Cost-Effectiveness of Alternative Management Strategies for Patients with Solitary Pulmonary Nodules

The solitary pulmonary nodule is a single, well-circumscribed, spherical radiographic opacity that measures less than 3 to 4 cm in diameter and is surrounded completely by aerated lung (1). There is no associated atelectasis, hilar enlargement, or pleural effusion. Most pulmonary nodules are discovered incidentally on chest radiographs, and 15% to 75% of such nodules are malignant, depending on the population studied (2, 3). Patients with pulmonary nodules and their physicians confront difficult decisions about the risks and rewards of different management strategies. When present, malignancy must be promptly identified to permit timely resection. Pulmonary nodule evaluation typically begins with imaging studies. Computed tomography (CT) localizes the nodule within the lung parenchyma, and CT density characteristics sometimes indicate occult calcification that suggests a benign cause (4). Other CT findings, such as spiculation, are strongly associated with malignancy (5). Positron emission tomography (PET) with the glucose analogue 18-fluorodeoxyglucose (FDG) identifies malignant tumors on the basis of their increased metabolic rate. The use of FDG-PET is rapidly gaining acceptance in clinical oncology to diagnose tumors, stage disease, and evaluate treatment response (6, 7). Because FDG-PET is believed to be highly sensitive for identifying malignant nodules, proponents argue that observation with serial chest radiographs is safe when PET results are negative (8). Management alternatives for patients with pulmonary nodules include surgical resection, transthoracic needle biopsy, and watchful waiting (9). Surgery is the diagnostic gold standard and the definitive treatment for malignant nodules that are resectable, but surgery should be avoided in patients with benign nodules. Needle biopsy often establishes a specific malignant or benign diagnosis, but biopsy is invasive, potentially risky, and frequently nondiagnostic. Watchful waiting avoids unnecessary surgery for benign nodules but may delay diagnosis and treatment of malignant nodules. We developed a decision analytic model to identify the most effective approaches to diagnose and manage solitary pulmonary nodules. We performed a cost-effectiveness analysis to quantify the health effects and economic costs associated with various management strategies. Because of the considerable recent interest in the use of FDG-PET, we specifically compared diagnostic strategies that used FDG-PET with strategies that did not include this potentially useful but expensive test. Methods We performed a cost-effectiveness analysis by following the recommendations of the Panel on Cost-Effectiveness in Health and Medicine for conducting and reporting a reference-case analysis (10). The analysis adopted a societal perspective that would permit comparisons across different health care interventions. We expressed our results in terms of costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. All costs and health effects were discounted at an annual rate of 3%. Additional details on our methods, data sources, and results can be found in the Appendix. An electronic decision aid that is based on our results will be available at www.annals. org in July 2003. Clinical Problem The target population for this analysis was all adult patients with a new, noncalcified solitary pulmonary nodule on chest radiograph and no known extra-thoracic malignancy. Our base-case analysis considered a hypothetical cohort of 62-year-old men and women. Decision Model Structure and Assumptions We considered 40 clinically plausible sequences of five diagnostic interventions: CT, FDG-PET, transthoracic needle biopsy, surgery, and watchful waiting (Appendix Figures 1 and 2. We assumed that CT and FDG-PET were never performed after needle biopsy or surgery because performing an imaging test after an invasive diagnostic procedure is unusual. Similarly, needle biopsy and observation were never performed after surgery. Needle biopsy was considered to be nondiagnostic unless a specific benign or malignant diagnosis was obtained. We assumed that surgery would be performed if the biopsy revealed malignancy. If the biopsy revealed a specific benign diagnosis, the patient would be managed accordingly. After a nondiagnostic needle biopsy, either surgery or watchful waiting could be selected as the next diagnostic intervention. A final diagnosis was established at the time of surgery or, alternatively, after 24 months of observation. In the watchful waiting strategy, serial chest radiographs were obtained at 1, 2, 4, and 6 months and every 3 months thereafter. We assumed that surgery would be performed if nodule growth was observed at any time. If no growth was observed after 24 months, we assumed that the nodule was benign. Modeling Long-Term Costs and Clinical Outcomes We developed a Markov model to estimate long-term outcomes and costs for patients