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Abstract
Background The National Lung Screening Trial (NLST) demonstrated that screening with low-dose CT compared to screening with chest radiography reduced lung cancer mortality. Several cost-effectiveness analyses of lung cancer screening have been performed and will be reviewed in the presentation. A team of investigators from the NLST developed detailed data collection instruments to prospectively collect information about the entire screening process and cost expenditures while the trial was ongoing with the specific intention of performing a cost-effectiveness analysis after conclusion of the study. The team has concluded this research and now reports the cost-effectiveness of CT screening within the setting of the NLST. Methods Mean life-years, quality-adjusted life-years (QALYs), and mean costs per person and incremental cost effectiveness ratios for three alternative screening strategies using the societal perspective were estimated. CT screening was compared to chest radiographic and no screening, assuming that chest radiographic screening was ineffective and only contributed costs directly related to screening, not lung cancer treatment. Life-years were based on all observed deaths within the trial and projected survival of those alive at the end. Quality adjustments were derived from a subset of participants selected for quality of life surveys. Costs were based on utilization rates, derived from a subset of participants selected for medical record abstraction, and Medicare reimbursements. Life-years, QALYs, and costs were discounted at 3% per year. Uncertainty was assessed using bootstrap sampling of participants, subset analyses based on age, gender, smoking history, and lung cancer risk, and one-way sensitivity analyses on several assumptions. Results In the base case, the CXR screening strategy was dominated. Compared to no screening, CT screening costs $1441 per person and provided an additional 0.0217 QALYs per person; the incremental cost effectiveness ratio was $67,000 per QALY gained. Conclusions CT screening for lung cancer as performed in the NLST appears to be cost effective under a wide range of assumptions. Whether screening outside the trial will be cost effective will depend on who is selected for screening, how screening is performed, and how screenees are subsequently managed. As the United States Preventive Services Task Force has given a draft recommendation of “B” for lung cancer screening, it will need to be covered without a deductible by insurance companies upon implementation of the Patient Protection and Affordable Care Act. Therefore, appropriate implementation of screening is critical. (Funded by the National Cancer Institute; National Lung Screening Trial ClinicalTrials.gov number, NCT00047385.)

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RECIST AND PERCIST CRITERIA FOR RESPONSE TO THERAPY Background We need to accurately assess response to therapy for our patients with cancer, early in their treatment. Because modern treatments are costly (up to $10,000 per month), it is important to determine whether the current regimen is being effective and whether the patient will respond well with this treatment. If judged effective, stay the course. If current treatment is not being effective, then one could change management early, thus saving costs, avoiding unnecessary toxicities and improving quality of life. Anatomic Methods Tumor shrinkage has long been the standard for judging response to therapy since Moertel et al. published studies in 1976, comparing measurements of palpable tumors. WHO: In 1979 the World Health Organization (WHO) Handbook established imaging criteria for following solid tumors during therapy. Response was judged by tumor shrinkage. Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were defined. Time to tumor progression (TTP), and progression free survival (PFS) defined when the disease recurred or progressed, including death in PFS. Measurable disease was defined with bidimensional tumor measurements, utilizing the product of longest diameter (LD) and short axis (SAX). RECIST 1.0: In 2000 the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute (NCI) task force published imaging criteria as the Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines. Measurable disease was defined unidimensionally, utilizing the LD. The LD of the target lesions was summed. CR: complete disappearance of all lesions. PR: ≥30% decrease of the sum. PD: ≥20% increase of the sum. For nontarget lesions, CR: complete resolution of all lesions; PD: unequivocal progression, or appearance of new lesions; SD: essentially stable, nontarget lesions