Lung cancers diagnosed at annual CT screening: volume doubling times.

PURPOSE: To empirically address the distribution of the volume doubling time (VDT) of lung cancers diagnosed in repeat annual rounds of computed tomographic (CT) screening in the International Early Lung Cancer Action Program (I-ELCAP), first and foremost with respect to rates of tumor growth but also in terms of cell types. MATERIALS AND METHODS: All CT screenings in I-ELCAP from 1993 to 2009 were performed according to HIPAA-compliant protocols approved by the institutional review boards of the collaborating institutions. All instances of first diagnosis of primary lung cancer after a negative screening result 7-18 months earlier were identified, with symptom-prompted diagnoses included. Lesion diameter was calculated by using the measured length and width of each cancer at the time when the nodule was first identified for further work-up and at the time of the most recent prior screening, 7-18 months earlier. The length and width were measured a second time for each cancer, and the geometric mean of the two calculated diameters was used to calculate the VDT. The χ(2) statistic was used to compare the VDT distributions. RESULTS: The median VDT for 111 cancers was 98 days (interquartile range, 108). For 56 (50%) cancers it was less than 100 days, and for three (3%) cancers it was more than 400 days. Adenocarcinoma was the most frequent cell type (50%), followed by squamous cell carcinoma (19%), small cell carcinoma (19%), and others (12%). Lung cancers manifesting as subsolid nodules had significantly longer VDTs than those manifesting as solid nodules (P < .0001). CONCLUSION: Lung cancers diagnosed in annual repeat rounds of CT screening, as manifest by the VDT and cell-type distributions, are similar to those diagnosed in the absence of screening.

Emphysema scores predict death from COPD and lung cancer.

OBJECTIVE: Our objective was to assess the usefulness of emphysema scores in predicting death from COPD and lung cancer. METHODS: Emphysema was assessed with low-dose CT scans performed on 9,047 men and women for whom age and smoking history were documented. Each scan was scored according to the presence of emphysema as follows: none, mild, moderate, or marked. Follow-up time was calculated from time of CT scan to time of death or December 31, 2007, whichever came first. Cox regression analysis was used to calculate the hazard ratio (HR) of emphysema as a predictor of death. RESULTS: Median age was 65 years, 4,433 (49%) were men, and 4,133 (46%) were currently smoking or had quit within 5 years. Emphysema was identified in 2,637 (29%) and was a significant predictor of death from COPD (HR, 9.3; 95% CI, 4.3-20.2; P < .0001) and from lung cancer (HR, 1.7; 95% CI, 1.1-2.5; P = .013), even when adjusted for age and smoking history. CONCLUSIONS: Visual assessment of emphysema on CT scan is a significant predictor of death from COPD and lung cancer.

Chemotherapy significantly increases the risk of radiation pneumonitis in radiation therapy of advanced lung cancer.

INTRODUCTION: The reported rate of developing radiation pneumonitis (RP) in patients receiving definitive radiation therapy (RT) for lung cancer is 5% to 36%. However, this incidence is probably underreported because of the nonspecific symptoms of RP that may be erroneously attributed to another cardiovascular or respiratory disorder. The objective of this study was to evaluate the incidence of RP in lung cancer patients receiving RT or chemoradiation therapy. METHODS: Of the 110 patients that were reviewed, 86 were chosen for a retrospective analysis. A diagnosis of RP was made based on clinical assessment in the first 6 to 12 months after RT. Radiation pneumonitis was graded as per Radiation Therapy Oncology Group grading criteria. RESULTS: The incidence of developing grade 2 or higher RP was significantly associated with addition of chemotherapy. The incidence of RP in patients receiving chemotherapy was 62.7% (42/67) versus 15.8% (3/19) in patients receiving no chemotherapy (P < 0.001). However, there was no significant effect of the type or sequence of chemotherapy on the incidence of RP. The risk of developing RP is 5 times greater in patients receiving chemotherapy when compared with those not receiving this treatment (hazard ratio: 5.0; 95% confidence interval 1.5, 16.1). In addition, patients in age group 61 to 70 years had a significantly increased risk of developing RP compared with patients of age 60 or younger (hazard ratio: 3.0; 95% confidence interval: 1.4, 6.5). Histology and radiation dose were not significant factors in development of RP. CONCLUSION: The incidence of RP in patients receiving external-beam RT is significantly increased with addition of chemotherapy and 61 to 70 year age group.

Ordinal scoring of coronary artery calcifications on low-dose CT scans of the chest is predictive of death from cardiovascular disease.