with malignant and benign pulmonary nodules (Appendix Figure 3). The model followed patients in the hypothetical study cohort over their remaining life span. We estimated the monthly probability of cancer recurrence after surgical treatment for patients with malignant nodules by using survival data from the Surveillance, Epidemiology and End Results (SEER) tumor registry (11). We used SEER data and a model of the natural history of untreated lung cancer to estimate the probability of disease progression in patients with malignant nodules who were managed by watchful waiting. Data and Assumptions We derived estimates for patient and nodule characteristics, diagnostic testing variables, costs and utilities from clinical and administrative sources (Appendix Table 1). Appendix Table 1. Input Variable Values and Sources Patient and Nodule Characteristics In the base-case analysis, we assumed that the pulmonary nodule measured 2 cm in diameter. We assumed that 12.5% of patients with malignant nodules would have regional lymph node involvement, the median prevalence of mediastinal metastases in eight studies of CT for staging in patients with T1 tumors (12-19). We derived the distribution of tumor growth rates for patients with malignant nodules from the Veterans AdministrationArmed Forces Cooperative Study on Asymptomatic Pulmonary Nodules (20). Pretest Probability We performed separate analyses for representative patients with low (26%), intermediate (55%), and high (79%) pretest probabilities of malignancy. Although most clinicians assess this intuitively, investigators have developed quantitative models to estimate the probability of cancer. One model that has undergone preliminary validation used logistic regression to identify six independent predictors of malignancy: age, smoking status, history of cancer, nodule diameter, spiculation, and upper lobe location (21). Additional information about this model, including the prediction equation, can be found in the Appendix. Diagnostic Test Performance We performed a meta-analysis to estimate the diagnostic accuracy of FDG-PET; our methods and results have been published elsewhere (22). We identified 13 studies of FDG-PET that enrolled 450 patients with pulmonary nodules (23-35). We used the method of Moses and colleagues (36, 37) to construct a summary receiver-operating characteristic (ROC) curve for FDG-PET. For our base-case estimates, we selected an operating point on the ROC curve that corresponded to the median specificity of FDG-PET in the 13 studies. At this point on the curve, sensitivity and specificity for identifying malignancy were 94.2% and 83.3%, respectively. To estimate diagnostic performance for CT and transthoracic needle biopsy, we searched MEDLINE and applied Moses and colleagues' method to construct summary ROC curves for these tests. For CT, base-case estimates of sensitivity and specificity for identifying malignancy were 96.5% and 55.8%, respectively (2-4, 38-47). In this report, the terms possibly malignant and benign describe CT results that are positive and negative for malignancy, respectively. We estimated that CT-guided needle biopsy would not reveal a specific diagnosis in 8% of patients with malignant nodules and 44% of patients with benign nodules (27, 48-55). When fluoroscopic guidance was used, we assumed that the frequency of nondiagnostic biopsy results would be 10% higher (56-58). When needle biopsy revealed a specific benign or malignant diagnosis, we estimated that the false-negative and false-positive rates were 3.7% and 2.0%, respectively (27, 48-55). Base-case estimates of the probability of minor pneumothorax and major pneumothorax requiring chest tube drainage were 24% and 5%, respectively (27, 48-55). We assumed that video-assisted thoracoscopy would be used to perform surgical biopsy and that the procedure would be converted to a thoracotomy with lobectomy if the frozen section revealed malignancy. We derived estimates for probabilities of fatal and non-fatal surgical complications from sources in the clinical literature (59-67). Costs We converted all costs to 2001 U.S. dollars by using the gross domestic product deflator (68, 69). To derive costs for imaging tests and needle biopsy, we added procedure costs and professional fees that were based on Medicare reimbursement rates (70, 71). To estimate costs for surgical procedures and complications, we added professional fees (70) and median cost-adjusted charges from the 1996 Health Care Utilization Project database (72). To estimate long-term costs for patients with local, regional, and distant-stage lung cancer, we analyzed Medicare claims files linked with data from the SEER tumor registry for the years 1990 to 1993 (73). To estimate health care costs for patients with benign nodules and for patients with malignant nodules who survived more than 5 years after diagnosis, we used age-specific, annual health care expenditures from the Consumer Expenditures Study (74). Utilities We adjusted life expect