such as pleural effusion. RECIST 1.1: Revised in 2009. Measurable disease defined unidimensionally, with the LD, except for lymph nodes in which the SAX is measured and must be ≥15mm at baseline. Normal lymph nodes defined as ≤10mm SAX. The SAX of the target lymph nodes is added to the sum of the LD of other target lesions. With conventional techniques (such as CXR or palpable lesions), target lesions need to be ≥20mm at baseline, or ≥10mm for spiral CT. CR: complete resolution. PR: ≥30% decrease of the sum. PD: ≥20% increase of the sum. For nontarget lesions, CR: complete disappearance, such as effusions or lymphangietic tumor. PD: “unequivocal” progression, or appearance of new lesions. PD can also be new “PET positive” lesions. Biomarkers We currently have several clinically accepted biomarkers for evaluating active tumors: serum thyroglobulin (TG) for thyroid cancer, prostate specific antigen (PSA) for prostate cancer, and CA-125 for ovarian cancer. With the advent of personalized medicine, other individual biomarkers, cell markers and genetic makers for a tumor are increasingly utilized and may require biopsy to evaluate evolving tumor mutations and chemo-resistance. New biomarkers include (HER2) for breast cancer, and KRAS gene mutations for epidermal growth factor receptor (EGFR) in colorectal cancer and lung cancer. PET-CT with FDG has also become an established imaging biomarker for hypermetabolic tumor activity. Functional Methods Functional methods for judging tumor response include dynamic contrast enhancement (DCE) with CT or MRI, MR spectroscopy (MRS), MR diffusion weighted imaging (DWI), ultrasound contrast enhancement, and optical coherence techniques. DCE is well accepted for GIST tumors and is being studied for lung cancer and breast cancer at UC Davis. Molecular Methods As early as 1990, gallium-67 was utilized with gamma cameras and then SPECT, for judging tumor response in lymphomas and Hodgkin’s disease, and to determine tumor activity if CT showed residual masses. In 2007, the Harmonization Criteria were established for judging tumor response with CT and PET-CT in malignant lymphomas and essentially replaced gallium. PET-CT with flourine-18 fluorodeoxyglucose (FDG) has become clinical standard-of-care in the staging and follow-up of many tumors, including lung cancer, esophageal cancer, head and neck cancers, brain tumors, lymphomas, GIST tumors (Choi criteria, 2007), colorectal cancer, melanoma, cervical and ovarian cancers. PET-CT is a quantitative technology but is often used with qualitative evaluation, comparing tumor uptake to background, liver or blood pool activity. Viewing the whole body MIP (Maximum Intensity Projection) images can often quickly determine whether the primary lesion and metastatic lesions have greatly increased or decreased in number or metabolic activity. However, quantitative techniques are more objective and likely more precise in judging response to therapy. Quantitative techniques include measuring various forms of Standard Uptake Value (SUV) and total glycolytic volume (TGV). The same acquisition principles of PET-CT with FDG are also being studied for other radiopharmaceuticals such as F-18-fluorothymidine (FLT) for DNA synthesis, F-18-fluoroethyltyrosine (FET) for amino acid metabolism, F-18-fluoromisonidazole for hypoxia imaging, and numerous other PET radiotracers. PERCIST: In 2009, Wahl et al. published a landmark article for PET-CT, “From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors”. PERCIST (Positron Emission tomography Response Criteria In Solid Tumors) is a set of recommendations to help make PET-CT even more quantitative and more precise. Current recommendations involve stringent quality control for equipment, software standardization, standard dosing, consistent timing from injection to acquisition, SUV peak rather than SUV max, SUL (SUV with lean body mass) and standardized ROI shape and size. Current recommendation is for a 1 cm[3], spherical ROI placed within the most hypermetabolic area of the tumor (SUV peak). Setting the required number of lesions and judging the summed response are still being evaluated. Conclusions RECIST 1.1 criteria and anatomic measurements will continue to play an important central role in clinical trials and for individual patients. PERCIST criteria are evolving and will slowly be introduced in carefully planned clinical trials. PET-CT with FDG has been proven to judge tumor response sooner than anatomic techniques alone, and it is thought that PERCIST criteria will help decrease the costs and duration of clinical trials, as well as improve the quality of life by decreasing prolonged exposures to ineffective treatments and associated toxicities.

