Chest X-ray screening for lung cancer: overdiagnosis, endpoints, and randomized population trials.

Publication of the National Lung Screening Trial (NLST) generated excitement by concluding that CT screening reduces lung cancer mortality when compared to chest X-ray (CXR) screening. In contrast, CXR screening has long been considered to be ineffective. This is because randomized population trials (RPTs) have failed to demonstrate significant mortality reductions in populations randomized to CXR screening. While these studies demonstrate that CXR screening is associated with significant survival advantages, these advantages have been widely interpreted as spurious, due to the inference that CXR screening leads to substantial lung cancer overdiagnosis. Indeed, the reality of the overdiagnosis hypothesis is the only alternative to the conclusion that CXR screening was effective in these trials and that survival more accurately reflected the benefit of CXR screening than mortality. Mortality comparisons would be biased if randomization fails to create comparison groups with an equal probability of mortality from the target cancer. The objective of this manuscript is to review existing RPTs on CXR screening for lung cancer, and to analyze which endpoint most accurately reflects screening efficacy. We conclude that the evidence supports that CXR screening is superior to no screening, and the magnitude of overdiagnosis is minimal in the context of CXR screening.

Adjuvant Gamma Knife radiosurgery following surgical resection of brain metastases: a 9-year retrospective cohort study.

Given the potential morbidity of whole brain radiation therapy (WBRT), there has been an increasing trend to defer WBRT and deliver Gamma Knife stereotactic radiosurgery (GKS) to cerebral metastatic lesions. We analyzed our experience delivering GKS to the tumor cavity following surgical resection of brain metastases and compared our results to patients receiving WBRT after surgical resection of a metastatic lesion. We performed a retrospective review of patients undergoing surgical resection of at least one brain metastasis between December 1999 and December 2008. Both univariate and multivariate Cox proportional hazards regression were utilized to analyze the influence of various prognostic factors on survival. Twenty-five patients had a metastatic lesion resected followed by adjuvant GKS to the resection cavity while another 18 had surgical resection followed by WBRT. Aside from a disparity in gender distribution (72% of GKS patients were female while women only constituted 28% of the WBRT group), no significant differences existed between groups. The median survival for patients receiving GKS was 15.00 months as compared to 6.81 months among those receiving WBRT (P = 0.08). Univariate Cox regression analysis identified the number of metastases (HR 1.65, 95% CI 1.07-2.54, P = 0.02) and regional recurrence (RR 5.23, 95% CI 1.78-15.38, P = 0.003) as poor prognostic factors. Multivariate regression analysis showed that regional recurrence (HR 5.17, 95% CI 1.69-15.78, P = 0.004) was again strongly associated with worse survival. Although limited by the retrospective nature of our study and lack of some clinical measures, patients undergoing GKS to the resection cavity had a trend towards longer median survival.

Management of early-stage lung cancer: past, present, and future adjuvant trials.

The standard of care with regard to adjuvant chemotherapy of lung cancer has changed remarkably over the past 3 years. Until the initial report of the International Adjuvant Lung Trial in 2003, there was no real evidence from any individual randomized clinical trial (RCT) that adjuvant chemotherapy improves survival in resectable non-small-cell lung cancer. However, five RCTs that have now been reported indicate that adjuvant chemotherapy is effective, at least in certain subgroups of resectable patients. Moreover, numerous meta-analyses have also reported a positive effect from adjuvant treatment. Nonetheless, because of methodologic. issues and conflicting results, the question of who should be treated and what constitutes optimal adjuvant therapy remains controversial. This article reviews the recent randomized trials that have contributed to a change in the state of the art, as well as some of the methodologic problems that may have confounded their proper interpretation. It also considers newer approaches to adjuvant therapy, with a particular focus on strategies that incorporate our growing knowledge of molecular medicine and predictive factors to the field of adjuvant chemotherapy of lung cancer.

The Mayo Lung Cohort: a regression analysis focusing on lung cancer incidence and mortality.

