M. Patricia Rivera

Induction and Concurrent Chemotherapy With High-Dose Thoracic Conformal Radiation Therapy in Unresectable Stage IIIA and IIIB Non–Small-Cell Lung Cancer: A Dose-Escalation Phase I Trial

PURPOSE Local control rates at conventional radiotherapy doses (60 to 66 Gy) are poor in stage III non-small-cell lung cancer (NSCLC). Dose escalation using three-dimensional thoracic conformal radiation therapy (TCRT) is one strategy to improve local control and perhaps survival. PATIENTS AND METHODS Stage III NSCLC patients with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] 5, irinotecan 100 mg/m(2), and paclitaxel 175 mg/m(2) days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly for 7 to 8 weeks) beginning on day 43. Pre- and postchemotherapy computed tomography scans defined the initial clinical target volume (CTV(I)) and boost clinical target volume (CTV(B)), respectively. The CTV(I) received 40 to 50 Gy; the CTV(B) received escalating doses of TCRT from 78 Gy to 82, 86, and 90 Gy. The primary objective was to escalate the TCRT dose from 78 to 90 Gy or to the maximum-tolerated dose. RESULTS Twenty-nine patients were enrolled (25 assessable patients; median age, 59 years; 62% male; 45% stage IIIA; 38% PS 0; and 38% > or = 5% weight loss). Induction CIP was well tolerated (with filgrastim support) and active (partial response rate, 46.2%; stable disease, 53.8%; and early progression, 0%). The TCRT dose was escalated from 78 to 90 Gy without dose-limiting toxicity. The primary acute toxicity was esophagitis (16%, all grade 3). Late toxicity consisted of grade 2 esophageal stricture (n = 3), bronchial stenosis (n = 2), and fatal hemoptysis (n = 2). The overall response rate was 60%, with a median survival time and 1-year survival probability of 24 months and 0.73 (95% CI, 0.55 to 0.89), respectively. CONCLUSION Escalation of the TCRT dose from 78 to 90 Gy in the context of induction and concurrent chemotherapy was accomplished safely in stage III NSCLC patients.

Induction chemotherapy with carboplatin, irinotecan, and paclitaxel followed by high dose three-dimension conformal thoracic radiotherapy (74 Gy) with concurrent carboplatin, paclitaxel, and gefitinib in unresectable stage IIIA and stage IIIB non-small cell lung cancer.

Introduction: Combined modality therapy is a standard therapy for patients with unresectable stage III non-small cell lung cancer (NSCLC). Gefitinib is active in advanced NSCLC, and in preclinical models, it potentiates the activity of radiation therapy. We investigate the tolerability of gefitinib in combined modality therapy in combination with three-dimensional thoracic conformal radiation therapy (3-dimensional TCRT). Methods: Stage III patients with a good performance status were treated with induction chemotherapy (carboplatin area under the curve [AUC] of 5, irinotecan 100 mg/m2, and paclitaxel 175 mg/m2 days 1 and 22) with pegfilgrastim support followed by concurrent chemotherapy (carboplatin AUC 2, and paclitaxel 45 mg/m2 weekly) and gefitinib 250 mg daily beginning on day 43 with 3-dimensional TCRT to 74 Gy. Results: Between March 2004 and January 2006, 23 patients received treatment on the trial: median age 62 years (range 44–82), 52% female, 61% stage IIIA, 61% performance status 0, 17% ≥5% weight loss, and 91% underwent positron emission tomography staging. Induction chemotherapy with pegfilgrastim support was well tolerated and active (partial response rate, 24%; stable disease, 76%; and early progression, 0%). Twenty-one patients initiated the concurrent chemoradiation, and 20 patients completed therapy to 74 Gy. The primary toxicities of concurrent chemoradiation were grade 3 esophagitis (19.5%) and cardiac arrhythmia (atrial fibrillation) (9.5%). The median progression-free survival and overall survival were 9 months (95% confidence intervals [CI]: 7–13 months) and 16 months (95% CI: 10–20 months), respectively. Conclusions: Treatment with induction chemotherapy and gefitinib concurrent with 3-dimensional TCRT has an acceptable toxicity and tolerability, but the survival results were disappointing.