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Patient-derived xenotransplant (PDX) models are generated by engrafting human tumor material directly from surgery or biopsy into an immune-compromised mouse without any intervening in vitro culturing. Previous efforts to accomplish this were hampered by poor tumor “take rates” of all but the highest grade tumors, limiting the spectrum of cancer types available for study. Several technical advances have led to improved model formation, including the advent of the NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mouse by The Jackson Laboratories: a new immunodeficient strain that, in addition to a compromised complement system, have defective dendritic cell and macrophage activity, lack mature T and B cells, and have no functional NK cells. This strain has demonstrated high rates of engraftment of a wide variety of tumor types, with the resulting xenografts retaining the tumor heterogeneity and oncogenic driver activity of the patient’s tumor; thus providing a model system that more closely reflects what is seen in the clinic. The University of California, Davis Comprehensive Cancer Center and The Jackson Laboratory have collaborated to establish over 50 fully functional NSCLC PDX models. Testing to date has demonstrated a high fidelity between the contributing patient tumor and the resultant PDX model (at passages 1 and 2) in terms of driving mutations, histology and treatment response. Models developed from tumors known to harbor alterations in EGFR, KRAS or ALK all retain the exact mutational characteristics of the donor tumor. Additionally, these models clearly recapitulate the tumor histologic characteristics and grade of their donors. Squamous cell carcinoma PDX models in this panel have a high incidence of p53 mutations, with several models harboring PIK3CA or PTEN mutations, amplification of PIK3CA and FGFR1. KRAS-mutant models have a high incidence of KRAS and MYC amplification. EGFR-mutant positive adenocarcinomas include models derived from patient tumors prior to or following acquisition of resistance to erlotinib, and in models tested to date recapitulate the clinical results of the contributing patient when treated with the matching therapy. By the third passage, a large number of matched sister models can be generated, sufficient for multi-armed therapeutic testing with an n of 10 or more per arm. Additionally, short-term molecular effects of targeted agents, particularly kinase inhibitors, can easily be measured. Inhibition of drug target and the resultant downstream effects on kinase pathways have already been documented in ongoing studies (Mack et al, WCLC 2013), granting unique insight into drug activity, resistance and cellular compensatory effects. Such studies provide a rational basis for determining appropriate therapeutic combinations of signal transduction inhibitors and receptor tyrosine kinase inhibitors to achieve complete signaling blockade. Similarly, PDX models should aid in identification of targeted strategies to improve activity of chemotherapy. The use of early passage (or passage 0) PDX models as “avatars” for patient response to therapy is also under investigation, although the parameters in which models can be treated in a time-frame sufficient for patients with advanced NSCLC need to be determined. In summary, the PDX platform, with its high degree of fidelity to patient tumors and minimized culture-induced artifacts, should significantly improve the predictive ability of preclinical modeling in the era of personalized therapy.

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Most patients affected by malignant pleural mesothelioma (MPM) are candidates for chemotherapy during the course of the disease, as single modality treatment or within the context of a multimodality approach. Following the results of a large phase III trial, the combination of cisplatin and pemetrexed has become the preferred first-line chemotherapy, although there is also evidence for the activity of the combination with carboplatin. Unfortunately, nearly all MPM patients progress during or after first-line treatment. Second-line therapies are being increasingly used in the clinical practice because patients are frequently still in good clinical conditions at the time of disease progression. However, the role of these treatments in MPM is unproven, and the optimal regimens still remain to be defined. In pemetrexed-naïve patients, data from a randomized trial vs. best supportive care suggest the use of single-agent pemetrexed as a standard second-line treatment. This evidence is supported also by the results of the Expanded Access Programs. To date, there is no standard approach for pemetrexed-pre-treated patients. Several phase II and a few phase III trials have been performed or are ongoing, and this remains a field of active research. Unfortunately, studies available until now have frequently severe limitations, due to the small number and to the heterogeneity of patients included, and often to the design of the studies themselves. In selected cases with a prolonged response to first-line pemetrexed-containing chemotherapy (less than 25% of the whole population of MPM patients treated in