PURPOSE: The Mayo Lung Project has been interpreted as negative because it failed to demonstrate a significant mortality reduction among those randomized to chest x-ray and cytology. In contrast, survival suggests that screening is highly effective. This report was undertaken to analyze the trial as a closed cohort study, in an effort to identify predictors of lung cancer incidence and mortality, and to determine whether survival or mortality was unbiased. PATIENTS AND METHODS: The Mayo Lung Cohort comprised all 9,192 randomized individuals. Cox proportional hazards regression was used both to determine predictors of incidence and mortality in the population and to identify predictors of mortality among cases. Survival analyses using intent-to-treat principles and measuring survival from randomization were used to evaluate length bias and lead-time bias. Multivariate Cox regression was used to investigate the extent to which the data are consistent with overdiagnosis. RESULTS: Cox regression demonstrates that, in addition to age and smoking, randomization to screening predicted increased lung cancer incidence (hazard ratio, 1.30; 95% confidence interval [CI], 1.06 to 1.60). Predictors of mortality were similar, except randomization to screening was not significant (hazard ratio, 1.06; 95% CI, 0.83 to 1.37). Among cases, survival was significantly superior in the experimental population. Higher incidence in the experimental group accounts for the mortality/survival discrepancy. Both lead-time and length biases can be excluded, because survival from randomization was superior in the experimental population. Overdiagnosis is eliminated because resection was the only significant multivariate predictor of survival. Overall, 50% of resected and 0% of unresected cases were cured. CONCLUSION: Survival was superior in the screened population, and this advantage was not attributable to lead-time bias, length bias, or overdiagnosis bias. Mortality was biased, because incidence differences confounded the ability of mortality to reflect the true effect of screening. Indeed, survival provided an unbiased surrogate for cure in the Mayo Lung Cohort.

Como international conference position statement: lung cancer screening for early diagnosis 5 years after the 1998 Varese conference.

BACKGROUND: Lung cancer is the most common cause of cancer death in the world. Nonetheless, public policy organizations have consistently recommended against screening for lung cancer, with the result that screening is not widely practiced. The Como Conference was undertaken to consider the need for a change in the existing recommendations against screening. PURPOSES: The primary objective of the Como Conference was to consider whether there is sufficient scientific evidence to advise screening for lung cancer among asymptomatic individuals outside the context of a clinical trial. Methodological issues that are relevant to the proper interpretation of early detection trials were carefully considered. Advantages and problems associated with technological advances in CT scans and digital chest radiographs (CXRs) were fully explored. Economic issues relevant to screening were also considered. RECOMMENDATIONS: It is recommended that physicians assume responsibility for informing high-risk individuals regarding options for screening for lung cancer. Targeted high-risk individuals include middle-aged or elderly men and women who are current or former cigarette smokers of > 20 to 30 pack-years without serious medical comorbidities. It is recommended that such persons be informed that symptomatic lung cancer is usually advanced and incurable, while surgery for early lung cancer offers a far better chance of cure. They should also be informed about advances in imaging technology, as they relate to CT scans and CXRs. CONCLUSIONS: Whenever possible, high-risk individuals should be encouraged to enroll in ongoing trials. For subjects who, though eligible, do not have access to such trials, a process of shared decision-making between physicians and at-risk individuals is strongly recommended. After discussion of the existing state of knowledge, high-risk individuals should be made aware that it is reasonable for them to choose to undergo testing for lung cancer.

Adjuvant chemotherapy of lung cancer: methodologic issues and therapeutic advances.

This article discusses methodologic issues relevant to the interpretation of recent studies focusing on adjuvant chemotherapy of lung cancer. It also attempts to conclude where we currently stand in this field.

The benefit of chemotherapy in elderly patients with small cell lung cancer.

Elderly patients with small cell lung cancer derive a statistically significant benefit from the administration of combination chemotherapy. Numerous clinical trials have demonstrated high response rates and impressive median survivals with carboplatin and etoposide, cisplatin and etoposide, and other regimens. All elderly patients with small cell lung cancer should be evaluated by a medical oncologist to determine whether they are candidates for chemotherapy.

Cisplatin vs. carboplatin-based chemoradiotherapy in patients >65 years of age with stage III non-small cell lung cancer.

