Frank C. Detterbeck

Benefits and Harms of CT Screening for Lung Cancer: A Systematic Review

CONTEXT Lung cancer is the leading cause of cancer death. Most patients are diagnosed with advanced disease, resulting in a very low 5-year survival. Screening may reduce the risk of death from lung cancer. OBJECTIVE To conduct a systematic review of the evidence regarding the benefits and harms of lung cancer screening using low-dose computed tomography (LDCT). A multisociety collaborative initiative (involving the American Cancer Society, American College of Chest Physicians, American Society of Clinical Oncology, and National Comprehensive Cancer Network) was undertaken to create the foundation for development of an evidence-based clinical guideline. DATA SOURCES MEDLINE (Ovid: January 1996 to April 2012), EMBASE (Ovid: January 1996 to April 2012), and the Cochrane Library (April 2012). STUDY SELECTION Of 591 citations identified and reviewed, 8 randomized trials and 13 cohort studies of LDCT screening met criteria for inclusion. Primary outcomes were lung cancer mortality and all-cause mortality, and secondary outcomes included nodule detection, invasive procedures, follow-up tests, and smoking cessation. DATA EXTRACTION Critical appraisal using predefined criteria was conducted on individual studies and the overall body of evidence. Differences in data extracted by reviewers were adjudicated by consensus. RESULTS Three randomized studies provided evidence on the effect of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 participants enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer−specific mortality, 274 vs 309 events per 100,000 person-years for LDCT and control groups, respectively; relative risk, 0.80; 95% CI, 0.73-0.93; absolute risk reduction, 0.33%; P = .004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, approximately 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and percentage of surgical procedures performed in patients with benign lesions. Major complications in those with benign conditions were rare. CONCLUSION Low-dose computed tomography screening may benefit individuals at an increased risk for lung cancer, but uncertainty exists about the potential harms of screening and the generalizability of results.

The New Lung Cancer Staging System

The International Association for the Study of Lung Cancer (IASLC) has conducted an extensive initiative to inform the revision of the lung cancer staging system. This involved development of an international database along with extensive analysis of a large population of patients and their prognoses. This article reviews the recommendations of the IASLC International Staging Committee for the definitions for the TNM descriptors and the stage grouping in the new non-small cell lung cancer staging system.

Methods for Staging Non-small Cell Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND Correctly staging lung cancer is important because the treatment options and prognosis differ significantly by stage. Several noninvasive imaging studies and invasive tests are available. Understanding the accuracy, advantages, and disadvantages of the available methods for staging non-small cell lung cancer is critical to decision-making. METHODS Test accuracies for the available staging studies were updated from the second iteration of the American College of Chest Physicians Lung Cancer Guidelines. Systematic searches of the MEDLINE database were performed up to June 2012 with the inclusion of selected meta-analyses, practice guidelines, and reviews. Study designs and results are summarized in evidence tables. RESULTS The sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were approximately 55% and 81%, respectively, confirming that CT scanning has limited ability either to rule in or exclude mediastinal metastasis. For PET scanning, estimates of sensitivity and specificity for identifying mediastinal metastasis were approximately 77% and 86%, respectively. These findings demonstrate that PET scanning is more accurate than CT scanning, but tissue biopsy is still required to confirm PET scan findings. The needle techniques endobronchial ultrasound-needle aspiration, endoscopic ultrasound-needle aspiration, and combined endobronchial ultrasound/endoscopic ultrasound-needle aspiration have sensitivities of approximately 89%, 89%, and 91%, respectively. In direct comparison with surgical staging, needle techniques have emerged as the best first diagnostic tools to obtain tissue. Based on randomized controlled trials, PET or PET-CT scanning is recommended for staging and to detect unsuspected metastatic disease and avoid noncurative resections. CONCLUSIONS Since the last iteration of the staging guidelines, PET scanning has assumed a more prominent role both in its use prior to surgery and when evaluating for metastatic disease. Minimally invasive needle techniques to stage the mediastinum have become increasingly accepted and are the tests of first choice to confirm mediastinal disease in accessible lymph node stations. If negative, these needle techniques should be followed by surgical biopsy. All abnormal scans should be confirmed by tissue biopsy (by whatever method is available) to ensure accurate staging. Evidence suggests that more complete staging improves patient outcomes.