PURPOSE: To assess the usefulness of ordinal scoring of the visual assessment of coronary artery calcification (CAC) on low-dose computed tomographic (CT) scans of the chest in the prediction of cardiovascular death. MATERIALS AND METHODS: All participants consented to low-dose CT screening according to an institutional review board-approved protocol. The amount of CAC was assessed on ungated low-dose CT scans of the chest obtained between June 2000 and December 2005 in a cohort of 8782 smokers aged 40-85 years. The four main coronary arteries were visually scored, and each participant received a CAC score of 0-12. The date and cause of death was obtained by using the National Death Index. Follow-up time (median, 72.3 months; range, 0.3-91.9 months) was calculated as the time between CT and death, loss to follow-up, or December 31, 2007, whichever came first. Logistic regression analysis was used to determine the risk of mortality according to CAC category adjusted for age, pack-years of cigarette smoking, and sex. The same analysis to determine the hazard ratio for survival from cardiac death was performed by using Cox regression analysis. RESULTS: The rate of cardiovascular deaths increased with an increasing CAC score and was 1.2% (43 of 3573 subjects) for a score of 0, 1.8% (66 of 3569 subjects) for a score of 1-3, 5.0% (51 of 1015 subjects) for a score of 4-6, and 5.3% (33 of 625 subjects) for a score of 7-12. With use of subjects with a CAC score of 0 as the reference group, a CAC score of at least 4 was a significant predictor of cardiovascular death (odds ratio [OR], 4.7; 95% confidence interval: 3.3, 6.8; P < .0001); when adjusted for sex, age, and pack-years of smoking, the CAC score remained significant (OR, 2.1; 95% confidence interval: 1.4, 3.1; P = .0002). CONCLUSION: Visual assessment of CAC on low-dose CT scans provides clinically relevant quantitative information as to cardiovascular death.

Thalidomide and rituximab in Waldenstrom macroglobulinemia.

Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m(2) per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie,

Survival of patients with stage I lung cancer detected on CT screening.

BACKGROUND: The outcome among patients with clinical stage I cancer that is detected on annual screening using spiral computed tomography (CT) is unknown. METHODS: In a large collaborative study, we screened 31,567 asymptomatic persons at risk for lung cancer using low-dose CT from 1993 through 2005, and from 1994 through 2005, 27,456 repeated screenings were performed 7 to 18 months after the previous screening. We estimated the 10-year lung-cancer-specific survival rate among participants with clinical stage I lung cancer that was detected on CT screening and diagnosed by biopsy, regardless of the type of treatment received, and among those who underwent surgical resection of clinical stage I cancer within 1 month. A pathology panel reviewed the surgical specimens obtained from participants who underwent resection. RESULTS: Screening resulted in a diagnosis of lung cancer in 484 participants. Of these participants, 412 (85%) had clinical stage I lung cancer, and the estimated 10-year survival rate was 88% in this subgroup (95% confidence interval [CI], 84 to 91). Among the 302 participants with clinical stage I cancer who underwent surgical resection within 1 month after diagnosis, the survival rate was 92% (95% CI, 88 to 95). The 8 participants with clinical stage I cancer who did not receive treatment died within 5 years after diagnosis. CONCLUSIONS: Annual spiral CT screening can detect lung cancer that is curable.

CT screening for lung cancer: the value of short-term CT follow-up.

BACKGROUND: Although CT screening for lung cancer results in a diagnosis of stage I > 80% of the time, benign noncalcified nodules are also found. We recognized that some nodules appeared to represent infectious bronchopneumonia or other inflammatory processes, as they resolved on follow-up CT, sometimes after antibiotic therapy. To determine the extent to which short-term CT radiographic follow-up might shorten the workup of nodules, we reviewed our experience with baseline and annual repeat CT screenings performed subsequent to the original Early Lung Cancer Action Project series. METHODS: The initial CT of 1,968 consecutive baseline and 2,343 annual repeat screenings performed from 1999 to 2002 was reviewed. We identified all those recommended for antibiotics on the initial CT who had a follow-up CT within 2 months and determined whether the nodule(s) resolved, decreased in size, remained unchanged, or grew. We then determined whether further follow-up resulted in a diagnosis of cancer. RESULTS: At baseline, among the 41 individuals who had follow-up CT within 2 months of the initial CT, 12 patients (29%) had complete or partial resolution; none of them subsequently received a diagnosis of lung cancer. On annual repeat screening, among the 39 individuals who had follow-up CT within 2 months of the initial CT, 29 patients (74%) had complete or partial resolution; none of them subsequently received a diagnosis of lung cancer. Among the 29 patients with nodules at baseline that were unchanged or grew, a total of 15 cancers were subsequently diagnosed; among the 10 patients on annual repeat scanning, there were 2 cancers. CONCLUSIONS: In asymptomatic individuals undergoing CT screening for lung cancer, short-term follow-up CT within 2 months with or without antibiotics may circumvent the need for further evaluation in some individuals, particularly on annual repeat screening.

