A randomised phase II study of extended pleurectomy/decortication preceded or followed by chemotherapy in patients with early-stage pleural mesothelioma: EORTC 1205.

BACKGROUND: The role of surgery in pleural mesothelioma remains controversial. It may be appropriate in highly selected patients as part of a multimodality treatment including chemotherapy. Recent years have seen a shift from extrapleural pleuropneumonectomy toward extended pleurectomy/decortication. The most optimal sequence of surgery and chemotherapy remains unknown. METHODS: EORTC-1205-LCG was a multicentric, noncomparative phase 2 trial, 1:1 randomising between immediate (arm A) and deferred surgery (arm B), followed or preceded by chemotherapy. Eligible patients (Eastern Cooperative Oncology Group 0-1) had treatment-naïve, borderline resectable T1-3 N0-1 M0 mesothelioma of any histology. Primary outcome was rate of success at 20 weeks, a composite end-point including 1) successfully completing both treatments within 20 weeks; 2) being alive with no signs of progressive disease; and 3) no residual grade 3-4 toxicity. Secondary end-points were toxicity, overall survival, progression-free survival and process indicators of surgical quality. FINDINGS: 69 patients were included in this trial. 56 (81%) patients completed three cycles of chemotherapy and 58 (84%) patients underwent surgery. Of the 64 patients in the primary analysis, 21 out of 30 patients in arm A (70.0%; 80% CI 56.8-81.0%) and 17 out of 34 patients (50.0%; 80% CI 37.8-62.2%) in arm B reached the statistical end-point for rate of success. Median progression-free survival and overall survival were 10.8 (95% CI 8.5-17.2) months and 27.1 (95% CI 22.6-64.3) months in arm A, and 8.0 (95% CI 7.2-21.9) months and 33.8 (95% CI 23.8-44.6) months in arm B. Macroscopic complete resection was obtained in 82.8% of patients. 30- and 90-day mortality were both 1.7%. No new safety signals were found, but treatment-related morbidity was high. INTERPRETATION: EORTC 1205 did not succeed in selecting a preferred sequence of pre- or post-operative chemotherapy. Either procedure is feasible with a low mortality, albeit consistent morbidity. A shared informed decision between surgeon and patient remains essential.

Comparing modeling strategies combining changes in multiple serum tumor biomarkers for early prediction of immunotherapy non-response in non-small cell lung cancer.

BACKGROUND: Patients treated with immune checkpoint inhibitors (ICI) are at risk of adverse events (AEs) even though not all patients will benefit. Serum tumor markers (STMs) are known to reflect tumor activity and might therefore be useful to predict response, guide treatment decisions and thereby prevent AEs. OBJECTIVE: This study aims to compare a range of prediction methods to predict non-response using multiple sequentially measured STMs. METHODS: Nine prediction models were compared to predict treatment non-response at 6-months (n = 412) using bi-weekly CYFRA, CEA, CA-125, NSE, and SCC measurements determined in the first 6-weeks of therapy. All methods were applied to six different biomarker combinations including two to five STMs. Model performance was assessed based on sensitivity, while model training aimed at 95% specificity to ensure a low false-positive rate. RESULTS: In the validation cohort, boosting provided the highest sensitivity at a fixed specificity across most STM combinations (12.9% -59.4%). Boosting applied to CYFRA and CEA achieved the highest sensitivity on the validation data while maintaining a specificity >95%. CONCLUSIONS: Non-response in NSCLC patients treated with ICIs can be predicted with a specificity >95% by combining multiple sequentially measured STMs in a prediction model. Clinical use is subject to further external validation.

Prevalence and Predictors of Physician-Patient Discordance in Prognostic Perceptions in Advanced Cancer.