BACKGROUND AND PURPOSE: Combined chemoradiotherapy (CRT) is considered the standard care for unresectable stage III non-small cell lung cancer (NSCLC). There have been limited data comparing outcomes of carboplatin vs. cisplatin-based CRT, particularly in elderly. MATERIAL AND METHODS: From the Surveillance, Epidemiology and End Results-Medicare registry, we identified 1878 patients >65 years of age with unresected stage III NSCLC that received concurrent CRT between 2002 and 2009. We fitted a propensity score model predicting use of cisplatin-based therapy and compared adjusted overall and lung-cancer specific survival of carboplatin- vs. cisplatin-treated patients. Rates of severe toxicity requiring hospital admission were compared in propensity score adjusted analyses. RESULTS: Overall 1552 (83%) received carboplatin (77% in combination with paclitaxel) and 17% cisplatin (67% in combination with etoposide). Adjusted cox models showed similar overall (hazard ratio [HR]: 0.98; 95% confidence interval [CI]: 0.86-1.12) and lung cancer-specific (HR: 0.99; 95% CI: 0.84-1.17) survival among patients treated with carboplatin vs. cisplatin. Adjusted rates of neutropenia (odds ratio [OR]: 0.35; 95% CI: 0.21-0.61), anemia (OR: 0.67; 95% CI: 0.51-0.89), and thrombocytopenia (OR: 0.51; 95% CI: 0.31-0.85) were lower among carboplatin-treated patients; other toxicities were not different between groups. CONCLUSION: Carboplatin-based CRT is associated with similar long-term survival but lower rates of toxicity. These findings suggest carboplatin may be the most appropriate chemotherapeutic agent for elderly stage III patients.

Effects of chemotherapy on survival of elderly patients with small-cell lung cancer: analysis of the SEER-medicare database.

INTRODUCTION: This retrospective cohort study was designed to analyze factors associated with administration of chemotherapy and to examine the impact of chemotherapy on survival among elderly patients with small-cell lung cancer (SCLC) in the community. METHODS: Elderly patients aged 65 years and older with SCLC diagnosed between 1992 and 2001 were selected from the Surveillance, Epidemiology, and End Results-Medicare database. Logistic regression was used to evaluate which covariates influenced receipt of chemotherapy. Cox proportional hazards regression was used to examine the influence of clinical and demographic variables on survival. The independent effect of chemotherapy on survival was determined using propensity scores and quantile regression. RESULTS: In the final cohort of 10,428 patients, 67.1% received chemotherapy, 39.1% received radiation, 3.4% received surgery, and 21.8% received no treatment. The most common chemotherapy regimens included etoposide combined with either cisplatin or carboplatin. Patients aged 85 years and older were significantly less likely to receive chemotherapy compared with patients aged 65 to 69 years (odds ratio 0.17; 95% confidence interval 0.14-0.21). Median survival for all patients was 7 months. Factors associated with improved survival were being female, black race, having limited-stage disease, receiving any treatment, and having a lower comorbidity score. Quantile regression demonstrated that chemotherapy provided a 6.5-month improvement in median survival (95% confidence interval 6.3-6.6; p<0.001). CONCLUSIONS: Statistically significant differences in the receipt of chemotherapy exist among elderly patients with SCLC. Chemotherapy is associated with a greater than 6-month improvement in median survival among elderly patients with SCLC, even in patients over the age of 80 years.

Development of The American Association for Thoracic Surgery guidelines for low-dose computed tomography scans to screen for lung cancer in North America: recommendations of The American Association for Thoracic Surgery Task Force for Lung Cancer Screening and Surveillance.