An official American Thoracic Society/American College of Chest Physicians policy statement: implementation of low-dose computed tomography lung cancer screening programs in clinical practice.

RATIONALE Annual low-radiation-dose computed tomography (LDCT) screening for lung cancer has been shown to reduce lung cancer mortality among high-risk individuals and is now recommended by multiple organizations. However, LDCT screening is complex, and implementation requires careful planning to ensure benefits outweigh harms. Little guidance has been provided for sites wishing to develop and implement lung cancer screening programs. OBJECTIVES To promote successful implementation of comprehensive LDCT screening programs that are safe, effective, and sustainable. METHODS The American Thoracic Society (ATS) and American College of Chest Physicians (ACCP) convened a committee with expertise in lung cancer screening, pulmonary nodule evaluation, and implementation science. The committee reviewed the evidence from systematic reviews, clinical practice guidelines, surveys, and the experience of early-adopting LDCT screening programs and summarized potential strategies to implement LDCT screening programs successfully. MEASUREMENTS AND MAIN RESULTS We address steps that sites should consider during the main three phases of developing an LDCT screening program: planning, implementation, and maintenance. We present multiple strategies to implement the nine core elements of comprehensive lung cancer screening programs enumerated in a recent ACCP/ATS statement, which will allow sites to select the strategy that best fits with their local context and workflow patterns. Although we do not comment on cost-effectiveness of LDCT screening, we outline the necessary costs associated with starting and sustaining a high-quality LDCT screening program. CONCLUSIONS Following the strategies delineated in this policy statement may help sites to develop comprehensive LDCT screening programs that are safe and effective.

Late Complications of High-Dose (≥66 Gy) Thoracic Conformal Radiation Therapy in Combined Modality Trials in Unresectable Stage III Non-small Cell Lung Cancer

Background: Combined modality treatment is the standard of care for patients (pts) with unresectable stage III non-small cell lung cancer. Dose escalation of radiotherapy is one strategy used to improve locoregional control and survival, but it increases the risk of both early and late treatment related toxicities. Methods: From May 1996 to August 2004, a total of 112 stage III non-small cell lung cancer pts were treated on 4 phase I/II or phase II trials to assess the safety and feasibility of high-dose (60–90 Gy) thoracic conformal radiotherapy. Patients who received ≥66 Gy (n = 88) were included in an analysis of late complications. Late complications were defined as complications that developed or persisted ≥90 days postradiotherapy. The classic lung toxicities of radiation pneumonitis and fibrosis were not included in this analysis. Results: Of the 88 patients included in this analysis of late complications, 21 patients (24%) developed a late complication and a total of 28 late complications were observed. The late complications were: pulmonary (n = 5; bronchial stenosis [n = 3] and fatal pulmonary hemoptysis [n = 2]), esophageal (n = 6), cardiac (n = 9), osseous (n = 6), and second primary tumor (n = 2). The median survival for all patients enrolled on the 4 trials (with 95% confidence interval [CI]) was 24.7 months (18.1–30.4 months), and the 5-year overall survival (with 95% CI) was 24% (16–32%). Data to assess for radiographic evidence of local progression were available for 99 patients, and the rate of local progression was 43% (95% CI 34–53%). Conclusions: High-dose thoracic conformal radiotherapy is feasible and results in promising survival outcomes. Late complications occur in a minority of patients.