BACKGROUND: Discordance between physicians' and patients' prognostic perceptions in advanced cancer care threatens informed medical decision-making and end-of-life preparation, yet this phenomenon is poorly understood. We sought to: (1) describe the extent and direction of prognostic discordance, patients' prognostic information preferences in cases of prognostic discordance, and physicians' awareness of prognostic discordance; and (2) examine which patient, physician, and caregiver factors predict prognostic discordance. MATERIALS AND METHODS: Oncologists and advanced cancer patients (median survival ≤12 months; n = 515) from 7 Dutch hospitals completed structured surveys in a cross-sectional study. Prognostic discordance was operationalized by comparing physicians' and patients' perceptions of the likelihood of cure, 2-year mortality risk, and 1-year mortality risk. RESULTS: Prognostic discordance occurred in 20% (likelihood of cure), 24%, and 35% (2-year and 1-year mortality risk) of physician-patient dyads, most often involving patients with more optimistic perceptions than their physician. Among patients demonstrating prognostic discordance, the proportion who preferred not knowing prognosis varied from 7% (likelihood of cure) to 37% (1-year mortality risk), and 45% (2-year mortality risk). Agreement between physician-perceived and observed prognostic discordance or concordance was poor (kappa = 0.186). Prognostic discordance was associated with several patient factors (stronger fighting spirit, self-reported absence of prognostic discussions, an information source other than the healthcare provider), and greater physician-reported uncertainty about prognosis. CONCLUSION: Up to one-third of the patients perceive prognosis discordantly from their physician, among whom a substantial proportion prefers not knowing prognosis. Most physicians lack awareness of prognostic discordance, raising the need to explore patients' prognostic information preferences and perceptions, and to tailor prognostic communication.

Characteristics of patients with advanced cancer preferring not to know prognosis: a multicenter survey study.

BACKGROUND: For some patients with advanced cancer not knowing prognosis is essential. Yet, in an era of informed decision-making, the potential protective function of unawareness is easily overlooked. We aimed to investigate 1) the proportion of advanced cancer patients preferring not to know prognosis; 2) the reasons underlying patients' prognostic information preference; 3) the characteristics associated with patients' prognostic information preference; and 4) the concordance between physicians' perceived and patients' actual prognostic information preference. METHODS: This is a cross-sectional study with structured surveys (PROSPECT). Medical and thoracic oncologists included patients (n = 524), from seven Dutch hospitals, with metastatic/inoperable cancer and an expected median overall survival of ≤ 12 months. For analysis, descriptive statistics and logistic regression models were used. RESULTS: Twenty-five to 31% of patients preferred not to know a general life expectancy estimate or the 5/2/1-year mortality risk. Compared to patients preferring to know prognosis, patients preferring unawareness more often reported optimism, avoidance and inability to comprehend information as reasons for wanting limited information; and less often reported expectations of others, anxiety, autonomy and a sense of control as reasons for wanting complete information. Females (p < .05), patients receiving a further line of systemic treatment (p < .01) and patients with strong fighting spirit (p < .001) were more likely to prefer not to know prognosis. Concordance between physicians' perceived and patients' actual prognostic information preference was poor (kappa = 0.07). CONCLUSIONS: We encourage physicians to explore patients' prognostic information preferences and the underlying reasons explicitly, enabling individually tailored communication. Future studies may investigate changes in patients' prognostic information preferences over time and examine the impact of prognostic disclosure on patients who prefer unawareness.

Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy.

BACKGROUND: This phase I/II study determined the maximal tolerable dose, dose limiting toxicities, antitumor activity, the pharmacokinetics and pharmacodynamics of ruthenium compound NAMI-A in combination with gemcitabine in Non-Small Cell Lung Cancer patients after first line treatment. METHODS: Initial dose escalation of NAMI-A was performed in a 28 day cycle: NAMI-A as a 3 h infusion through a port-a-cath at a starting dose of 300 mg/m(2) at day 1, 8 and 15, in combination with gemcitabine 1,000 mg/m(2) at days 2, 9 and 16. Subsequently, dose escalation of NAMI-A in a 21 day schedule was explored. At the maximal tolerable dose level of this schedule an expansion group was enrolled of which 15 patients were evaluable for response. RESULTS: Due to frequent neutropenic dose interruptions in the third week, the 28 day schedule was amended into a 21 day schedule. The maximal tolerable dose was 300 and 450 mg/m(2) of NAMI-A (21 day schedule). Main adverse events consisted of neutropenia, anemia, elevated liver enzymes, transient creatinine elevation, nausea, vomiting, constipation, diarrhea, fatigue, and renal toxicity. CONCLUSION: NAMI-A administered in combination with gemcitabine is only moderately tolerated and less active in NSCLC patients after first line treatment than gemcitabine alone.