Postoperative Radiotherapy for Stage II or III Non–Small-Cell Lung Cancer Using the Surveillance, Epidemiology, and End Results Database

PURPOSE To investigate the association between survival and postoperative radiotherapy (PORT) in patients with resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Within the Surveillance, Epidemiology, and End Results database, we selected patients with stage II or III NSCLC who underwent a lobectomy or pneumonectomy. Only those patients coded as receiving PORT or observation were included. To account for perioperative mortality, we excluded patients who survived less than 4 months. As a result of our inclusion criteria, we selected a total of 7,465 patients, with a median follow-up time of 3.5 years for patients still alive. RESULTS Predictors for the use of PORT included age less than 50 years, higher American Joint Committee on Cancer stage, T3-4 tumor stage, larger tumor size, advanced node stage, greater number of lymph nodes involved, and a ratio of lymph nodes involved to lymph nodes sampled approaching 1.00. On multivariate analysis, older age, T3-4 tumor stage, N2 node stage, male sex, fewer sampled lymph nodes, and greater number of involved lymph nodes had a negative impact on survival. The use of PORT did not have a significant impact on survival. However, in subset analysis for patients with N2 nodal disease (hazard ratio [HR] = 0.855; 95% CI, 0.762 to 0.959; P = .0077), PORT was associated with a significant increase in survival. For patients with N0 (HR = 1.176; 95% CI, 1.005 to 1.376; P = .0435) and N1 (HR = 1.097; 95% CI, 1.015 to 1.186; P = .0196) nodal disease, PORT was associated with a significant decrease in survival. CONCLUSION In a population-based cohort, PORT use is associated with an increase in survival in patients with N2 nodal disease but not in patients with N1 and N0 nodal disease.

Systematic Review Evaluating the Timing of Thoracic Radiation Therapy in Combined Modality Therapy for Limited-Stage Small-Cell Lung Cancer

PURPOSE We employed meta-analytic techniques to evaluate early (E) versus late (L) timing of thoracic radiation therapy (RT) in limited-stage small-cell lung cancer (LS-SCLC). In addition, we assessed the impact of radiation fractionation and chemotherapeutic regimen on timing. METHODS Randomized trials published after 1985 addressing timing of RT relative to chemotherapy in LS-SCLC were included. Trials were analyzed by risk ratio (RR), risk difference, and number-needed-to-treat methods. RESULTS Overall survival (OS) RRs for all studies were 1.17 at 2 years (95% CI, 1.02 to 1.35; P = .03) and 1.13 at 3 years (95% CI, 0.92 to 1.39; P = .2), indicating a significantly increased 2-year survival for ERT versus LRT patients and suggestive of a similar trend at 3 years. Subset analysis of studies using hyperfractionated RT revealed OS RR for ERT versus LRT of 1.44 (95% CI, 1.17 to 1.77; P = .001) and 1.39 (95% CI, 1.02 to 1.90; P = .04) at 2 and 3 years, respectively, indicating a survival benefit of ERT versus LRT. Studies using once-daily fractionation showed no difference in 2- and 3-year OS RRs for ERT compared with LRT. Studies using platinum-based chemotherapy had OS RRs of 1.30 (95% CI, 1.10 to 1.53; P = .002) and 1.35 (95% CI, 1.07 to 1.70; P = .01) at 2 and 3 years, respectively, favoring ERT. Studies using nonplatinum-based chemotherapy regimens had nonsignificant differences in OS. CONCLUSION A small but significant improvement in 2-year OS for ERT versus LRT in LS-SCLC was observed, similar to the benefit of adding RT to chemotherapy or prophylactic cranial irradiation. A greater difference was evident for hyperfractionated RT and platinum-based chemotherapy.