Long-Term Follow-Up of a Phase I/II Trial of Dose Escalating Three-Dimensional Conformal Thoracic Radiation Therapy with Induction and Concurrent Carboplatin and Paclitaxel in Unresectable Stage IIIA/B Non-small Cell Lung Cancer

Background: We conducted a modified phase I/II trial investigating the incorporation of three-dimensional conformal thoracic radiation therapy (TCRT) into the treatment paradigm of induction and concurrent carboplatin and paclitaxel in patients with unresectable stage IIIA/B non-small cell lung cancer. Methods: Patients received 2 cycles of induction carboplatin (area under the curve of 6) and paclitaxel (225 mg/m2) on days 1, and 22. On day 43 concurrent TCRT and weekly ×6 of carboplatin (area under the curve = 2) and paclitaxel (45 mg/m2) was initiated. The TCRT dose was escalated from 60 to 74 Gy in 4 cohorts (60, 66, 70, and 74 Gy), and the 74 Gy cohort was expanded into a phase II trial. Results: Sixty-two patients were enrolled; the median age 57 years (range, 36–82), 39 were male (63%), 61 (98%) had a performance status of 0 or 1, 28 (45%) had stage IIIA disease, 21 (34%) had >5% weight loss, and the median forced expiratory volume 1 = 2.10 liters (range, 1.02–3.75). With a median follow-up for survivors of approximately 9 years (range, 7–11 years) the median progression-free survival, time to tumor progression, and overall survival (OS) (with 95% confidence intervals) were 10 (8.5–17), 15 (9–50), and 25 months (18–37), respectively. The 5-year progression-free survival and OS rates were 21% (12–32%) and 27% (17–39%), respectively. The 10-year OS rate was 14% (7–25%). Conclusion: The long term survival rate compares favorably to other treatment approaches for stage III non-small cell lung cancer.

Impact of Preoperative Chemotherapy on Pulmonary Function Tests in Resectable Early-Stage Non-small Cell Lung Cancer

BACKGROUND Several chemotherapy agents, including gemcitabine and paclitaxel, have been reported to cause interstitial pneumonitis. The incidence of pulmonary toxicity from the combination of gemcitabine and paclitaxel is reported to be approximately 5%. In this report, pulmonary function test (PFT) results were analyzed from two similar randomized phase 2 trials that tested platinum and nonplatinum regimens preoperatively in patients with stage I or II non-small cell lung cancer (NSCLC). METHODS The regimens included gemcitabine plus carboplatin, paclitaxel, or cisplatin. PFT and dyspnea scores were obtained at baseline and postchemotherapy, and were compared to one of several secondary end points, including ability to undergo surgical resection. RESULTS Baseline PFT scores varied with smoking status. Mean levels of diffusing capacity of the lung for carbon monoxide (Dlco) adjusted for hemoglobin declined 8% from pre- to postinduction (Wilcoxon signed rank test, p < 0.0001). Changes in FVC, FEV(1), and total lung capacity were not statistically significant after chemotherapy. Although 27% of patients in the study had some reduction in PFT results, only 2 of the 85 eligible patients did not undergo surgery due to PFT reduction following chemotherapy. One patient in the study experienced a clinically significant respiratory toxicity (grade 3 dyspnea). Pulmonary toxicity was only statistically associated with male gender. CONCLUSION In the preoperative setting, gemcitabine-based chemotherapy was well tolerated. The most commonly affected PFT parameter postchemotherapy was the Dlco. Although 15% of patients had a significant reduction in the Dlco postchemotherapy, it did not correlate with clinical symptoms or affect the ability to undergo surgical resection.