(18)F-fluorodeoxyglucose positron emission tomography versus computed tomography in predicting histopathological response to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in resectable non-small cell lung cancer.

PURPOSE: To prospectively evaluate diagnostic computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for identification of histopathologic response to neoadjuvant erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with resectable non-small cell lung cancer (NSCLC). METHODS: This study was designed as an open-label phase 2 trial, performed in four hospitals in the Netherlands. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. CT and FDG-PET/CT were performed at baseline and after 3 weeks of treatment. CT was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. FDG-PET/CT, tumor FDG uptake, and changes were measured by standardized uptake values (SUV). Radiologic and metabolic responses were compared to the histopathological response. RESULTS: Sixty patients were enrolled onto this study. In 53 patients (22 men, 31 women), the combination of CT, FDG-PET/CT, and histopathological evaluation was available for analysis. Three patients (6 %) had radiologic response. According to European Organisation for Research and Treatment of Cancer (EORTC) criteria, 15 patients (28 %) showed metabolic response. In 11 patients, histopathologic response (≥50 % necrosis) was seen. In predicting histopathologic response, relative FDG change in SUVmax showed more SUVmax decrease in the histopathologic response group (-32 %) versus the group with no pathologic response (-4 %) (p = 0.0132). Relative change in tumor size on diagnostic CT was similar in these groups with means close to 0. CONCLUSIONS: FDG-PET/CT has an advantage over CT as a predictive tool to identify histopathologic response after 3 weeks of EGFR-TKI treatment in NSCLC patients.

Prognostic Value of Nivolumab Clearance in Non-Small Cell Lung Cancer Patients for Survival Early in Treatment.

INTRODUCTION: Immune checkpoint inhibitors improved survival of advanced stage non-small cell lung cancer patients, but the overall response rate remains low. A biomarker that identifies non-responders would be helpful to allow treatment decisions. Clearance of immune checkpoint inhibitors is related to treatment response, but its prognostic potential early in treatment remains unknown. Our primary aim was to investigate the prognostic potential of nivolumab clearance for overall survival early in treatment. Our secondary aim was to evaluate the performance of nivolumab clearance as prognostic biomarker. PATIENTS AND METHODS: Individual estimates of nivolumab clearances at first dose, 6 and 12 weeks after treatment initiation were obtained via nonlinear mixed-effects modelling. Prognostic value of nivolumab clearance was estimated using univariate Cox regression at first dose and for the ratios between 6 and 12 weeks to first dose. The performance of nivolumab clearance as biomarker was assessed by calculating sensitivity and specificity. RESULTS: During follow-up of 75 months, 69 patients were included and 865 died. Patients with a nivolumab clearance ≥ 7.3 mL/h at first dose were more likely to die compared to patients with a nivolumab clearance < 7.3 mL/h at first dose (hazard ratio [HR] = 3.55, 955 CI 1.75-7.20). The HRs of dose nivolumab clearance ratios showed similar results with a HR of 3.93 (955 CI 1.66-9.32) for 6 weeks to first-dose clearance ratio at a 0.953 cut-point and a HR of 2.96 (955 CI 1.32-6.64) for 12 weeks to first-dose clearance ratio at a cut-point of 0.814. For nivolumab clearance at all early time points, sensitivity was high (≥ 0.95) but specificity was low (0.11-0.29). CONCLUSION: Nivolumab clearance is indicative of survival early in treatment. Our results encourage to further assess the prognostic potential of immunotherapy clearance.

Identification of protein biomarkers for prediction of response to platinum-based treatment regimens in patients with non-small cell lung cancer.

The majority of patients with resected stage II-IIIA non-small cell lung cancer (NSCLC) are treated with platinum-based adjuvant chemotherapy (ACT) in a one-size-fits-all approach. However, a significant number of patients do not derive clinical benefit, and no predictive patient selection biomarker is currently available. Using mass spectrometry-based proteomics, we have profiled tumour resection material of 2 independent, multi-centre cohorts of in total 67 patients with NSCLC who underwent ACT. Unsupervised cluster analysis of both cohorts revealed a poor response/survival sub-cluster composed of ~ 25% of the patients, that displayed a strong epithelial-mesenchymal transition signature and stromal phenotype. Beyond this stromal sub-population, we identified and validated platinum response prediction biomarker candidates involved in pathways relevant to the mechanism of action of platinum drugs, such as DNA damage repair, as well as less anticipated processes such as those related to the regulation of actin cytoskeleton. Integration with pre-clinical proteomics data supported a role for several of these candidate proteins in platinum response prediction. Validation of one of the candidates (HMGB1) in a third independent patient cohort using immunohistochemistry highlights the potential of translating these proteomics results to clinical practice.

