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The Role of Surgical Resection in Stage IIIA Non-Small Cell Lung Cancer: A Decision and Cost-Effectiveness Analysis
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The Role of Surgical Resection in Stage IIIA Non-Small Cell Lung Cancer: A Decision and Cost-Effectiveness Analysis Pamela Samson, MD, Aalok Patel, BS, Cliff G. Robinson, MD, Daniel Morgensztern, MD, Su-Hsin Chang, PhD, Graham A. Colditz, MD, Saiama Waqar, MD, Traves D. Crabtree, MD, A. Sasha Krupnick, MD, Daniel Kreisel, MD, G. Alexander Patterson, MD, Bryan F. Meyers, MD, MPH, and Varun Puri, MD, MSCI Divisions of Cardiothoracic Surgery, Medical Oncology, and Public Health Sciences, Departments of Radiation Oncology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
Background. This study evaluated the costeffectiveness of combination chemotherapy, radiotherapy, and surgical intervention (CRS) vs definitive chemotherapy and radiotherapy (CR) in clinical stage IIIA non-small cell lung cancer (NSCLC) patients at academic and nonacademic centers. Methods. Patients with clinical stage IIIA NSCLC receiving CR or CRS from 1998 to 2010 were identified in the National Cancer Data Base. Propensity score matching on patient, tumor, and treatment characteristics was performed. Medicare allowable charges were used for treatment costs. The incremental cost-effectiveness ratio (ICER) was based on probabilistic 5-year survival and calculated as cost per life-year gained. Results. We identified 5,265 CR and CRS matched patient pairs. Surgical resection imparted an increased effectiveness of 0.83 life-years, with an ICER of $17,618. Among nonacademic centers, 1,634 matched CR and CRS patients demonstrated a benefit with
surgical resection of 0.86 life-years gained, for an ICER of $17,124. At academic centers, 3,201 matched CR and CRS patients had increased survival of 0.81 life-years with surgical resection, for an ICER of $18,144. Finally, 3,713 CRS patients were matched between academic and nonacademic centers. Academic center surgical patients had an increased effectiveness of 1.5 months gained and dominated the model with lower surgical cost estimates associated with lower 30-day mortality rates. Conclusions. In stage IIIA NSCLC, the selective addition of surgical resection to CR is cost-effective compared with definitive chemoradiation therapy at nonacademic and academic centers. These conclusions are valid over a range of clinically meaningful variations in cost and treatment outcomes.
T
cancer (NSCLC) is usually treated with a combination of chemotherapy and radiotherapy, whereas surgical resection may be offered to patients showing remission or lack of progression of tumor burden after induction therapy. Randomized trials have not shown a clear long-term benefit to surgical resection, but these studies have been criticized for suboptimal short-term outcomes after surgical resection [6, 7]. In contrast, several single-center studies have reported improved long-term outcomes with the addition of surgical resection to chemotherapy and radiotherapy [8–11]. A review of stage IIIA NSCLC treatment outcomes from the National Cancer Data Base (NCDB) found improved overall survival for propensitymatched patients receiving trimodality therapy including
he National Cancer Institute estimates that 226,160 lung cancer cases were diagnosed in the United States (U.S.) in 2012, and 160,340 patients died from lung cancer in the same period. It is estimated that the annual medical cost of lung cancer treatment exceeds $10 billion and that lost productivity costs society an additional $30 billion in the U.S. [1, 2]. Because lung cancer presents most commonly in the elderly, costs are primarily absorbed by federal and state governments through Medicare and Medicaid programs and are expected to increase [3]. For stage IIIA patients, the 5-year overall survival is typically less than 20% [4, 5]. Stage IIIA non-small cell lung
(Ann Thorac Surg 2015;100:2026–32) Ó 2015 by The Society of Thoracic Surgeons
Accepted for publication May 15, 2015. Presented at the Fifty-first Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 24–28, 2015. Address correspondence to Dr Puri, Washington University School of Medicine in St. Louis, Division of Cardiothoracic Surgery, Campus Box 8234, 660 S Euclid Ave, St. Louis, MO 63110; e-mail: puriv@wudosis. wustl.edu.
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
The Appendix can be viewed in the online version of this article [http://dx.doi.org/10.1016/j.athoracsur.2015. 05.091] on http://www.annalsthoracicsurgery.org.
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.05.091
surgical resection vs definitive chemotherapy and radiotherapy [12]. Multimodality treatment for stage IIIA NSCLC is associated with greater use of resources, and appropriate tailoring of evidence-based therapies is needed. Stage I NSCLC has been the focus of recent cost-effectiveness analyses, but treatment options for stage IIIA disease have not yet been examined in this manner [13–15]. The objective of this study was to compare the relative costeffectiveness of chemotherapy and radiotherapy (CR) alone vs chemotherapy, radiotherapy, and surgical resection (CRS), in any sequence, for clinical stage IIIA NSCLC patients treated in academic and community settings.
Material and Methods Using deidentified patient information from the NCDB participant user file, we abstracted patients with clinical stage IIIA NSCLC who received treatment with CR or CRS, in any sequence, between 1998 and 2010. Information on patient, tumor, and treatment characteristics with short-term and long-term outcomes was obtained. The Charlson-Deyo score was abstracted as a measure of comorbidity and is recorded by the NCDB as 0, 1, or 2 or more (excluding points from a patient’s lung malignancy). Last known vital status and the time between diagnosis and follow-up were used to determine survival using a Kaplan-Meier analysis. All analyses were performed using SPSS 21 software (IBM Corp, Armonk, NY). To overcome the influence of selection bias in treatment allocation, patients in the CR group were matched with CRS patients using a propensity score technique.