Detection of Pre-Invasive Lung Cancer: Technical Aspects of the LIFE Project

Lung cancer is the leading cause of cancer deaths in both men and women in the United States. The LIFE (Light Induced Fluorescence Endoscopy) Project was initiated at the University of North Carolina Medical Center in November, 1999, for the dual purposes of (1) detecting pre-invasive lung cancer in high-risk patients and (2) studying the molecular biology of pre-invasive lesions of the bronchus for possible development of molecular biomarkers. Of the 47 patients enrolled, all were current or former tobacco smokers, except for 1. Fluorescence endoscopy was utilized, in addition to white light bronchoscopy, to increase the detection of intraepithelial lesions. Adjacent biopsies were submitted for permanent and frozen sections, respectively, from four predetermined sites as well as from any abnormal areas. The snap-frozen specimens were cryostat sectioned, and the mucosal epithelial cells laser capture microdissected for DNA analysis. The great majority of specimens yielded sufficiently abundant and intact DNA to accomplish the molecular objectives. Histologic concordance of adjacent permanent and frozen sections was equivalent to the concordance of adjacent permanent sections, suggesting that frozen section diagnosis was adequate for the research purpose of correlating histology with molecular analysis.

Preinvasive Lesions of the Bronchus

It has been proposed that invasive carcinoma of the bronchus develops through a transition from preinvasive lesions to overt malignancy. Newer diagnostic technologies have provided a more sensitive way to diagnose preinvasive lesions and a better understanding of the prevalence of such lesions. The natural history of preinvasive lesions has not been well defined; however, there is evidence that high-grade lesions are at a higher risk of progression to carcinoma. Molecular alterations have been described in preinvasive lesions and may help better predict which lesions will progress. Several noninvasive techniques are available for the treatment of high-grade lesions.

Multidisciplinary quality improvement initiative to standardize reporting of lung cancer screening

Structured reporting of lung cancer screening (LCS) results with low-dose computed tomography (LDCT) is necessary for appropriate follow-up and management of lung nodules. We describe processes for standardizing the reporting and tracking of screen-detected lung nodules by increasing documentation of Lung-RADS categorization of lung nodules. Our multidisciplinary team developed a project charter and key driver diagram, revised the radiology reporting template, and provided monthly audit reports to thoracic radiologists. Quarterly from Q1-2015 to Q2-2016, we measured the proportion of screening LDCT reports that included a documented Lung-RADS category. In Q1- and Q2-2015, no LDCT scans contained a Lung-RADS assessment. By the end of Q1-2016, 94% of screening LDCTs contained a Lung-RADS assessment with a recommended follow-up action. We developed systematic processes for lung nodule categorization, documentation, and tracking using Lung-RADS that improved structured reporting at one academic medical center.

Opinions, practice patterns, and perceived barriers to lung cancer screening among attending and resident primary care physicians

Introduction The US Preventive Services Task Force recommended annual lung cancer screening with low-dose computed tomography (LDCT) for high-risk patients in December 2013. We compared lung cancer screening-related opinions and practices among attending and resident primary care physicians (PCPs). Methods In 2015, we conducted a 23-item survey among physicians at a large academic medical center. We surveyed 100 resident PCPs (30% response rate) and 86 attending PCPs (49% response rate) in Family Medicine and Internal Medicine. The questions focused on physicians’ opinions, knowledge of recommendations, self-reported practice patterns, and barriers to lung cancer screening. In 2015 and 2016, we compared responses among attending versus resident PCPs using chi-square/Fisher’s exact tests and 2-samples t-tests. Results Compared with resident PCPs, attending PCPs were older (mean age =47 vs 30 years) and more likely to be male (54% vs 37%). Over half of both groups concurred that inconsistent recommendations make deciding whether or not to screen difficult. A substantial proportion in both groups indicated that they were undecided about the benefit of lung cancer screening for patients (43% attending PCPs and 55% resident PCPs). The majority of attending and resident PCPs agreed that barriers to screening included limited time during patient visits (62% and 78%, respectively), cost to patients (74% and 83%, respectively), potential for complications (53% and 70%, respectively), and a high false-positive rate (67% and 73%, respectively). Conclusion There was no evidence to suggest that attending and resident PCPs had differing opinions about lung cancer screening. For population-based implementation of lung cancer screening, physicians and trainees will need resources and time to address the benefits and harms with their patients.