Germline polymorphisms in patients with advanced nonsmall cell lung cancer receiving first-line platinum-gemcitabine chemotherapy: a prospective clinical study.

BACKGROUND: The authors assessed the impact of germline polymorphisms on clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC) who received platinum-gemcitabine (PG) chemotherapy. METHODS: In total, 137 patients with stage IIIB/IV NSCLC were included who received first-line PG chemotherapy (74% of patients received cisplatin, and 26% received carboplatin). Twenty-three germline polymorphisms that were identified in peripheral blood samples were analyzed for progression-free survival (PFS), treatment response, overall survival (OS), and toxicity. RESULTS: The median PFS was 5.8 months, the median OS was 10.2 months, and 44 patients (32%) had a partial treatment response. Carriers of the excision repair cross-complementation group 1 (ERCC1) mutant thymine (T) allele had a lower treatment response rate (29% vs 52%; P = .02), shorter PFS (adjusted hazard ratio [HR], 1.60; P = .04), and shorter OS (adjusted HR, 1.54; P = .05) compared with carriers of the wild-type cytosine/cytosine (CC) genotype. The xeroderma pigmentosum group A member 10 (XPD10) mutant adenine (A) allele (adjusted HR, 0.64; P = .04) and the x-ray cross-complementing group 1 (XRCC1) mutant guanine (G) allele (adjusted HR, 0.51; P = .02) also were independent predictors of OS. Carriers of the mutant adenosine triphosphate-dependent DNA helicase Q1 (RECQ1) C allele or the mutant cytidine deaminase (CDA) C allele were more likely to experience severe leukocytopenia (26% vs 10% [P = .03] and 28% vs 11% [P = .02], respectively) compared with wild-type genotype carriers. Patients who carried the homozygous mutant glutathione S-transferase π 1(GSTP1) GG genotype were at considerable risk for severe platinum-associated polyneuropathy (18% vs 3% in wild-type vs heterozygous mutant patients, respectively; P = .01). CONCLUSIONS: To the authors' knowledge, this is the first prospective study to date in patients with advanced NSCLC describing predictive germline polymorphisms not only for the clinical activity of PG chemotherapy (ERCC1, XPD10) but also for its toxicity (GSTP1, RECQ1, CDA). Nonplatinum-containing chemotherapy in carriers of the ERCC1 T allele or the XPD10 G allele should be studied prospectively.

Local treatment of pulmonary metastases: from open resection to minimally invasive approach? Less morbidity, comparable local control.

BACKGROUND: The level of evidence for efficacy of local treatment of pulmonary metastases is low; therefore, complication rates should be minimized. Minimally invasive techniques may have the potential to reduce morbidity but potentially lead to more local and/or ipsilateral recurrences. The objective of this study was to evaluate the introduction of a new treatment strategy incorporating the increased use of video-assisted thoracic surgery (VATS) and radiofrequency ablation (RFA), weighing complications against recurrence rates. METHODS: We retrospectively reviewed results of all local treatment of pulmonary metastases in the Netherlands Cancer Institute from 2002 to 2007. Each of 158 identified interventions was analyzed separately to retrieve procedure-related data. Overall survival data were analyzed per patient. To evaluate the introduction of a strategy incorporating minimally invasive techniques, the study period was split in two (before and after the introduction of this strategy in July 2004). RESULTS: In Strategy I, 47 interventions (2 VATS, no RFA) were performed in 37 patients; in Strategy II 111 interventions (51 VATS and RFA) in 86 patients. Metastases of a variety of primary tumors were treated. Median hospital stay was shorter (5 vs. 7 days) and procedure-related morbidity was less with Strategy II (p < 0.01). Time-to-recurrence rates were comparable (p = 0.18), as were local and ipsilateral recurrence rates within 3 years (p = 0.72). Estimated overall 3-year survival was 59% for patients treated with Strategy I and 54% with Strategy II. CONCLUSIONS: Increased use of minimally invasive techniques for local treatment of pulmonary metastatic disease is associated with low morbidity, without apparent reduction in (local) disease control.