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The propensity score between the CR and CRS groups was based on preoperative characteristics and was estimated using a backwards stepwise logistic regression model including age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo comorbidity score, tumor size, and facility type. Patients for whom the propensity scores matched to the third decimal place (0.0001) were matched in 1:1 fashion. Automated matching was performed using the Fuzzy extension command in SPSS [16]. Subgroup analysis was performed by repeating these propensity-matching techniques to identify CR and CRS patient pairs by institution type. A Consolidated Standards of Reporting Trials flowchart is shown in Figure 1. A decision analysis model was created using Tree Age Pro 2013 software (TreeAge Software Inc, Williamstown, MA). Inputs to the model for probabilistic 5-year patient survival were obtained from the NCDB analysis described above. Such models have been previously described in thoracic surgery [17, 18]. The model created for this analysis is shown in Supplementary Figure 1. Expenditures were based on the Medicare allowable costs (in 2014 US $) [19]. The incremental costeffectiveness ratio (ICER) was calculated as the cost per additional life-year gained over a 5-year horizon. Length of survival (life-years) was used as the measure of utility in the model. One- and two-way sensitivity analyses were performed where the value of each variable was varied across a clinically relevant range, and the model was recalculated. To test the overall stability of the model, we conducted probabilistic sensitivity analysis. Costeffectiveness acceptability graphs were plotted. Fig 1. Consolidated Standards of Reporting Trials flowchart demonstrates non-small cell lung cancer (NSCLC) patient selection criteria and propensity matched analysis. *CR and CRS patients were matched by age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo score, tumor size, and facility type (academic vs nonacademic). ySubgroup analyses with academic and nonacademic CR and CRS patients were matched on age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo score, and tumor size. z Nonacademic CR and CRS patients were matched on age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo score, and tumor size. ⋄Academic and nonacademic CRS patients were matched on age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo score, and tumor size.
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Table 1. Five-Year Probabilistic Survival for Patients Receiving Chemotherapy and Radiotherapy or Chemotherapy, Radiotherapy, and Surgical Resectiona Variable
CR, % (95% CI) CRS, % (95% CI)
Probability of survival at 1 year 2 years if surviving 1 year 3 years if surviving 2 years 4 years if surviving 3 years 5 years if surviving 4 years
66.4 60.1 65.9 75.3 80.3
(65.0–67.8) (57.7–62.5) (61.8–70.0) (68.8–81.8) (71.4–89.2)
83.4 73.5 78.5 82.1 85.8
(82.4–84.4) (71.6–75.4) (75.4–81.6) (77.9–86.3) (80.2–91.4)
a
Five-year survival (with 95% CI), demonstrated for the CR group and the CRS group at 1-year intervals. CI ¼ confidence intervals; CR ¼ chemotherapy and radiotherapy; CRS ¼ chemotherapy, radiotherapy, and surgical resection.
Results In the overall NCDB cohort, 51,979 patients (84.7%) received CR, and 9,360 patients (15.3%) received CRS. We identified 5,265 matched patient pairs in the CR and CRS groups and used them to determine survival probabilities for the decision analysis model. In the CRS arm, 3,708 patients (70.4%) received a lobectomy, 682 (13.0%) received a pneumonectomy, and 875 (16.6%) were classified as “other.” Sequence of therapy was available for 4,535 of the CRS patients (86%): 2,758 (60.8%) received neoadjuvant therapy and 1,777 (39.2%) received adjuvant therapy. One-year intervals of probabilistic survival for the matched CR and CRS groups from the NCDB over a 5-year period are reported in Table 1. Additional inputs to the model included the 30-day surgical mortality of 2.2% for the CRS patients and 30-day mortality for CR patients of 0.003%. Medicare allowable cost-estimate calculations are reported in Table 2.
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On the basis of Medicare allowable costs, the incremental cost increase of CRS compared with CR was $14,722. In this propensity-matched population, there was an increase in effectiveness (patient survival) of 0.84 years (10.2 months) for patients in the CRS arm. The ICER is obtained by dividing the increased cost of a therapy by the incremental benefit that the therapy provides. Therefore, the ICER for CRS was $17,618. Results of this base cost-effectiveness analysis are reported in Table 3. The minimal increase in survival among CRS patients needed to obtain a traditional ICER of $50,000 is 0.29 years (3.5 months). Therefore, on the basis of the NCDB propensity-matched population, CRS was cost-effective with a relatively low ICER and a survival benefit substantially greater than that needed as a “cutoff” value. A one-way sensitivity analysis was performed by varying the total cost of treatment in the CRS group from $30,000 to $100,000, while keeping the cost estimates of the CR group constant. Here, the model tolerated more than doubling of surgical costs (from a base cost of $16,891 to an increase of $40,352) with an ICER of $48,291. An additional one-way sensitivity analysis was performed by varying the potential total cost of 30-day mortality after surgical resection from $50,000 to $250,000 (baseline cost of surgical mortality was $55,513), while keeping the expected mortality rate constant at the base-case value of 2.2%. Even at a hypothetical cost of $250,000 for charges associated with 30-day mortality, the ICER was $22,273. A two-way sensitivity analysis was performed varying both the risk of death at 30 days (from 2% to 12%) and associated costs of a death at 30 days (from $50,000 to $250,000). With a 30-day mortality rate of 12%, CRS continued to dominate the model up to $135,000.00 of perioperative hospitalization charges that could be incurred. At a mortality rate of 8%, CRS dominated the
Table 2. Medicare Allowable Costs by Treatment Modalitya Base Costs of Treatment
Medicare Allowable Cost Estimate (2014 US $)
CR group: Definitive chemotherapyb Definitive radiotherapyc Cost of 30-day mortality definitive therapyd Total cost of definitive therapy CRS group: Induction CR therapyb,c Surgical resectione Cost of 30-day mortality from surgical resectionf Total costs of CRS
1,725 15,889.24 12,148 17,614.24 14,955.14 16,890.91 55,513.12 31,846.06
a b These charges were used as base cost estimates for the decision analysis model. Average Medicare allowable cost of docetaxel, etoposide/cisplatin, c Definitive and induction radiation oncology treatment and paclitaxel/carboplatin regimens for induction and definitive chemotherapy protocols. costs were calculated using the Medicare allowable charges for professional and technical fees, assuming one-half of the patients were treated with d intensity-modulated radiotherapy and one-half with three-dimensional conformal therapy. Cost of 30-day mortality from induction chemotherapy e was assumed to be primarily from aggressive treatment of febrile neutropenia, and this cost was estimated from the literature [20]. Medicare f allowable cost of mediastinoscopy, thoracotomy, and lobectomy, with a 5% complication rate with pneumonia or atrial fibrillation factored in. Medicare allowable cost of 30-day mortality from pulmonary resection, including pneumonia, atrial fibrillation, ventilator care, and death.