OBJECTIVE: The study objective was to establish The American Association for Thoracic Surgery (AATS) lung cancer screening guidelines for clinical practice. METHODS: The AATS established the Lung Cancer Screening and Surveillance Task Force with multidisciplinary representation including 4 thoracic surgeons, 4 thoracic radiologists, 4 medical oncologists, 1 pulmonologist, 1 pathologist, and 1 epidemiologist. Members have engaged in interdisciplinary collaborations regarding lung cancer screening and clinical care of patients with, and at risk for, lung cancer. The task force reviewed the literature, including screening trials in the United States and Europe, and discussed local best clinical practices in the United States and Canada on 4 conference calls. A reference library supported the discussions and increased individual study across disciplines. The task force met to review the literature, state of clinical practice, and recommend consensus-based guidelines. RESULTS: Nine of 14 task force members were present at the meeting, and 3 participated by telephone. Two absent task force members were polled afterward. Six unanimous recommendations and supporting work-up algorithms were presented to the Council of the AATS at the 2012 annual meeting in San Francisco, California. CONCLUSIONS: Annual lung cancer screening and surveillance with low-dose computed tomography is recommended for smokers and former smokers with a 30 pack-year history of smoking and long-term lung cancer survivors aged 55 to 79 years. Screening may begin at age 50 years with a 20 pack-year history of smoking and additional comorbidity that produces a cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Screening should be undertaken with a subspecialty qualified interdisciplinary team. Patient risk calculator application and intersociety engagement will provide data needed to refine future lung cancer screening guidelines.

The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.

OBJECTIVE: Lung cancer is the leading cause of cancer death in North America. Low-dose computed tomography screening can reduce lung cancer-specific mortality by 20%. METHOD: The American Association for Thoracic Surgery created a multispecialty task force to create screening guidelines for groups at high risk of developing lung cancer and survivors of previous lung cancer. RESULTS: The American Association for Thoracic Surgery guidelines call for annual lung cancer screening with low-dose computed tomography screening for North Americans from age 55 to 79 years with a 30 pack-year history of smoking. Long-term lung cancer survivors should have annual low-dose computed tomography to detect second primary lung cancer until the age of 79 years. Annual low-dose computed tomography lung cancer screening should be offered starting at age 50 years with a 20 pack-year history if there is an additional cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Lung cancer screening requires participation by a subspecialty-qualified team. The American Association for Thoracic Surgery will continue engagement with other specialty societies to refine future screening guidelines. CONCLUSIONS: The American Association for Thoracic Surgery provides specific guidelines for lung cancer screening in North America.

Survival and risk of adverse events in older patients receiving postoperative adjuvant chemotherapy for resected stages II-IIIA lung cancer: observational cohort study.

OBJECTIVE: To compare the survival and risk of serious adverse events in older patients with stages II-IIIA non-small cell lung cancer treated with or without postoperative platinum based chemotherapy. DESIGN: Observational cohort study. SETTING: Cases of lung cancer in Surveillance Epidemiology and End Results registry linked to Medicare files, 1992-2005, and follow-up data to December 2007. PARTICIPANTS: 3324 patients aged more than 65 years with resected stages II-IIIA lung cancer. MAIN OUTCOME MEASURES: Primary outcome was overall survival and secondary outcome was the rate of serious adverse events among older patients treated with or without adjuvant chemotherapy. RESULTS: Overall, 21% (n = 684) of patients received platinum based chemotherapy. Analyses adjusted, stratified, or matched by propensity scores showed that chemotherapy was associated with improved survival (hazard ratio range 0.78-0.81). The beneficial effect of chemotherapy was also observed among patients treated with radiation therapy (0.75-0.77) or without radiation therapy (0.74-0.77); however, chemotherapy was not beneficial for patients aged 80 or more (1.32-1.46). Adjuvant chemotherapy was associated with an increased odds of serious adverse events (odds ratio 2.0, 95% confidence interval 1.5 to 2.6). CONCLUSIONS: Platinum based adjuvant chemotherapy is associated with reduced mortality and increased risk of serious adverse events in older patients with stages II-IIIA lung cancer. The magnitude of the benefit is similar to that observed in randomised controlled trials carried out among selected patients.

Reproductive factors, hormone use, and risk for lung cancer in postmenopausal women, the Nurses' Health Study.