Modeling strategies to analyse longitudinal biomarker data: An illustration on predicting immunotherapy non-response in non-small cell lung cancer.

Serum tumor markers acquired through a blood draw are known to reflect tumor activity. Their non-invasive nature allows for more frequent testing compared to traditional imaging methods used for response evaluations. Our study aims to compare nine prediction methods to accurately, and with a low false positive rate, predict progressive disease despite treatment (i.e. non-response) using longitudinal tumor biomarker data. Bi-weekly measurements of CYFRA, CA-125, CEA, NSE, and SCC were available from a cohort of 412 advanced stage non-small cell lung cancer (NSCLC) patients treated up to two years with immune checkpoint inhibitors. Serum tumor marker measurements from the first six weeks after treatment initiation were used to predict treatment response at 6 months. Nine models with varying complexity were evaluated in this study, showing how longitudinal biomarker data can be used to predict non-response to immunotherapy in NSCLC patients.

Immunotherapy in non-small-cell lung carcinoma: from inflammation to vaccination.

The treatment of non-small-cell lung cancer (NSCLC) on an immunologic basis has been both welcomed and rejected in the past decades. Negative outcomes of immunotherapy studies have been commonly explained by the poor immunogenicity of tumors arising in the lungs. On the other hand, there is an overwhelming body of literature on the importance of the inflammatory and immune responses in lung carcinogenesis. Interaction between inflammatory cells and tumor cells facilitates pro-cancer processes, such as angiogenesis and tumor cell migration. In addition to these interactions, antigen-specific antitumor responses are overtly present in NSCLC. These data suggest a role for immunotherapy in the treatment of NSCLC when properly applied. Targeting the antigen-specific immune response with modern vaccines has shown promising results. In this review the inflammatory process in NSCLC is described. The relevance of the specific immune response and immunotherapy studies and potential targets for future immunotherapy are discussed.

Transesophageal endoscopic ultrasound with fine needle aspiration in the preoperative staging of malignant pleural mesothelioma.

PURPOSE: Surgical resection as part of a multimodality approach in malignant pleural mesothelioma (MPM) has a high morbidity and mortality. Because mediastinal lymph node (MLN) metastases are a negative prognostic factor, preoperative staging is of paramount importance. Transesophageal endoscopic ultrasound with real-time guided fine needle aspiration (EUS-FNA) enables accurate MLN staging in lung cancer. EXPERIMENTAL DESIGN: The feasibility and yield of EUS-FNA in MLN staging were prospectively analyzed in patients with presumed early-stage MPM considered for multimodality therapy. MLN reference pathology was defined by either pathologic staging or the formal demonstration of malignant cells by either EUS-FNA or mediastinoscopy. RESULTS: Thirty-two consecutive patients (81% males; median age, 61 years) with proven MPM underwent EUS-FNA. In 11 (34%) patients, a negative EUS-FNA or mediastinoscopy was not confirmed by surgical MLN dissection because of clinical deterioration or disease progression. In 21 (66%) patients, a formal pathology of the MLN was obtained and staging with EUS-FNA was positive in 4 (19%). Mediastinoscopy did not result in a greater yield of MLN metastasis as compared with EUS-FNA. Thoracotomy with complete lymph node dissection was done in 17 (81%). The overall prevalence of MLN metastasis was 24%, and the sensitivity of EUS-FNA was 80% (95% confidence interval, 28-99%) with a specificity of 100% (95% confidence interval, 79-100%). One patient had esophageal perforation related to EUS-FNA. CONCLUSIONS: EUS-FNA is feasible and sensitive for MLN staging in patients with MPM who are candidate for multimodality treatment. These data warrant further evaluation.

Crizotinib-induced fatal fulminant liver failure.

