Patients with previously treated NSCLC were treated with gemcitabine (1000 mg/m(2)) on days 1, 8 and 15 in a 28-day cycle. Eighty patients were included; median age was 57 years (range 38-77). Prior treatment consisted of platinum-containing chemotherapy in 29 patients and high-dose thoracic radiotherapy in 51 patients. Median number of cycles was three (range 1-6). Granulocytopenia CTC grade 3 and 4 occurred in 9% and thrombocytopenia CTC grade 3 and 4 in 9% of cycles. Non-haematological toxicity was mild. Tumour response was achieved in 13% of the patients (95% CI 7-20), median survival time was 26 weeks and 1-year survival was 22%. Tumour response to second-line gemcitabine could not be predicted from response to first-line therapy, first-line treatment modality or treatment interval. In a subset of 35 patients HRQL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-LC13 questionnaires and showed improvement or control of symptoms and functioning in approximately 30% of patients. We conclude that gemcitabine in second-line treatment has modest anti-tumour activity, is well tolerated, and may control tumour-related symptoms and improve HRQL in a significant minority of patients.

Background: To find the maximum tolerated dose for ifosfamide in combination with paclitaxel and carboplatin in small-cell lung cancer patients (SCLC), who are resistant to cyclophosphamide, doxorubicin and etoposide (CDE)., Patients and Methods: Different dose schedules of ifosfamide were combined with fixed doses of paclitaxel 175 mg/m2 and carboplatin AUC 6 mg/ml min. Included were 30 patients, with a median age of 60 years, and median time off prior cytotoxic treatment of 8 weeks. All patients were previously treated with CDE and 11 had received re-induction CDE., Results: Dose limiting toxicity of our schedule was persistent thrombocytopenia. None of the patients developed neutropenic fever. Non-haematological toxicity was mild, although two treatment-related deaths occurred. Fifty-four percent of patients had a partial response and median survival time was twenty-five weeks., Conclusions: The maximum tolerated dose of this combination for patients with resistant SCLC is ifosfamide 2000 mg/m2 in combination with paclitaxel 175 mg/m2 and carboplatin AUC 6 mg/ml min administered on the first day of a 21-day cycle.

Objective: This study was conducted to assess the activity and toxicity ofgemcitabine in patients with resistant small-cell lung cancer (SCLC). PATIENTS TAND METHODS: Forty-one patients with limited- or extensive-stage SCLC, who were previously treated with at least one chemotherapeutic regimen and progressed during or within three months of finishing the last regimen, were treated with 1000 mg/m2 gemcitabine on days 1, 8, and 15 of a four-week cycle., Results: Thirty-eight patients were evaluable for response. Five partial and no complete responses were seen, for an overall response rate of 13% (95% confidence interval (CI): 6%-27%). Time to progression varied from 4 to 20 weeks, with a median of 8 weeks. Median survival was 17 weeks (range 4-84 weeks). Hematological toxicity mainly consisted of NCI-CTC grade 3 thrombocytopenia (29% of patients) and, to a lesser extent, grade 3 leukopenia (18% of patients). Non-hematological toxicity was mild, with nausea being the most commonly reported event., Conclusions: Gemcitabine has modest activity in patients with resistant SCLC. There is some non-cross resistance to most agents against SCLC.