CR ¼ chemotherapy and radiotherapy;
CRS ¼ chemotherapy, radiotherapy, and surgical resection.
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Table 3. Results of Base Cost-Effectiveness Analysisa Strategy CRS CR a
Total Cost (2014 US $)
Incremental Cost (2014 US $)
$32,319 $17,598
$14,722
Total Effectiveness (y)
Incremental Effectiveness (y)
Incremental Cost-Effectiveness Ratio
2.93 2.10
0.83
$17,617.80
Total costs for CRS and CR modalities here are adjusted by the model to include the 30-day mortality rate and associated costs for each therapy modality.
CR ¼ chemotherapy and radiotherapy;
CRS ¼ chemotherapy, radiotherapy, and surgical resection.
model for this entire range of cost-estimates. This two-way sensitivity analysis is depicted in Figure 2. A cost-effectiveness acceptability curve was created with probabilistic sensitivity analysis to examine iterations over which CRS would be cost-effective over a willingness-to-pay range varying from $0 to $50,000. At a willingness-to-pay threshold of $25,000, 100% of the 1,000 theoretical iterations favored CRS as a cost-effective treatment strategy in stage IIIA NSCLC (Fig 3). To test the model in different types of treatment centers, a propensity-matched analysis was performed for CR or CRS patients at academic centers and a separate but similar model was created for nonacademic centers. For the academic center model, there were 1,634 matched patient pairs. The incremental cost for CRS patients at academic centers was $14,738, and the incremental effectiveness was 0.81 years. The ICER for CRS at academic centers was $18,144. At nonacademic centers, 3,201 matched patient pairs were identified. The incremental cost for CRS patients at nonacademic centers was $14,780, and the incremental effectiveness was 0.86 years. The ICER for CRS at nonacademic centers was $17,124. Finally, CRS patients at academic and nonacademic institutions were propensity matched to yield 3,713 matched patient pairs. The incremental effectiveness of CRS at academic centers was 0.12 years, with a lower cost
compared with nonacademic centers (–$135). The negative ICER for receiving an operation at a nonacademic center (–$1,144) indicates that academic centers have a small but favorable cost-effectiveness profile compared with nonacademic centers.
Comment This study addresses the relative cost-effectiveness of combined chemotherapy, radiotherapy, and surgical resection compared with definitive chemotherapy and radiotherapy. With current Medicare allowable fee estimates, the addition of surgical resection to chemotherapy and radiation extends the life expectancy of selected patients with clinical stage IIIA NSCLC in a cost-effective manner. These results were consistent across both academic and community centers. The ICER for including surgical resection as part of a treatment plan in stage IIIA NSCLC varied from $17,000 to $18,000 in our paired comparisons by institution type and was well below or similar to other ICERs in thoracic surgery. For example, the ICER for bilateral lung transplantation vs medical management is $176,817 [21], lung volume reduction vs medical management is $140,000 [22], and coronary artery bypass grafting vs drug-eluting percutaneous coronary intervention for left main or multivessel disease is $16,537 [23].
Fig 2. Two-way sensitivity analysis varying the probability of surgical survival after pulmonary resection in stage IIIA non-small cell lung cancer from 88% to 98% and the cost of 30-day hospitalization charges from $50,000 to $250,000. Willingness to pay was set at a conventional threshold of $50,000. For propensity-matched patients who received chemotherapy and radiotherapy (CR; blue) and those who received chemotherapy, radiotherapy, and surgical resection (CRS; red), the 30-day mortality rate was 2.2%, and the base cost of 30-day mortality was $55,513. This figure indicates that even with decreases in 30-day surgical survival and increases in associated costs, CRS dominates the decision model over CR for these clinical variations.
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Fig 3. Cost-effectiveness acceptability curve with a willingness-topay threshold varying from $0 to $50,000. A total of 1,000 iterations of chemotherapy and radiotherapy (CR, blue line) vs chemotherapy, radiotherapy, and surgical resection (CRS, red line) for propensitymatched stage IIIA non-small cell lung cancer patients were run in a Monte Carlo simulation, using survival inputs from the National Cancer Data Base and Medicare allowable costs. At a willingness-topay threshold of $18,000, surgical resection begins to dominate the model choices. At a willingness-to-pay threshold of $25,000, 100% of model patient simulations favor CRS over CR.
Several previous single-center studies demonstrated longer median overall survival with various combinations of neoadjuvant chemoradiation, followed by surgical resection, in both stage IIIA and IIIB patients [8–11, 24, 25]. The findings from the larger treatment population of the NCDB are consistent with these studies [12]. To date, four randomized controlled trials have attempted to study the role of surgical resection in stage IIIA NSCLC. Two of these studies did not meet accrual goals [26, 27], and the others demonstrated a survival benefit for patients receiving a lobectomy but not for the overall surgical cohorts [6, 7]. Of note, the perioperative mortality rate for the INT-0139 pneumonectomy group was approximately 25%, whereas the 30-day mortality after pneumonectomy in our NCDB analysis was 8.6% [6]. In this regard, findings from the NCDB are congruent with previous reports [28, 29]. In the European Organization for Research and Treatment of Cancer (EORTC) trial for surgical resection in stage IIIA-N2 NSCLC after induction therapy, approximately one-half of patients in the surgical arm received a pneumonectomy [7]. This was disproportionate compared with the NCDB, where 13% of stage IIIA patients underwent a pneumonectomy. Current recommendations by the National Comprehensive Cancer Network (NCCN) advocate for consideration of pulmonary resection after induction chemotherapy for T1-3, N2 disease if there is no evidence of progression of mediastinal disease after treatment [30]. A previous cost-effectiveness study using Canadian Health Care cost estimates from the 1990s found that multimodal therapy (including preoperative and postoperative chemotherapy, surgical resection, and postoperative radiotherapy) for stage III NSCLC (per the