Herein we describe a case of a 62-year-old female in good clinical condition with non-small-cell lung cancer who was treated with crizotinib. After 24 days of crizotinib therapy she presented with acute liver failure. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from normal prior to crizotinib start to 2053 IU/L and 6194 IU/L, respectively. Total bilirubin and prothrombin time (PT-INR) increased up to 443 IU/L and 5.33, respectively, and symptoms of hepatic encephalopathy and hepatorenal syndrome emerged. Despite crizotinib discontinuation and intensive supportive therapy, the patient died 40 days after treatment with crizotinib was initiated due to acute liver failure with massive liver cell necrosis.

Pulmonary function changes after radiotherapy in non-small-cell lung cancer patients with long-term disease-free survival.

PURPOSE: To evaluate the changes in pulmonary function after high-dose radiotherapy (RT) for non-small-cell lung cancer in patients with a long-term disease-free survival. METHODS AND MATERIALS: Pulmonary function was measured in 34 patients with inoperable non-small-cell lung cancer before RT and at 3 and 18 months of follow-up. Thirteen of these patients had a pulmonary function test (PFT) 36 months after RT. The pulmonary function parameters (forced expiratory volume in 1 s [FEV(1)], diffusion capacity [T(lcoc)], forced vital capacity, and alveolar volume) were expressed as a percentage of normal values. Changes were expressed as relative to the pre-RT value. We evaluated the impact of chronic obstructive pulmonary disease, radiation pneumonitis, mean lung dose, and PFT results before RT on the changes in pulmonary function. RESULTS: At 3, 18, and 36 months, a significant decrease was observed for the T(lcoc) (9.5%, 14.6%, and 22.0%, respectively) and the alveolar volume (5.8%, 6.6%, and 15.8%, respectively). The decrease in FEV(1) was significant at 18 and 36 months (8.8% and 13.4%, respectively). No recovery of any of the parameters was observed. Chronic obstructive pulmonary disease was an important risk factor for larger PFT decreases. FEV(1) and T(lcoc) decreases were dependent on the mean lung dose. CONCLUSION: A significant decrease in pulmonary function was observed 3 months after RT. No recovery in pulmonary function was seen at 18 and 36 months after RT. The decrease in pulmonary function was dependent on the mean lung dose, and patients with chronic obstructive pulmonary disease had larger reductions in the PFTs.

Improving the specificity of fluorescence bronchoscopy for the analysis of neoplastic lesions of the bronchial tree by combination with optical spectroscopy: preliminary communication.

Detection of malignancies of the bronchial tree in an early stage, such as carcinoma in situ (CIS), augments the cure rate considerably. It has been shown that the sensitivity of autofluorescence bronchoscopy is better than white light bronchoscopy for the detection of CIS and dysplastic lesions. Autofluorescence bronchoscopy is, however, characterized by a low specificity with a high rate of false positive findings. In the present paper we propose to combine autofluorescence bronchoscopy with optical spectroscopy to improve the specificity of autofluorescence imaging, while maintaining the high sensitivity. Standard autofluorescence bronchoscopy was used to find suspect lesions in the upper bronchial tree, and these lesions were subsequently characterized spectroscopically using a custom made fiberoptic probe. Autofluorescence spectra of the lesions as well as reflectance spectra were measured. We will show in this preliminary report that the addition of either of these spectroscopic techniques decreases the rate of false positives findings, with the best results obtained when both spectroscopic modalities are combined.

Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: a case report.

Here we describe a case of striking tumor flare after start of treatment with sorafenib and metformin as part of a phase II clinical trial. Previous reports have described a paradoxal activation of the MAPK pathway after treatment with a weak RAF inhibitor. This mechanism is based on inhibition of a negative feedback loop to upstream effectors of RAF and subsequently increased stimulation of the RAS-RAF-MEK-ERK (MAPK) pathway. We suggest that sorafenib may contribute to tumor progression through this mechanism and clinicians should be aware of this phenomenon when treating NSCLC patients with sorafenib.

Concentrations of Erlotinib in Tumor Tissue and Plasma in Non-Small-Cell Lung Cancer Patients After Neoadjuvant Therapy.