CT screening for lung cancer Assessing a regimen's diagnostic performance.

PURPOSE: The purpose of this study was to characterize the diagnostic performance of a regimen of CT screening for lung cancer. METHODS: Using a common protocol/regimen of screening, 2968 asymptomatic persons at high risk for lung cancer were enrolled in two studies [Early Lung Cancer Action Projects (ELCAP) I and II] for baseline and annual repeat screening. A total of 4538 annual repeat screenings were performed. The regimen's diagnostic performance was characterized in terms of frequency of positive result of the initial CT as well as of screen-diagnosis and Stage I screen-diagnosis among all diagnoses (interim-diagnoses included), all separately for baseline and annual repeat screenings. RESULTS: The proportions with positive result of the initial CT were 12% and 6% in the baseline and repeat screenings, respectively. The proportions of screen-diagnoses among all diagnoses (interim-diagnoses included) were 97% and 99% in the baseline and repeat cycles, respectively. The corresponding proportions of pre-surgical Stage I screen-diagnoses were 95% and 93%. CONCLUSION: The performance of the ELCAP regimen is quite satisfactory in avoiding over many positive results of the initial CT, and it produces highly promising diagnostic results as for the attainment of cure by early intervention.

Managing the small pulmonary nodule discovered by CT.

OBJECTIVES: To review the Early Lung Cancer Action Project experience and the medical literature from 1993 to 2003 on detection of the small, noncalcified pulmonary nodule by CT in order to formulate a management algorithm for these nodules. DESIGN: Prospective noncomparative study of smokers without prior malignancy and a review of the medical literature of CT screening of lung cancer. INTERVENTIONS: Chest CT and, where appropriate, CT observation for nodule growth, antibiotics, CT-guided fine-needle aspiration (FNA) biopsy, fiberoptic bronchoscopy, and video-assisted thoracoscopic surgery (VATS). RESULTS: The following factors influence the probability of malignancy in a CT-detected, small, noncalcified pulmonary nodule: size, change in size, age, smoking history, density, number of nodules, gender, circumstance of the CT, spirometry, occupational history, and endemic granulomatous disease. The two diagnostic techniques most useful in evaluating the CT-detected, small, noncalcified nodule are short-term observation of nodule growth by CT and CT-guided FNA. Due to small nodule size and the frequent finding of nonsolid or part-solid nodules, positron emission tomography, fiberoptic bronchoscopy, and VATS were less useful. CONCLUSIONS: Pulmonologists are frequently asked to evaluate the CT-detected, small, noncalcified nodule invisible on standard chest radiography. Immediate biopsy is justified if the likelihood of cancer is high, but if that likelihood is low or intermediate, a period of observation by CT is appropriate. VATS or thoracotomy are rarely necessary for a diagnosis of lung cancer in the CT-detected small pulmonary nodule.

CT screening for lung cancer: suspiciousness of nodules according to size on baseline scans.

PURPOSE: To assess the frequency with which a particular, possibly optimal work-up of noncalcified nodules less than 5.0 mm in diameter identified on initial computed tomographic (CT) images at baseline screening leads to a diagnosis of malignancy prior to first annual repeat screening, compared with a possibly optimal work-up of larger nodules. MATERIALS AND METHODS: Two series of baseline CT screenings in high-risk people were retrospectively reviewed. The first series (n = 1,000) was performed in 1993-1998; the second (n = 1,897), in 1999-2002. In each series, cases in which the largest noncalcified nodule detected was less than 5.0 mm in diameter and those in which it was 5.0-9 mm were reviewed to determine whether diagnostic work-up prior to first annual repeat screening showed or would have shown nodule growth and led or would have led to a diagnosis based on biopsy or surgical specimens. RESULTS: The frequency with which malignancy was or could have been diagnosed when the largest noncalcified nodule was less than 5.0 mm in diameter was 0 of 378, whereas when the largest noncalcified nodule was 5.0-9 mm in diameter, the frequency was 13 or 14 of 238. If persons with only nodules smaller than 5.0 mm had merely been referred for first annual repeat screening without immediate further work-up, the referrals for such work-up would have been reduced by 54% (from 817 [28%] to 385 [13%] of 2,897). CONCLUSION: In modern CT screening for lung cancer at baseline, detected noncalcified nodules smaller than 5.0 mm in diameter do not justify immediate work-up but only annual repeat screening to determine whether interim growth has occurred.