BACKGROUND: There is increasing evidence suggesting that female hormones may play a significant role in lung cancer development. We evaluated the associations between reproductive factors, exogenous hormone use, and lung cancer incidence in the Nurses' Health Study. METHODS: We assessed age at menopause, age at menarche, type of menopause, parity, age at first birth, postmenopausal hormone (PMH) use, and past oral contraceptive use in 107,171 postmenopausal women. Cox models were used to estimate the hazard ratios for each exposure, adjusting for smoking and other covariates. RESULTS: We identified 1,729 lung cancer cases during follow-up from 1984 to 2006. Menopause onset before 44 years of age (hazard ratio, 1.39; 95% confidence interval, 1.14-1.70) and past oral contraceptive use for >5 years (hazard ratio, 1.22; 95% confidence interval, 1.05-1.42) were associated with increased lung cancer risk. These associations were strongest in current smokers and small cell histology. In never smokers, increased parity was associated with decreased risk among parous women (P trend = 0.03), whereas in current smokers, older age at first birth was associated with increased risk (P trend = 0.02). PMH use was not associated with overall lung cancer incidence. However, nonsignificant results of increased risk in adenocarcinoma were seen with current PMH use. CONCLUSIONS: Our findings suggest female hormones may influence lung carcinogenesis, although the effect is likely modest, varied by histologic subtype, and altered by smoking. IMPACT: Further investigation of the pathophysiology of female hormones in lung cancer subtypes and their interaction with smoking will lead to better understanding of lung carcinogenesis.

Prognostic significance of mucin and p53 expression in stage IB non-small cell lung cancer: a laboratory companion study to CALGB 9633.

INTRODUCTION: Cancer and Leukemia Group B 9633 was a phase III trial that randomized patients with stage IB non-small cell lung cancer to observation or four cycles of carboplatin and paclitaxel. A statistically significant effect in favor of adjuvant chemotherapy was seen for disease-free survival (DFS) and overall survival (OS) in the subgroup of patients with tumors > or =4 cm. A laboratory companion study was conducted to see whether molecular and clinical factors could provide additional prognostic information. METHODS: Formalin-fixed, paraffin-embedded blocks were obtained for 250 of the 344 patients enrolled. Immunohistochemical staining for bcl-2, p53, blood group antigen A, and mucin was correlated with DFS and OS. RESULTS: The prevalence of the markers was bcl-2, 17%; p53, 47%; blood group antigen A, 25%; and mucin, 45%. Univariate analysis for DFS showed a statistically significant effect for the presence of mucin (p = 0.0005) and p53 (p = 0.05) and for OS showed a significant effect for mucin (p = 0.0005). In the multivariate Cox model, there was a statistically significant association between shorter DFS and presence of mucin (p = 0.002; hazard ratio [HR] 2.05) and p53 (p = 0.003; HR 1.95) and between shorter OS and presence of mucin (p = 0.004; HR 2.03) and p53 (p = 0.0005; HR 2.30). Of the clinical factors, male gender and larger tumor volume were also significant adverse prognostic factors (p 0.05). CONCLUSIONS: A statistically significant association between shorter DFS and OS was seen for the patients with p53 protein expression, mucin expression, male gender, and larger tumors in this cohort of patients with stage IB non-small cell lung cancer treated on Cancer and Leukemia Group B 9633.

Differences in clinical trial patient attributes and outcomes according to enrollment setting.

PURPOSE: During the last 25 years, National Cancer Institute (NCI) cooperative trial groups have extended trial networks from academic centers to include certain community and Veterans Health Administration (VHA) centers. We compared trial patients' attributes and outcomes by these enrollment settings. PATIENTS AND METHODS: Studying 2,708 patients on one of 10 cooperative group, randomized lung trials at 272 institutions, we compared patient attributes by enrollment setting (ie, academic, community, and VHA affiliates). We used adjusted Cox regression to evaluate for survival differences by setting. RESULTS: Main member institutions enrolled 44% of patients; community affiliates enrolled 44%; and VHAs enrolled 12%. Patient attributes (ie, case-mix) of age, ethnicity, sex, and performance status varied by enrollment setting. After analysis was adjusted for patient case-mix, no mortality differences by enrollment setting were noted. CONCLUSION: Although trial patients with primarily advanced-stage lung cancer from nonacademic centers were older and had worse performance statuses than those from academic centers, survival did not differ by enrollment setting after analysis accounted for patient heterogeneity. An answer for whether long-term outcomes for patients at community and VHA centers affiliated with cooperative trial groups are equivalent to those at academic centers when care is delivered through NCI trials requires additional research among patients with longer survival horizons.

Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups.

PURPOSE: Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC. PATIENTS AND METHODS: Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival. RESULTS: Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043). CONCLUSION: Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors > or = 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.