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staging criteria at the time) was cost-effective, with a cost per life-year gained estimate ranging from $3,300 to $15,000 [31]. More recent studies have limited costeffectiveness analyses to comparisons between surgical approaches without addressing the overall treatment plan in locally advanced NSCLC patients [32, 33]. External-beam radiotherapy may be delivered by 3dimensional conformal radiotherapy or intensitymodulated radiotherapy (IMRT). Recent work has shown that the national use of IMRT has increased, which is more costly [34]. For the years of treatment evaluated in this study, the 50% estimate of IMRT use is likely higher than the percentage of IMRT actually used. However, this estimate appears to be on trend with current data, and may eventually represent an underestimate of radiotherapy expenditures as IMRT use increases or as more centers begin using proton therapy. We believe that the population-based NCDB data provide a realistic approximation of practice patterns in the U.S. and provide appropriate survival inputs for our base case analysis. An assumption of this model is that the costs of long-term cancer care, which can include clinical follow-up, treatment of recurrence, and palliative care, would be similar between the CR and CRS groups. However, given the greater 5-year survival in the CRS group seen in the NCDB data, higher long-term cancer care costs would be anticipated in this population. Quantifying this amount is unlikely to affect the overall model, because the greatest amount of health care expenditure among all lung cancer patients is in the last year of life [35]. Previous work by our group has demonstrated a lower 30-day mortality rate and improved overall survival for patients receiving surgical resection for stage IIIA NSCLC at academic facilities [36]. Specifically, receiving surgical resection at an academic center for stage IIIA NSCLC was independently associated with decreased 30day mortality and improved overall survival [36]. In our propensity-matched analysis of academic and nonacademic CRS patients, these conclusions are again supported by a small but significant improvement in survival outcomes and lower cost of CRS therapy at academic centers. We acknowledge some limitations to our analysis. Our base-case analysis model is subject to the biases associated with retrospective studies, including selection bias in treatment allocation. Propensity matching cannot account for unmeasured potential confounders. Specific data regarding pathologic nodal staging was not available for 93% of the CR patients and could not be included as a matching variable. Therefore, it is possible that patients with bulky N2 disease were more prevalent in the CR arm, thus making the outcomes appear worse. In continuing to refine the role of surgical resection in locally advanced NSCLC, considering quality of life (QoL) outcomes is important. National databases do not routinely collect QoL measures because these can involve lengthy questionnaires that are costly to administer. Although patients receiving pneumonectomy are known to have significantly lower QoL outcome measures than
those undergoing a lobectomy or bilobectomy, prospective comparative information on QoL measures in patients undergoing CR or CRS for stage IIIA NSCLC is lacking [37]. The model presented above can be further refined with these data. Dr Samson has support through National Institutes of Health Surgical Oncology grant T32-CA-009621-25. Dr Puri has funding through National Institutes of Health grants K07-CA-178120 and K12-CA-167540-02.
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DISCUSSION DR SCOTT J. SWANSON (Boston, MA): Great paper. I think I understood it. But do you have any sense of how radiation plays into this in terms of the cost piece? If it was just induction chemotherapy, can you predict what you would see? DR SAMSON: Right. So we assumed an induction regimen of chemoradiation, and specifically we used a 50% mix of both three-dimensional (3D) conformal radiation therapy and intensity-modulated radiotherapy (IMRT), which has been gaining in popularity. So we estimated half the cost with 3D and half the cost with IMRT and came up with an average and put that into the model. If anything, this probably overestimates the cost because the years of the study, 1998 to 2010, it is likely that more patients received 3D conformal than IMRT, which is more expensive. It does not include proton therapy at this time. But we could certainly do a variation where we have 100% IMRT; although, that is not still quite yet in clinical practice. DR SWANSON: My question was really if you eliminate radiation and just go straight chemo induction, I would assume that makes the cost effectiveness go way up. Because there are some data that show radiation may not be helpful. And if we are looking at a cost issue here, you might find that really drives it into a real positive. DR SAMSON: Understood. Sorry, I misinterpreted your question. Thank you. You are right, it would increase the cost effectiveness of surgery; but if they receive radiation therapy adjuvantly, the cost estimates we provide in the model would probably remain quite similar. DR JOSEPH B. SHRAGER (Stanford, CA): I think this is a great effort to shed light on a very important problem. But I am afraid there could be an apples and oranges problem substantial enough that if you presented this to an oncology group—medical oncologists—that they would point this out to you critically. The problem is that your propensity analysis is totally dependent on what you are able to propensity match for. And in the National Cancer Data Base, I gather you do not have any information on the number of N2 nodes, size of N2 nodes, essentially extent of N2 disease, which are probably the pieces of information that really determine how the patients do, more than any other factors. So when you calculated your benefit of .84, it may have more to do with the patients who are being selected for surgery than it does to the fact that they are having surgery.
DR SAMSON: Right. DR SHRAGER: I do not know. You guys are the great statisticians, so I do not know how you would try to account for that. DR SAMSON: Thank you for that point. Of the definitive chemotherapy and radiation therapy population, only 7% of that propensity-matched population underwent any type of nodal staging. So it is just not a variable we are able to match on because then otherwise we would not have enough patients to study. Our hope is that in the propensity matching we capture the fittest of the definitive chemoradiation patients when we match on things such as age and comorbidity score in particular. In other words, we are capturing a population of definitive chemotherapy and radiotherapy (CR) patients that would be hypothetically eligible for surgery. DR SHRAGER: You can not get the radiologic reports or the positron emission tomography scan reports or anything from the National Cancer Data. DR SAMSON: Unfortunately, no. DR SHRAGER: I am saying that facetiously. DR RICHARD K. FREEMAN (Indianapolis, IN): Great presentation and I congratulate you and your colleagues on the methodology that you used. Do you have any insight into that about 6% difference between academic and nonacademic? Was it chemotherapy? Was it imaging? Do you have any subset analysis there? DR SAMSON: Yes. In a previous study we did with the National Cancer Data Base that is currently under review, we compared the 30-day surgical outcomes and overall mortality of stage IIIA lung cancer patients at academic and nonacademic centers. We found that stage IIIA academic center patients were more likely to receive neoadjuvant chemotherapy than nonacademic center patients. Furthermore, receiving surgery at an academic center was independently associated with a decreased 30-day mortality and improved overall survival. At this time, we do not know which factors specifically lead to improved outcomes at academic centers, but hypothesize that it may be due to neoadjuvant therapy, and higher patient volumes. Also, if more patients at academic centers are receiving neoadjuvant therapy, this may be selecting out relatively healthier patients that are still fit for surgery after undergoing chemoradiation therapy.