Unlabelled: L-3-[123I]iodo-alpha-methyl-tyrosine (IMT) is a modified amino acid that is avidly taken up by many tumors. Uptake is based on the increased transmembrane transport of amino acids in malignancies. IMT is the only amino acid tracer suitable for SPECT. The aim of this study was to determine the feasibility of IMT SPECT in the detection, staging, and treatment evaluation of non-small cell lung cancer., Methods: We evaluated 44 IMT SPECT studies in 17 patients with histologically proven non-small cell lung cancer, stage III. IMT SPECT and planar imaging of the chest was performed before, 2 wk after, and 3 mo after 60 Gy radiotherapy. Staging was based on the findings of bronchoscopy, chest CT, mediastinoscopy, or explorative thoracotomy. After radiotherapy, CT and bronchoscopy were repeated to assess tumor response., Results: In 15 of 16 evaluable primary tumors, avid IMT uptake was present (sensitivity, 94%), with a mean (+/-SD) tumor-to-background ratio (T/B) of 2.95 +/- 0.78 (range, 1.7-4.9). In 12 of 14 patients (86%) with mediastinal involvement, IMT SPECT detected one or more mediastinal metastases. However, only 13 of 20 mediastinal metastases were detected in lesion analysis (lesion-based sensitivity, 65%). For lesions < 2 cm in diameter, sensitivity was 42%. FDG PET (available for 5 patients) detected more known and unknown lesions than did IMT SPECT. After radiotherapy, T/B had fallen to 1.84 +/- 0.29 (P < 0.001 vs. baseline), and 3 mo later to 1.61 +/- 0.41 (not statistically significant vs. second study). Considerable nonspecific uptake was found in irradiated normal lung tissue (mean ratio to nonirradiated tissue, 1.79 +/- 0.53), persisting for > 3 mo. No relationship was observed between various IMT uptake parameters and the presence of residual viable tumor tissue or survival., Conclusion: IMT SPECT has a high sensitivity for the detection of primary non-small cell lung cancer. Although patient-based sensitivity in detecting mediastinal spread was adequate, sensitivity for individual lesions, especially for small metastases (<2 cm in diameter) was too low to be clinically helpful. Radiotherapy caused considerable nonspecific IMT uptake, which also limits applicability in evaluating the results of treatment.

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment.

A comparison was made between methods for determining ifosfamide (IF), 2- (2DCE) and 3-dechloroethylifosfamide (3DCE) using gas chromatography with nitrogen-phosphorus detection (GC-NPD) versus positive ion electron-impact ion-trap mass spectrometry (GC-MS2). Sample pretreatment involved liquid-liquid extraction with ethyl acetate after adding trofosfamide as internal standard and alkalinization. The GC-NPD was linear, specific, and sensitive for all analytes in the range of 0.0500-100 microg/mL with lower limits of quantification (LLQ) of 0.0500 microg/mL using a 50-microgL plasma sample. The GC-MS2 was linear, specific, and sensitive for IF, 2DCE, and 3DCE in the ranges of 0.250-100, 0.500-25.0, and 0.500-25.0 microg/mL, respectively, with LLQs of 0.250, 0.500, and 0.500 microg/mL. The ranges of accuracy, within-day precision, and between-day precision for analysis of all compounds with GC-NPD did not exceed 93.3% to 105.4%, 8.0% and 9.8%, respectively. The ranges of accuracy, within-day precision, and between-day precision for analysis of all compounds with GC-MS2 did not exceed 86.5% to 99.0%, 9.0% and 12.7%, respectively. In conclusion, GC-NPD proved to be superior to GC-MS2 in sensitivity, detection range, accuracy, and precisions. Therefore GC-NPD is the method of choice for fast un-derivatized determination of IF, 2DCE, and 3DCE in human plasma, and it can readily be used for clinical pharmacokinetic studies and routine monitoring of IF-treated patients in a hospital setting.

Background: Determining the stage of non-small-cell lung cancer often requires multiple preoperative tests and invasive procedures. Whole-body positron-emission tomography (PET) may simplify and improve the evaluation of patients with this tumor., Methods: We prospectively compared the ability of a standard approach to staging (computed tomography [CT], ultrasonography, bone scanning, and, when indicated, needle biopsies) and one involving PET to detect metastases in mediastinal lymph nodes and at distant sites in 102 patients with resectable non-small-cell lung cancer. The presence of mediastinal metastatic disease was confirmed histopathologically. Distant metastases that were detected by PET were further evaluated by standard imaging tests and biopsies. Patients were followed postoperatively for six months by standard methods to detect occult metastases. Logistic-regression analysis was used to evaluate the ability of PET and CT to identify malignant mediastinal lymph nodes., Results: The sensitivity and specificity of PET for the detection of mediastinal metastases were 91 percent (95 percent confidence interval, 81 to 100 percent) and 86 percent (95 percent confidence interval, 78 to 94 percent), respectively. The corresponding values for CT were 75 percent (95 percent confidence interval, 60 to 90 percent) and 66 percent (95 percent confidence interval, 55 to 77 percent). When the results of PET and CT were adjusted for each other, only PET results were positively correlated with the histopathological findings in mediastinal lymph nodes (P<0.001). PET identified distant metastases that had not been found by standard methods in 11 of 102 patients. The sensitivity and specificity of PET for the detection of both mediastinal and distant metastatic disease were 95 percent (95 percent confidence interval, 88 to 100 percent) and 83 percent (95 percent confidence interval, 74 to 92 percent), respectively. The use of PET to identify the stage of the disease resulted in a different stage from the one determined by standard methods in 62 patients: the stage was lowered in 20 and raised in 42., Conclusions: PET improves the rate of detection of local and distant metastases in patients with non-small-cell lung cancer.