INTRODUCTION: Tumors might not optimally respond to systemic therapy if minimal effective levels are not reached within the tumor. Erlotinib has mainly been studied in the adjuvant or palliative setting and, therefore, little is known about erlotinib tumor penetration. The purpose of this exploratory study was to investigate lung tumor tissue erlotinib concentrations after neoadjuvant therapy for non-small-cell lung cancer. PATIENTS AND METHODS: Patients were treated preoperatively with erlotinib (150 mg once daily for 3 weeks) up to 48 hours before surgery. Plasma samples were collected during treatment. Surgical resection involved radical resection of the lung tumor and tumor biopsies were frozen directly after surgery. Erlotinib and O-desmethyl erlotinib concentrations in lung tumor tissue and predose plasma were determined using high performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: Thirteen evaluable patients were included. The mean plasma and lung tumor tissue erlotinib levels were 1222 ng/mL (SD, 678) and 149 ng/g (SD, 153), respectively. In 2 individual patients, erlotinib and O-desmethyl erlotinib concentrations in lung tumor tissue were detectable up to 13 days and 7 days after erlotinib intake, respectively. Mean erlotinib tissue concentrations extrapolated to a time point directly after intake of erlotinib were approximated at > 200 ng/g tissue, which is greater than the reported half maximal inhibitory concentration (IC50) of wild type epidermal growth factor receptor (EGFR) (183 ng/mL). CONCLUSION: No strong accumulation of erlotinib in lung tumor tissue was observed. Nevertheless, extrapolated intratumoral concentrations during erlotinib therapy were greater than the IC50 of wild type EGFR.

Curative radiotherapy for a second primary lung cancer arising after pneumonectomy -- techniques and results.

BACKGROUND AND PURPOSE: Only limited data exist on the outcome of curative radiotherapy in patients who develop a second primary lung tumour after pneumonectomy. The treatment of eight such patients is described. MATERIALS AND METHODS: The case records of patients who underwent curative radiotherapy for stage I non-small cell lung cancer after a previous pneumonectomy were reviewed. Treatment was delivered using 3D external radiotherapy to a dose of 50-70 Gy, in once-daily fractions of 2-2.5 Gy. An endobronchial brachytherapy boost was used in three patients. Original treatments were re-planned in an attempt to minimize the volume of irradiated lung. RESULTS: A complete remission was achieved in five (of six) evaluable patients, but two patients subsequently developed a local relapse. All patients survived for a minimum of 1 year after treatment. Only one patient developed significant (grade 2) radiation pneumonitis. When treatments were re-planned to optimize beam arrangements, and when customized blocks were used, the mean lung volume receiving > or = 20 Gy (calculated for 70 Gy) decreased from 24.6+/-4.1 (range, 18-31%) to 17.3+/-5.1% (range, 12-26%). Similarly, the radiation conformity index improved from 0.44+/-0.11 to 0.61+/-0.06. CONCLUSIONS: Involved-field radiotherapy can be curative in patients who develop a new lung tumour after pneumonectomy. Recent advances in defining target volumes, treatment planning and delivery are likely to improve upon these results.

Raman microspectroscopic mapping studies of human bronchial tissue.

Characterization of the biochemical composition of normal bronchial tissue is a prerequisite for understanding the biochemical changes that accompany histological changes during lung cancer development. In this study, 12 Raman microspectroscopic mapping experiments are performed on frozen sections of normal bronchial tissue. Pseudocolor Raman images are constructed using principal component analysis and K-means cluster analysis. Subsequent comparison of Raman images with histologic evaluation of stained sections enables the identification of the morphologic origin (e.g., bronchial mucus, epithelium, fibrocollagenous stroma, smooth muscle, glandular tissue, and cartilage) of the spectral features. Raman spectra collected from the basal side of epithelium consistently show higher DNA contributions and lower lipid contributions when compared with superficial epithelium spectra. Spectra of bronchial mucus reveal a strong signal contribution of lipids, predominantly triolein. These spectra are almost identical to the spectra obtained from submucosal glands, which suggests that the bronchial mucus is mainly composed of gland secretions. Different parts of fibrocollagenous tissue are distinguished by differences in spectral contributions from collagen and actin/myosin. Cartilage is identified by spectral contributions of glycosaminoglycans and collagen. As demonstrated here, in situ analysis of the molecular composition of histologic structures by Raman microspectroscopic mapping creates powerful opportunities for increasing our fundamental understanding of tissue organization and function. Moreover, it provides a firm basis for further in vitro and in vivo investigations of the biochemical changes that accompany pathologic transformation of tissue.