The Role of Surgical Resection in Stage IIIA Non-Small Cell Lung Cancer: A Decision and Cost-Effectiveness Analysis Pamela Samson, MD, Aalok Patel, BS, Cliff G. Robinson, MD, Daniel Morgensztern, MD, Su-Hsin Chang, PhD, Graham A. Colditz, MD, Saiama Waqar, MD, Traves D. Crabtree, MD, A. Sasha Krupnick, MD, Daniel Kreisel, MD, G. Alexander Patterson, MD, Bryan F. Meyers, MD, MPH, and Varun Puri, MD, MSCI Divisions of Cardiothoracic Surgery, Medical Oncology, and Public Health Sciences, Departments of Radiation Oncology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
Background. This study evaluated the costeffectiveness of combination chemotherapy, radiotherapy, and surgical intervention (CRS) vs definitive chemotherapy and radiotherapy (CR) in clinical stage IIIA non-small cell lung cancer (NSCLC) patients at academic and nonacademic centers. Methods. Patients with clinical stage IIIA NSCLC receiving CR or CRS from 1998 to 2010 were identified in the National Cancer Data Base. Propensity score matching on patient, tumor, and treatment characteristics was performed. Medicare allowable charges were used for treatment costs. The incremental cost-effectiveness ratio (ICER) was based on probabilistic 5-year survival and calculated as cost per life-year gained. Results. We identified 5,265 CR and CRS matched patient pairs. Surgical resection imparted an increased effectiveness of 0.83 life-years, with an ICER of $17,618. Among nonacademic centers, 1,634 matched CR and CRS patients demonstrated a benefit with
surgical resection of 0.86 life-years gained, for an ICER of $17,124. At academic centers, 3,201 matched CR and CRS patients had increased survival of 0.81 life-years with surgical resection, for an ICER of $18,144. Finally, 3,713 CRS patients were matched between academic and nonacademic centers. Academic center surgical patients had an increased effectiveness of 1.5 months gained and dominated the model with lower surgical cost estimates associated with lower 30-day mortality rates. Conclusions. In stage IIIA NSCLC, the selective addition of surgical resection to CR is cost-effective compared with definitive chemoradiation therapy at nonacademic and academic centers. These conclusions are valid over a range of clinically meaningful variations in cost and treatment outcomes.
T
cancer (NSCLC) is usually treated with a combination of chemotherapy and radiotherapy, whereas surgical resection may be offered to patients showing remission or lack of progression of tumor burden after induction therapy. Randomized trials have not shown a clear long-term benefit to surgical resection, but these studies have been criticized for suboptimal short-term outcomes after surgical resection [6, 7]. In contrast, several single-center studies have reported improved long-term outcomes with the addition of surgical resection to chemotherapy and radiotherapy [8–11]. A review of stage IIIA NSCLC treatment outcomes from the National Cancer Data Base (NCDB) found improved overall survival for propensitymatched patients receiving trimodality therapy including
he National Cancer Institute estimates that 226,160 lung cancer cases were diagnosed in the United States (U.S.) in 2012, and 160,340 patients died from lung cancer in the same period. It is estimated that the annual medical cost of lung cancer treatment exceeds $10 billion and that lost productivity costs society an additional $30 billion in the U.S. [1, 2]. Because lung cancer presents most commonly in the elderly, costs are primarily absorbed by federal and state governments through Medicare and Medicaid programs and are expected to increase [3]. For stage IIIA patients, the 5-year overall survival is typically less than 20% [4, 5]. Stage IIIA non-small cell lung
(Ann Thorac Surg 2015;100:2026–32) Ó 2015 by The Society of Thoracic Surgeons
Accepted for publication May 15, 2015. Presented at the Fifty-first Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 24–28, 2015. Address correspondence to Dr Puri, Washington University School of Medicine in St. Louis, Division of Cardiothoracic Surgery, Campus Box 8234, 660 S Euclid Ave, St. Louis, MO 63110; e-mail: puriv@wudosis. wustl.edu.
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
The Appendix can be viewed in the online version of this article [http://dx.doi.org/10.1016/j.athoracsur.2015. 05.091] on http://www.annalsthoracicsurgery.org.
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.05.091
surgical resection vs definitive chemotherapy and radiotherapy [12]. Multimodality treatment for stage IIIA NSCLC is associated with greater use of resources, and appropriate tailoring of evidence-based therapies is needed. Stage I NSCLC has been the focus of recent cost-effectiveness analyses, but treatment options for stage IIIA disease have not yet been examined in this manner [13–15]. The objective of this study was to compare the relative costeffectiveness of chemotherapy and radiotherapy (CR) alone vs chemotherapy, radiotherapy, and surgical resection (CRS), in any sequence, for clinical stage IIIA NSCLC patients treated in academic and community settings.
Material and Methods Using deidentified patient information from the NCDB participant user file, we abstracted patients with clinical stage IIIA NSCLC who received treatment with CR or CRS, in any sequence, between 1998 and 2010. Information on patient, tumor, and treatment characteristics with short-term and long-term outcomes was obtained. The Charlson-Deyo score was abstracted as a measure of comorbidity and is recorded by the NCDB as 0, 1, or 2 or more (excluding points from a patient’s lung malignancy). Last known vital status and the time between diagnosis and follow-up were used to determine survival using a Kaplan-Meier analysis. All analyses were performed using SPSS 21 software (IBM Corp, Armonk, NY). To overcome the influence of selection bias in treatment allocation, patients in the CR group were matched with CRS patients using a propensity score technique.