Superior vena cava syndrome is most often caused by lung carcinoma. Two cases are described in whom venous obstruction in the superior mediastinum was caused by local vascular fibrosis due to radiotherapy five and seven years earlier. The development of radiation injury to greater vessels is discussed, together with the possibilities for treatment of superior vena cava syndrome.

The aim of the study was to evaluate efficacy and tolerance of epirubicin and gemcitabine as first-line chemotherapy in patients with advanced non-small-cell lung cancer. A phase I study was performed with the combination of escalating doses of epirubicin intravenously on day 1 and a fixed dose of gemcitabine on days 1 and 8 of a 21 -day cycle. Eighteen patients were included in the phase I part of the study before the maximum tolerated dose was found. Dose-limiting toxicity was febrile neutropenia. The phase II part of the study was continued with epirubicin 100 mg m(-2) on day 1 and gemcitabine 1125 mg m(-2) on days 1 and 8 of a 21-day cycle. Forty-three chemotherapy-naive patients were included. The median age of the patients was 60 years (range 26-75). Most patients (74%) were in stage IV. Granulocytopenia CTC grade 4 occurred in 32.5% and thrombocytopenia grade 4 in 11.6% of cycles. Febrile neutropenia occurred in six patients. Non-haematological toxicity was mainly mucositis CTC grade 2 and 3 in 35% of patients. The tumour response rate was 49% (95% confidence interval (CI) 35-63%). The median survival time for the patients was 42 weeks (95% CI 13-69).

Purpose: To evaluate the efficacy of paclitaxel and carboplatin (PC) in small-cell lung cancer (SCLC) patients resistant to cyclophosphamide, doxorubicin, and etoposide (CDE)., Patients and Methods: We performed a phase II study with PC in SCLC patients who relapsed within 3 months after first-line treatment with CDE. Paclitaxel administration (175 mg/m2 by a 3-hour intravenous infusion) was followed by a 30-minute infusion of carboplatin (area under the curve 7; Chatelut formula) once every 3 weeks for five cycles. Dexamethasone, clemastine, and ranitidine were standard premedication before every cycle., Results: Included were 35 patients (median age, 59 years; 16 with limited disease and 19 with extensive disease; Eastern Cooperative Oncology Group performance status of < or = 1; median time off treatment 6 weeks) who were previously treated with CDE (n = 33), oral etoposide (n = 2), and reinduction CDE (n = 15); only one patient had received three CDE treatments of five cycles. The CDE regimen was followed by local thoracic radiotherapy in seven patients. Hematologic toxicity of grade 3 or 4, for leukopenia was 27% and 6%, for thrombocytopenia 21% and 13%, and for anemia 17% and 0%, respectively, for a total of 132 cycles. Two patients had neutropenic fever; no toxic death occurred. Nonhematologic toxicity was paresthesia CTC grade 3, diarrhea grade 4, and myalgia grade 3 in one patient each. Reversible paresthesia (CTC grade 1 and 2) in toes and fingers was reported in 69% of patients. Thirty-four patients were assessable for response: complete response in two patients, partial response in 23 patients, stable disease in eight patients, and progressive disease in one patient (response rate, 73.5%; 95% confidence interval, 59% to 88%). One patient was found to have atypical carcinoid at pathologic review and was excluded. Median time to progression was 21 weeks (range, 3 to 40 weeks). Median survival was 31 weeks (range, 6 to 112 weeks). One-year survival was 9%., Conclusion: Second-line PC in CDE-resistant SCLC patients yields a high response rate and seems non-cross-resistant to CDE. Toxicity was mild in these poor-prognosis patients.