first-line), re-treatment with a pemetrexed-based regimen should be considered, based on preliminary evidence reported in small case series. Clinicians should be aware of the risk of hypersensitivity reactions when carboplatin is used in combination with pemetrexed in the re-treatment setting. For the remaining patients the evidence is still limited. Targeted therapies with agents such as EGFR and PDGFR inhibitors, anti-angiogenic compounds, and histone-deacetylase inhibitors have so far achieved disappointing results. Trials with small molecules or monoclonal antibodies that target different molecular pathways are ongoing. Patients should be encouraged to participate in these trials. When a trial is not available or patients are not eligible for an experimental approach, second-line chemotherapy can be a reasonable option for palliation. Gemcitabine and vinorelbine are the most commonly administered agents. However, prospective studies in this setting are sparse, and most evidence comes from retrospective reports. Gemcitabine has been studied mainly in combination with other compounds in small studies. Overall, all these studies showed a modest activity, with a response rate of 10% or less and a disease control (including also stable disease) in about half of patients. The incidence of severe toxicity was low, and mainly related to hematological adverse events. Vinorelbine has been studied in the second-line setting mainly as a single agent. There are at least 4 studies available, 2 of them with a retrospective design. These studies are difficult to compare, because of different patient selection and drug schedules. In the largest study patients were pretreated with various chemotherapy regimens, including pemetrexed-based regimens, while in the other studies all patients were pemetrexed-pretreated. Two studies included also patients treated beyond second line, while the others were pure second-line trials. Treatment schedules were different, and this was reflected by the higher hematological toxicity in studies with the higher vinorelbine dose-intensity. Overall, response rate ranged from 0 to 15%, with disease control rates variable according to patient selection. When gemcitabine and vinorelbine were used in combination, no survival benefit was observed as compared to single-agent chemotherapy, with a higher (mainly hematological) toxicity. In conclusion, evidence for a benefit of second-line chemotherapy in MPM patients is weak, and should be confirmed in prospective studies. A few trials with new chemotherapeutic compounds (e.g. trabectedin) are ongoing. Ideally, future second-line trials in MPM should be designed as at least randomized phase II trial and according to strict eligibility criteria, mainly as far as pre-treatment is concerned (prior regimens and numbers of treatment lines). Patients should be stratified according to the outcome of first-line therapy and to known prognostic factors (like EORTC prognostic score). Time-related events (median PFS or 3-month PFS) should be the primary endpoints. Finally, second-line setting is the ideal field for high-quality correlative studies aimed to identify the patients who will benefit from treatment, and to improve the knowledge of MPM biology.

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Although recent development of minimally invasive procedures contributed significantly to reduce of postoperative complications, as the population continues to age, as more patients receive induction therapies, and as more patients are immunocompromised, complications will continue to increase. Although many complications can be treated medically, some complications require another round of surgery. Postoperative complications after lung cancer surgery can take place both in early and late postoperative periods. As a matter of fact, major surgical errors during the surgery can result in mortality or major morbidity. Hence, the surgery for complications of surgery should begin with prevention of the intraoperative event during the initial surgery. Intraoperative complications During the major lung resection, various kinds of errors can take place. Poor surgical technique can cause injuries of the pulmonary vasculature as well as of the bronchus. The risk of intraoperative technical complication can occur either during VATS or thoracotomy procedures. However, it is more difficult to control in VATS. Minor bleeding can be easily controlled trough VATS. However, once a major vascular injury occurs, the bleeding focus should be compressed, and a prompt thoracotomy should be made. Any bronchial injuries should be detected during the surgery and appropriately fixed. Bleeding can also occur from the pulmonary parenchyma, especially after wedge resection in patients whose pulmonary arterial pressure is increased. For such patients, the staple lines should be oversewed meticulously as the elevated pulmonary arterial pressure may cause postoperative bleeding. Sometimes, lack of understanding of variations of intrathoracic anatomy can cause serious complications. Such structural variations should be acknowledged preoperatively by carefully reviewing the CT scans. According to a report from a dedicated thoracic surgical center, the catastrophic