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The propensity score between the CR and CRS groups was based on preoperative characteristics and was estimated using a backwards stepwise logistic regression model including age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo comorbidity score, tumor size, and facility type. Patients for whom the propensity scores matched to the third decimal place (0.0001) were matched in 1:1 fashion. Automated matching was performed using the Fuzzy extension command in SPSS [16]. Subgroup analysis was performed by repeating these propensity-matching techniques to identify CR and CRS patient pairs by institution type. A Consolidated Standards of Reporting Trials flowchart is shown in Figure 1. A decision analysis model was created using Tree Age Pro 2013 software (TreeAge Software Inc, Williamstown, MA). Inputs to the model for probabilistic 5-year patient survival were obtained from the NCDB analysis described above. Such models have been previously described in thoracic surgery [17, 18]. The model created for this analysis is shown in Supplementary Figure 1. Expenditures were based on the Medicare allowable costs (in 2014 US $) [19]. The incremental costeffectiveness ratio (ICER) was calculated as the cost per additional life-year gained over a 5-year horizon. Length of survival (life-years) was used as the measure of utility in the model. One- and two-way sensitivity analyses were performed where the value of each variable was varied across a clinically relevant range, and the model was recalculated. To test the overall stability of the model, we conducted probabilistic sensitivity analysis. Costeffectiveness acceptability graphs were plotted. Fig 1. Consolidated Standards of Reporting Trials flowchart demonstrates non-small cell lung cancer (NSCLC) patient selection criteria and propensity matched analysis. *CR and CRS patients were matched by age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo score, tumor size, and facility type (academic vs nonacademic). ySubgroup analyses with academic and nonacademic CR and CRS patients were matched on age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo score, and tumor size. z Nonacademic CR and CRS patients were matched on age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo score, and tumor size. ⋄Academic and nonacademic CRS patients were matched on age, gender, race, income, rural vs urban status, year of diagnosis, Charlson-Deyo score, and tumor size.
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Table 1. Five-Year Probabilistic Survival for Patients Receiving Chemotherapy and Radiotherapy or Chemotherapy, Radiotherapy, and Surgical Resectiona Variable
CR, % (95% CI) CRS, % (95% CI)
Probability of survival at 1 year 2 years if surviving 1 year 3 years if surviving 2 years 4 years if surviving 3 years 5 years if surviving 4 years
66.4 60.1 65.9 75.3 80.3
(65.0–67.8) (57.7–62.5) (61.8–70.0) (68.8–81.8) (71.4–89.2)
83.4 73.5 78.5 82.1 85.8
(82.4–84.4) (71.6–75.4) (75.4–81.6) (77.9–86.3) (80.2–91.4)
a
Five-year survival (with 95% CI), demonstrated for the CR group and the CRS group at 1-year intervals. CI ¼ confidence intervals; CR ¼ chemotherapy and radiotherapy; CRS ¼ chemotherapy, radiotherapy, and surgical resection.
Results In the overall NCDB cohort, 51,979 patients (84.7%) received CR, and 9,360 patients (15.3%) received CRS. We identified 5,265 matched patient pairs in the CR and CRS groups and used them to determine survival probabilities for the decision analysis model. In the CRS arm, 3,708 patients (70.4%) received a lobectomy, 682 (13.0%) received a pneumonectomy, and 875 (16.6%) were classified as “other.” Sequence of therapy was available for 4,535 of the CRS patients (86%): 2,758 (60.8%) received neoadjuvant therapy and 1,777 (39.2%) received adjuvant therapy. One-year intervals of probabilistic survival for the matched CR and CRS groups from the NCDB over a 5-year period are reported in Table 1. Additional inputs to the model included the 30-day surgical mortality of 2.2% for the CRS patients and 30-day mortality for CR patients of 0.003%. Medicare allowable cost-estimate calculations are reported in Table 2.
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On the basis of Medicare allowable costs, the incremental cost increase of CRS compared with CR was $14,722. In this propensity-matched population, there was an increase in effectiveness (patient survival) of 0.84 years (10.2 months) for patients in the CRS arm. The ICER is obtained by dividing the increased cost of a therapy by the incremental benefit that the therapy provides. Therefore, the ICER for CRS was $17,618. Results of this base cost-effectiveness analysis are reported in Table 3. The minimal increase in survival among CRS patients needed to obtain a traditional ICER of $50,000 is 0.29 years (3.5 months). Therefore, on the basis of the NCDB propensity-matched population, CRS was cost-effective with a relatively low ICER and a survival benefit substantially greater than that needed as a “cutoff” value. A one-way sensitivity analysis was performed by varying the total cost of treatment in the CRS group from $30,000 to $100,000, while keeping the cost estimates of the CR group constant. Here, the model tolerated more than doubling of surgical costs (from a base cost of $16,891 to an increase of $40,352) with an ICER of $48,291. An additional one-way sensitivity analysis was performed by varying the potential total cost of 30-day mortality after surgical resection from $50,000 to $250,000 (baseline cost of surgical mortality was $55,513), while keeping the expected mortality rate constant at the base-case value of 2.2%. Even at a hypothetical cost of $250,000 for charges associated with 30-day mortality, the ICER was $22,273. A two-way sensitivity analysis was performed varying both the risk of death at 30 days (from 2% to 12%) and associated costs of a death at 30 days (from $50,000 to $250,000). With a 30-day mortality rate of 12%, CRS continued to dominate the model up to $135,000.00 of perioperative hospitalization charges that could be incurred. At a mortality rate of 8%, CRS dominated the
Table 2. Medicare Allowable Costs by Treatment Modalitya Base Costs of Treatment
Medicare Allowable Cost Estimate (2014 US $)
CR group: Definitive chemotherapyb Definitive radiotherapyc Cost of 30-day mortality definitive therapyd Total cost of definitive therapy CRS group: Induction CR therapyb,c Surgical resectione Cost of 30-day mortality from surgical resectionf Total costs of CRS
1,725 15,889.24 12,148 17,614.24 14,955.14 16,890.91 55,513.12 31,846.06
a b These charges were used as base cost estimates for the decision analysis model. Average Medicare allowable cost of docetaxel, etoposide/cisplatin, c Definitive and induction radiation oncology treatment and paclitaxel/carboplatin regimens for induction and definitive chemotherapy protocols. costs were calculated using the Medicare allowable charges for professional and technical fees, assuming one-half of the patients were treated with d intensity-modulated radiotherapy and one-half with three-dimensional conformal therapy. Cost of 30-day mortality from induction chemotherapy e was assumed to be primarily from aggressive treatment of febrile neutropenia, and this cost was estimated from the literature [20]. Medicare f allowable cost of mediastinoscopy, thoracotomy, and lobectomy, with a 5% complication rate with pneumonia or atrial fibrillation factored in. Medicare allowable cost of 30-day mortality from pulmonary resection, including pneumonia, atrial fibrillation, ventilator care, and death.