Tumor size predicts survival within stage IA non-small cell lung cancer.

STUDY OBJECTIVES: The basic premise of CT screening is that size is an important determinant of survival in lung cancer. We sought to examine this hypothesis within stage IA non-small cell lung cancer (NSCLC). METHODS: A retrospective analysis of all patients with pathologically confirmed stage IA NSCLC resected from 1991 to 2001 was conducted. All but seven patients underwent anatomic lung resection and mediastinal lymph node dissection. Kaplan-Meier survival analysis was performed to estimate the 5-year overall and disease-specific survival probability stratified by tumor size. The influence of age, gender, histology, and tumor size on survival was also analyzed using a Cox proportional hazards regression model. RESULTS: There were 244 patients (mean age, 66.7 years; 45.1% were men). Lobectomy was performed in 229 patients, segmentectomy in 8 patients, and wedge resection in 7 patients. Operative mortality was 0.4%. Histologic breakdown was as follows: adenocarcinoma (59.4%), squamous (18.9%), bronchoalveolar (15.2%), large cell (4.5%), and poorly differentiated (2.0%). The median follow-up time for all patients was 2.6 years. The 5-year survival probability for all patients was 71.1% (95% confidence interval [CI], 63.6 to 78.6%). For 161 patients with tumor sizes < or = 2.0 cm, the 5-year survival probability was 77.2% (95% CI, 68.6 to 85.8%) in comparison with 60.3% (95% CI, 46.7 to 73.8%) in 83 patients with tumor size > 2.0 cm (p = 0.03 by log-rank test). The overall 5-year disease-specific survival was 74.9% (95% CI, 67.6 to 82.2%). Disease-specific survival was 81.4% (95% CI, 73.3 to 89.4%) for patients with tumors < or = 2.0 cm and 63.4% (95% CI, 49.6 to 77.1%) for patients with tumors > 2.0 cm. CONCLUSIONS: These data suggest that size within stage IA is an important predictor of survival and that further substaging should be considered.

Overdiagnosis in chest radiographic screening for lung carcinoma: frequency.

BACKGROUND: The pattern of results in the Mayo Lung Project (MLP), which is the basis for the prevailing recommendations against radiographic screening for lung carcinoma, has led to the assertion that up to 50% of the diagnosed cases of early-stage disease in that trial may have represented overdiagnosed, indolent cases. This finding suggests the possibility of such a high frequency of overdiagnosis in chest radiographic lung carcinoma screening in general. In the current study, the authors analyzed data from the MLP and its counterpart study at Memorial Sloan-Kettering Cancer Center (MSK) to estimate the frequency of overdiagnosis in these studies. METHODS: For the cases diagnosed as Stage I in the MLP and the MSK studies, the doubling times of tumor volumes were calculated. The calculations were based on size measurements recorded by the original investigators from chest radiographs taken during the course of each study. RESULTS: The median doubling times were 101 days in the MLP and 144 days in the MSK, times that are somewhat shorter than those reported in published series of adenocarcinoma cases diagnosed outside screening, and only 5% had doubling times exceeding 400 days. CONCLUSIONS: The hypothesis that early-stage lung tumors diagnosed on chest radiography during lung carcinoma screening may frequently be overdiagnosed, indolent cases needs to be rejected.

Computed tomography screening for lung cancer.

The development of CT technology reopened the lung cancer screening debate. Computed tomography screening for lung cancer certainly meets all the criteria required for an appropriate screening test. First and perhaps most importantly, the disease for which the screening is being performed should have a significant prevalence in the population being studied and be a significant health risk for those afflicted with it. Lung cancer is the leading cause of cancer death in both men and women, and one of the most lethal of all cancers.

Mammographic screening: no reliable supporting evidence?

Much confusion is being generated by the conclusion of a recent review that "there is no reliable evidence that screening for breast cancer reduces mortality." In that review, however, there was no appreciation of the appropriate mortality-related measure of screening's usefulness; and correspondingly, there was no estimation of the magnitude of this measure. We take this measure to be the proportional reduction in case-fatality rate, and studied its magnitude on the basis of the only valid and otherwise suitable trial. We found reliable evidence of fatality reduction, apparently substantial in magnitude.