Screening for Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND Lung cancer is by far the major cause of cancer deaths largely because in the majority of patients it is at an advanced stage at the time it is discovered, when curative treatment is no longer feasible. This article examines the data regarding the ability of screening to decrease the number of lung cancer deaths. METHODS A systematic review was conducted of controlled studies that address the effectiveness of methods of screening for lung cancer. RESULTS Several large randomized controlled trials (RCTs), including a recent one, have demonstrated that screening for lung cancer using a chest radiograph does not reduce the number of deaths from lung cancer. One large RCT involving low-dose CT (LDCT) screening demonstrated a significant reduction in lung cancer deaths, with few harms to individuals at elevated risk when done in the context of a structured program of selection, screening, evaluation, and management of the relatively high number of benign abnormalities. Whether other RCTs involving LDCT screening are consistent is unclear because data are limited or not yet mature. CONCLUSIONS Screening is a complex interplay of selection (a population with sufficient risk and few serious comorbidities), the value of the screening test, the interval between screening tests, the availability of effective treatment, the risk of complications or harms as a result of screening, and the degree with which the screened individuals comply with screening and treatment recommendations. Screening with LDCT of appropriate individuals in the context of a structured process is associated with a significant reduction in the number of lung cancer deaths in the screened population. Given the complex interplay of factors inherent in screening, many questions remain on how to effectively implement screening on a broader scale.

Blunt tracheobronchial injuries: treatment and outcomes

BACKGROUND Tracheobronchial injury is a recognized, yet uncommon, result of blunt trauma to the thorax. Often the diagnosis and treatment are delayed, resulting in attempted surgical repair months or even years after the injury. This report is an extensive review of the literature on tracheobronchial ruptures that examines outcomes and their association with the time from injury to diagnosis. METHODS We reviewed all patients with blunt tracheobronchial injuries published in the literature to determine the anatomic location of the injury, mechanism of the injury, time until diagnosis and treatment, and outcome. Only patients with blunt intrathoracic tracheobronchial traumas were included. RESULTS We identified 265 patients reported between 1873 and 1996. Motor vehicle accidents were the most frequent mechanism of injury (59%). The overall mortality among reported patients has declined from 36% before 1950 to 9% since 1970. The injury occurred within 2 cm of the carina in 76% of patients, and 43% occurred within the first 2 cm of the right main bronchus. The proximity of the injury to the carina had no detectable effect on mortality. Injuries on the right side were treated sooner but were associated with a higher mortality than left-sided injuries. No association was detected between delay in treatment and successful repair of the injury; ninety percent of patients undergoing treatment more than 1 year after injury were repaired successfully. CONCLUSIONS This review of patients with blunt tracheobronchial injuries represents the largest cohort studied to date. These data suggest an ability to repair tracheobronchial injuries successfully many months after they occur. We are also able to assess the mortality associated with the location and side of injury, examine the time from injury until diagnosis and treatment, and evaluate treatment outcome.

Concurrent radiation therapy and chemotherapy followed by esophagectomy for localized esophageal carcinoma.