CR ¼ chemotherapy and radiotherapy;
CRS ¼ chemotherapy, radiotherapy, and surgical resection.
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Table 3. Results of Base Cost-Effectiveness Analysisa Strategy CRS CR a
Total Cost (2014 US $)
Incremental Cost (2014 US $)
$32,319 $17,598
$14,722
Total Effectiveness (y)
Incremental Effectiveness (y)
Incremental Cost-Effectiveness Ratio
2.93 2.10
0.83
$17,617.80
Total costs for CRS and CR modalities here are adjusted by the model to include the 30-day mortality rate and associated costs for each therapy modality.
CR ¼ chemotherapy and radiotherapy;
CRS ¼ chemotherapy, radiotherapy, and surgical resection.
model for this entire range of cost-estimates. This two-way sensitivity analysis is depicted in Figure 2. A cost-effectiveness acceptability curve was created with probabilistic sensitivity analysis to examine iterations over which CRS would be cost-effective over a willingness-to-pay range varying from $0 to $50,000. At a willingness-to-pay threshold of $25,000, 100% of the 1,000 theoretical iterations favored CRS as a cost-effective treatment strategy in stage IIIA NSCLC (Fig 3). To test the model in different types of treatment centers, a propensity-matched analysis was performed for CR or CRS patients at academic centers and a separate but similar model was created for nonacademic centers. For the academic center model, there were 1,634 matched patient pairs. The incremental cost for CRS patients at academic centers was $14,738, and the incremental effectiveness was 0.81 years. The ICER for CRS at academic centers was $18,144. At nonacademic centers, 3,201 matched patient pairs were identified. The incremental cost for CRS patients at nonacademic centers was $14,780, and the incremental effectiveness was 0.86 years. The ICER for CRS at nonacademic centers was $17,124. Finally, CRS patients at academic and nonacademic institutions were propensity matched to yield 3,713 matched patient pairs. The incremental effectiveness of CRS at academic centers was 0.12 years, with a lower cost
compared with nonacademic centers (–$135). The negative ICER for receiving an operation at a nonacademic center (–$1,144) indicates that academic centers have a small but favorable cost-effectiveness profile compared with nonacademic centers.
Comment This study addresses the relative cost-effectiveness of combined chemotherapy, radiotherapy, and surgical resection compared with definitive chemotherapy and radiotherapy. With current Medicare allowable fee estimates, the addition of surgical resection to chemotherapy and radiation extends the life expectancy of selected patients with clinical stage IIIA NSCLC in a cost-effective manner. These results were consistent across both academic and community centers. The ICER for including surgical resection as part of a treatment plan in stage IIIA NSCLC varied from $17,000 to $18,000 in our paired comparisons by institution type and was well below or similar to other ICERs in thoracic surgery. For example, the ICER for bilateral lung transplantation vs medical management is $176,817 [21], lung volume reduction vs medical management is $140,000 [22], and coronary artery bypass grafting vs drug-eluting percutaneous coronary intervention for left main or multivessel disease is $16,537 [23].
Fig 2. Two-way sensitivity analysis varying the probability of surgical survival after pulmonary resection in stage IIIA non-small cell lung cancer from 88% to 98% and the cost of 30-day hospitalization charges from $50,000 to $250,000. Willingness to pay was set at a conventional threshold of $50,000. For propensity-matched patients who received chemotherapy and radiotherapy (CR; blue) and those who received chemotherapy, radiotherapy, and surgical resection (CRS; red), the 30-day mortality rate was 2.2%, and the base cost of 30-day mortality was $55,513. This figure indicates that even with decreases in 30-day surgical survival and increases in associated costs, CRS dominates the decision model over CR for these clinical variations.
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Fig 3. Cost-effectiveness acceptability curve with a willingness-topay threshold varying from $0 to $50,000. A total of 1,000 iterations of chemotherapy and radiotherapy (CR, blue line) vs chemotherapy, radiotherapy, and surgical resection (CRS, red line) for propensitymatched stage IIIA non-small cell lung cancer patients were run in a Monte Carlo simulation, using survival inputs from the National Cancer Data Base and Medicare allowable costs. At a willingness-topay threshold of $18,000, surgical resection begins to dominate the model choices. At a willingness-to-pay threshold of $25,000, 100% of model patient simulations favor CRS over CR.
Several previous single-center studies demonstrated longer median overall survival with various combinations of neoadjuvant chemoradiation, followed by surgical resection, in both stage IIIA and IIIB patients [8–11, 24, 25]. The findings from the larger treatment population of the NCDB are consistent with these studies [12]. To date, four randomized controlled trials have attempted to study the role of surgical resection in stage IIIA NSCLC. Two of these studies did not meet accrual goals [26, 27], and the others demonstrated a survival benefit for patients receiving a lobectomy but not for the overall surgical cohorts [6, 7]. Of note, the perioperative mortality rate for the INT-0139 pneumonectomy group was approximately 25%, whereas the 30-day mortality after pneumonectomy in our NCDB analysis was 8.6% [6]. In this regard, findings from the NCDB are congruent with previous reports [28, 29]. In the European Organization for Research and Treatment of Cancer (EORTC) trial for surgical resection in stage IIIA-N2 NSCLC after induction therapy, approximately one-half of patients in the surgical arm received a pneumonectomy [7]. This was disproportionate compared with the NCDB, where 13% of stage IIIA patients underwent a pneumonectomy. Current recommendations by the National Comprehensive Cancer Network (NCCN) advocate for consideration of pulmonary resection after induction chemotherapy for T1-3, N2 disease if there is no evidence of progression of mediastinal disease after treatment [30]. A previous cost-effectiveness study using Canadian Health Care cost estimates from the 1990s found that multimodal therapy (including preoperative and postoperative chemotherapy, surgical resection, and postoperative radiotherapy) for stage III NSCLC (per the