complications took place in 1% of patients, including main pulmonary arterial and main pulmonary venous transection requiring reanastomosis, unplanned pneumonectomies, unplanned bilobectomy, tracheoesophageal fistula, membranous airway injury to the bronchus intermedius, complete staple line disruption of the inferior pulmonary vein, injury to the azygos/superior vena cava junction, and splenectomy. The third and perhaps the most important cause of intraoperative complication is negligence. Thus, establishment of standardized surgical protocol is mandatory in training hospital. Postoperative complications Common postoperative complications such as prolonged air leak, atrial fibrillation, aspiration and pneumonia can be treated by medical methods. The early postoperative course is often compromised by chylothorax. The initial treatment is to give nothing by mouth and wait until the chest tube drainage decreases. However, if the chylothorax persists, reoperation with duct ligation should be considered. Empyema is an uncommon complication after pulmonary resection. The key treatment principle is control of the pleural space, which can be established by lung expansion. If there is any question of a BPF, repeat thoracotomy with muscle or omental harvesting is mandatory to drain the empyema and to decorticate the lung, and to buttress the open bronchus. Superficial wound infections are managed with antibiotics, drainage, and local wound care. Management options of deep sternal infection include sternal debridement or sternectomy, prolonged open wound care or irrigation, muscle flap reconstruction, or some combination of these. Postpneumonectomy bronchopleural fistula (BPF) is difficult-to-manage. Management is determined by the timing of complication, the condition of the patient, and the presence or absence of empyema. Patients should be positioned with their operated side down. Chest tube drainage of the empyema should be performed. For repair of the bronchus, a long stump can be resected and closed primarily if the BPF took place in the early postoperative period. In some cases, primary closure of postpneumonectomy BPF may not be tenable. In such situations, the bronchial leak point can be closed with a vascularized flap. Sterile or minimally contaminated cavities can be irrigated, filled with antibiotic solution, and then closed. Eloesser flaps are ideal for long-term open drainage and irrigation. Alternatively, after the pleural cavity is granulating and healthy, it can be filled with antibiotic solution and closed. Rarely, BPFs have been managed nonoperatively with endoscopic techniques combined with antibiotics. Residual space after lobectomy can also occur. Intraoperative maneuvers to lessen the risk for space problems include pleural tents, phrenic nerve crush, muscle or omental transposition, thoracoplasty, and pneumoperitoneum. If a patient is clinically well, continued observation and antibiotics are appropriate while the space fills. Lobar torsion is one of the most serious complications and commonly affects the right middle lobe after right upper lobectomy. Visual confirmation of anatomic position and proper lung inflation allows detection of twisted or ischemic lung before closure. The lung may be salvageable if the torsion is recognized early, before infarction occurs. However, usually the diagnosis is late, and resection is required. Postpneumonectomy syndrome is caused by displacement and rotation of the mediastinum into the operated chest. The remaining main stem bronchus is stretched and compressed over the spine or aorta. Surgical treatment principle is to reposition the mediastinum by placing intrathoracic prosthetic implants, which will relieve the airway compromise. Sleeve lobectomy or other bronchoplastic procedures may result in late airway stenosis. Repeated dilations sometimes stabilize strictures but usually the effect is temporarily. In some cases, reoperation is necessary. If the stenosis resulted from kinking of the anastomosis, resection and re-anastomosis may fix the problem. Usually, a completion pneumonectomy may be necessary. A fistula between the airway and pulmonary artery occur after bronchoplasty or tracheal resection. If a fistula is apparent, emergency surgery should be performed. The mortality rate of bronchovascular fistulas is high. Tracheoesophageal fistula can develop with prolonged intubation and mechanical ventilation. Surgical repair should be attempted after the patient's condition is optimized, and the patient is breathing spontaneously. Chest wall graft infection can happen even several years after chest wall resection and reconstruction. When chronic, often times, soft tissue flap support may be sufficient to obviate skeletal reconstruction. Conclusions An appropriate patient selection and meticulous surgery are the best prophylaxis against postoperative surgical complications. When complications arise, they require an experienced surgeon for identification and correction. Furthermore, training of surgical techniques, sound knowledge of anatomical variations, as well as stringent observances of surgical principle are mandatory to overcome intraoperative complications.

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