PURPOSE A prospective study was performed to determine the outcome of patients with esophageal cancer who received preoperative radiation therapy and chemotherapy followed by esophagectomy, and to determine the role of preresection esophagogastroduodenoscopy (EGD) in predicting the patients in whom surgery could possibly be omitted, and the impact of surgery on survival. MATERIALS AND METHODS Thirty-five patients with localized carcinoma of the esophagus received concurrent external-beam radiotherapy and chemotherapy followed by esophagectomy. Patients received 45 Gy in 25 fractions. Chemotherapy consisted of continuous infusion fluorouracil (5-FU; 1,000 mg/m2/d) on days 1 through 4 and 29 through 32 and cisplatin (100 mg/m2) on day 1. Patients underwent an Ivor-Lewis esophagectomy 18 to 33 days after completion of radiotherapy. RESULTS Eighty percent of the patients had squamous cell carcinoma and 20% had adenocarcinoma. In addition, 51% had a pathologic complete response (CR). Twenty-two of the 35 underwent a preresection EGD before resection. Seventeen of the 22 (77%) had negative pathology from the preresection EGD, but seven of the 17 (41%) had residual tumor at surgery. The median survival and disease-free survival rates for all patients were 25.8 months and 32.8 months, respectively. Eighteen patients (51%) had no tumor at resection. The median survival for these patients was 36.8 months; the median disease-free survival time has not been reached. The median survival and disease-free survival rate for the patients with residual tumor in the surgical specimen were 12.9 months and 10.8 months, respectively. CONCLUSION Preresection EGD is not reliable for determining the presence of residual disease or the patients in whom surgery could be omitted. Twenty-five percent of the patients with residual tumor in the resected surgical specimen were long-term survivors; this suggests a benefit from esophagectomy after concurrent radiotherapy and chemotherapy.

Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

OBJECTIVES Stage III non-small cell lung cancer (NSCLC) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky nodal disease. This review updates the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients. METHODS Systematic searches were conducted through MEDLINE, Embase, and the Cochrane Database for Systematic Review up to December 2011, focusing primarily on randomized trials, selected meta-analyses, practice guidelines, and reviews. RESULTS For individuals with stage IIIA or IIIB disease, good performance scores, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy alone. Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported. Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation. Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy; however, weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate. The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. Postoperative radiotherapy improves local control without improving survival. CONCLUSIONS Multimodality therapy is preferable in most subsets of patients with stage III lung cancer. Variability in the patients included in randomized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios. Future trials are needed to investigate the roles of individualized chemotherapy, surgery in particular cohorts or settings, prophylactic cranial radiation, and adaptive radiation.

Special Treatment Issues in Non-small Cell Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND This guideline updates the second edition and addresses patients with particular forms of non-small cell lung cancer that require special considerations, including Pancoast tumors, T4 N0,1 M0 tumors, additional nodules in the same lobe (T3), ipsilateral different lobe (T4) or contralateral lung (M1a), synchronous and metachronous second primary lung cancers, solitary brain and adrenal metastases, and chest wall involvement. METHODS The nature of these special clinical cases is such that in most cases, meta-analyses or large prospective studies of patients are not available. To ensure that these guidelines were supported by the most current data available, publications appropriate to the topics covered in this article were obtained by performing a literature search of the MEDLINE computerized database. Where possible, we also reference other consensus opinion statements. Recommendations were developed by the writing committee, graded by a standardized method, and reviewed by all members of the Lung Cancer Guidelines panel prior to approval by the Thoracic Oncology NetWork, Guidelines Oversight Committee, and the Board of Regents of the American College of Chest Physicians. RESULTS In patients with a Pancoast tumor, a multimodality approach appears to be optimal, involving chemoradiotherapy and surgical resection, provided that appropriate staging has been carried out. Carefully selected patients with central T4 tumors that do not have mediastinal node involvement are uncommon, but surgical resection appears to be beneficial as part of their treatment rather than definitive chemoradiotherapy alone. Patients with lung cancer and an additional malignant nodule are difficult to categorize, and the current stage classification rules are ambiguous. Such patients should be evaluated by an experienced multidisciplinary team to determine whether the additional lesion represents a second primary lung cancer or an additional tumor nodule corresponding to the dominant cancer. Highly selected patients with a solitary focus of metastatic disease in the brain or adrenal gland appear to benefit from resection or stereotactic radiosurgery. This is particularly true in patients with a long disease-free interval. Finally, in patients with chest wall involvement, provided that the tumor can be completely resected and N2 nodal disease is absent, primary surgical resection should be considered. CONCLUSIONS Carefully selected patients with more uncommon presentations of lung cancer may benefit from an aggressive surgical approach.