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staging criteria at the time) was cost-effective, with a cost per life-year gained estimate ranging from $3,300 to $15,000 [31]. More recent studies have limited costeffectiveness analyses to comparisons between surgical approaches without addressing the overall treatment plan in locally advanced NSCLC patients [32, 33]. External-beam radiotherapy may be delivered by 3dimensional conformal radiotherapy or intensitymodulated radiotherapy (IMRT). Recent work has shown that the national use of IMRT has increased, which is more costly [34]. For the years of treatment evaluated in this study, the 50% estimate of IMRT use is likely higher than the percentage of IMRT actually used. However, this estimate appears to be on trend with current data, and may eventually represent an underestimate of radiotherapy expenditures as IMRT use increases or as more centers begin using proton therapy. We believe that the population-based NCDB data provide a realistic approximation of practice patterns in the U.S. and provide appropriate survival inputs for our base case analysis. An assumption of this model is that the costs of long-term cancer care, which can include clinical follow-up, treatment of recurrence, and palliative care, would be similar between the CR and CRS groups. However, given the greater 5-year survival in the CRS group seen in the NCDB data, higher long-term cancer care costs would be anticipated in this population. Quantifying this amount is unlikely to affect the overall model, because the greatest amount of health care expenditure among all lung cancer patients is in the last year of life [35]. Previous work by our group has demonstrated a lower 30-day mortality rate and improved overall survival for patients receiving surgical resection for stage IIIA NSCLC at academic facilities [36]. Specifically, receiving surgical resection at an academic center for stage IIIA NSCLC was independently associated with decreased 30day mortality and improved overall survival [36]. In our propensity-matched analysis of academic and nonacademic CRS patients, these conclusions are again supported by a small but significant improvement in survival outcomes and lower cost of CRS therapy at academic centers. We acknowledge some limitations to our analysis. Our base-case analysis model is subject to the biases associated with retrospective studies, including selection bias in treatment allocation. Propensity matching cannot account for unmeasured potential confounders. Specific data regarding pathologic nodal staging was not available for 93% of the CR patients and could not be included as a matching variable. Therefore, it is possible that patients with bulky N2 disease were more prevalent in the CR arm, thus making the outcomes appear worse. In continuing to refine the role of surgical resection in locally advanced NSCLC, considering quality of life (QoL) outcomes is important. National databases do not routinely collect QoL measures because these can involve lengthy questionnaires that are costly to administer. Although patients receiving pneumonectomy are known to have significantly lower QoL outcome measures than
those undergoing a lobectomy or bilobectomy, prospective comparative information on QoL measures in patients undergoing CR or CRS for stage IIIA NSCLC is lacking [37]. The model presented above can be further refined with these data. Dr Samson has support through National Institutes of Health Surgical Oncology grant T32-CA-009621-25. Dr Puri has funding through National Institutes of Health grants K07-CA-178120 and K12-CA-167540-02.
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DISCUSSION DR SCOTT J. SWANSON (Boston, MA): Great paper. I think I understood it. But do you have any sense of how radiation plays into this in terms of the cost piece? If it was just induction chemotherapy, can you predict what you would see? DR SAMSON: Right. So we assumed an induction regimen of chemoradiation, and specifically we used a 50% mix of both three-dimensional (3D) conformal radiation therapy and intensity-modulated radiotherapy (IMRT), which has been gaining in popularity. So we estimated half the cost with 3D and half the cost with IMRT and came up with an average and put that into the model. If anything, this probably overestimates the cost because the years of the study, 1998 to 2010, it is likely that more patients received 3D conformal than IMRT, which is more expensive. It does not include proton therapy at this time. But we could certainly do a variation where we have 100% IMRT; although, that is not still quite yet in clinical practice. DR SWANSON: My question was really if you eliminate radiation and just go straight chemo induction, I would assume that makes the cost effectiveness go way up. Because there are some data that show radiation may not be helpful. And if we are looking at a cost issue here, you might find that really drives it into a real positive. DR SAMSON: Understood. Sorry, I misinterpreted your question. Thank you. You are right, it would increase the cost effectiveness of surgery; but if they receive radiation therapy adjuvantly, the cost estimates we provide in the model would probably remain quite similar. DR JOSEPH B. SHRAGER (Stanford, CA): I think this is a great effort to shed light on a very important problem. But I am afraid there could be an apples and oranges problem substantial enough that if you presented this to an oncology group—medical oncologists—that they would point this out to you critically. The problem is that your propensity analysis is totally dependent on what you are able to propensity match for. And in the National Cancer Data Base, I gather you do not have any information on the number of N2 nodes, size of N2 nodes, essentially extent of N2 disease, which are probably the pieces of information that really determine how the patients do, more than any other factors. So when you calculated your benefit of .84, it may have more to do with the patients who are being selected for surgery than it does to the fact that they are having surgery.
DR SAMSON: Right. DR SHRAGER: I do not know. You guys are the great statisticians, so I do not know how you would try to account for that. DR SAMSON: Thank you for that point. Of the definitive chemotherapy and radiation therapy population, only 7% of that propensity-matched population underwent any type of nodal staging. So it is just not a variable we are able to match on because then otherwise we would not have enough patients to study. Our hope is that in the propensity matching we capture the fittest of the definitive chemoradiation patients when we match on things such as age and comorbidity score in particular. In other words, we are capturing a population of definitive chemotherapy and radiotherapy (CR) patients that would be hypothetically eligible for surgery. DR SHRAGER: You can not get the radiologic reports or the positron emission tomography scan reports or anything from the National Cancer Data. DR SAMSON: Unfortunately, no. DR SHRAGER: I am saying that facetiously. DR RICHARD K. FREEMAN (Indianapolis, IN): Great presentation and I congratulate you and your colleagues on the methodology that you used. Do you have any insight into that about 6% difference between academic and nonacademic? Was it chemotherapy? Was it imaging? Do you have any subset analysis there? DR SAMSON: Yes. In a previous study we did with the National Cancer Data Base that is currently under review, we compared the 30-day surgical outcomes and overall mortality of stage IIIA lung cancer patients at academic and nonacademic centers. We found that stage IIIA academic center patients were more likely to receive neoadjuvant chemotherapy than nonacademic center patients. Furthermore, receiving surgery at an academic center was independently associated with a decreased 30-day mortality and improved overall survival. At this time, we do not know which factors specifically lead to improved outcomes at academic centers, but hypothesize that it may be due to neoadjuvant therapy, and higher patient volumes. Also, if more patients at academic centers are receiving neoadjuvant therapy, this may be selecting out relatively healthier patients that are still fit for surgery after undergoing chemoradiation therapy.