Mark W. Pasmantier

Early Lung Cancer Action Project: overall design and findings from baseline screening

BACKGROUND The Early Lung Cancer Action Project (ELCAP) is designed to evaluate baseline and annual repeat screening by low-radiation-dose computed tomography (low-dose CT) in people at high risk of lung cancer. We report the baseline experience. METHODS ELCAP has enrolled 1000 symptom-free volunteers, aged 60 years or older, with at least 10 pack-years of cigarette smoking and no previous cancer, who were medically fit to undergo thoracic surgery. After a structured interview and informed consent, chest radiographs and low-dose CT were done for each participant. The diagnostic investigation of screen-detected non-calcified pulmonary nodules was guided by ELCAP recommendations, which included short-term high-resolution CT follow-up for the smallest non-calcified nodules. FINDINGS Non-calcified nodules were detected in 233 (23% [95% CI 21-26]) participants by low-dose CT at baseline, compared with 68 (7% [5-9]) by chest radiography. Malignant disease was detected in 27 (2.7% [1.8-3.8]) by CT and seven (0.7% [0.3-1.3]) by chest radiography, and stage I malignant disease in 23 (2.3% [1.5-3.3]) and four (0.4% [0.1-0.9]), respectively. Of the 27 CT-detected cancers, 26 were resectable. Biopsies were done on 28 of the 233 participants with non-calcified nodules; 27 had malignant non-calcified nodules and one had a benign nodule. Another three individuals underwent biopsy against the ELCAP recommendations; all had benign non-calcified nodules. No participant had thoracotomy for a benign nodule. INTERPRETATION Low-dose CT can greatly improve the likelihood of detection of small non-calcified nodules, and thus of lung cancer at an earlier and potentially more curable stage. Although false-positive CT results are common, they can be managed with little use of invasive diagnostic procedures.

Celecoxib, a Selective Cyclo-Oxygenase-2 Inhibitor, Enhances the Response to Preoperative Paclitaxel and Carboplatin in Early-Stage Non–Small-Cell Lung Cancer

PURPOSE Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2). METHODS In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib. RESULTS All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone. CONCLUSION In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

Combination Chemotherapy of Advanced Diffuse Histiocytic Lymphoma with the Six-Drug COP-BLAM Regimen

A new multiple-drug protocol consisting of cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine, known as COP-BLAM, was administered to 48 patients with stage III or IV diffuse histiocytic lymphoma. Twenty-four of the 33 previously untreated patients had a complete remission, and eight patients had a partial response. The median survival for all previously untreated patients has not yet been reached at 23 months. Median survival for complte responders has not yet been attained at 26 months, although survival of partial responders is 12.5 months. There were no patients with a complete response who had a central nervous system relapse. The COP-BLAM therapy is an easily administered outpatient program capable of inducing a high frequency of durable complete remissions in advanced diffuse histiocytic lymphoma, a malignancy formerly considered to have a poor prognosis.

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, <or= 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient population. This trial is registered at www.clinicaltrials.gov as #NCT00142116.

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.

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.

Early lung cancer action project: annual screening using single-slice helical CT.

The advent of helical CT imaging held promise for the early diagnosis, and thereby, for enhanced curability of lung cancer—a highly fatal disease. In 1993, the Early Lung Cancer Action Project (ELCAP) was initiated and experimentally screened a cohort of 1,000 high‐risk persons. Here we summarize the results of the baseline and annual repeat CT screening of these 1,000 subjects. CT‐based screening (compared to traditional radiology) was clearly shown to enhance the detection of lung cancer at earlier and more curable stages. A discussion follows of the meaning of the results and possible future screening protocols.

Morbidity of staging laparotomy in Hodgkin's disease.

The morbidity of exploratory laparotomy and splenectomy in Hodgkins disease was determined at three institutions--a university hospital, a major university affiliated hospital and a large community hospital. Of the 90 patients who underwent exploratory laparotomy, 33 (37%) sustained a major or minor complication within two weeks of surgery. Seventeen patients (19%) sustained a minor complication and 16 patients (18%) a major complication. There was no mortality. A higher complication rate occurred in patients more than 28 years of age (p = 0.01), and in patients with advanced clinical stage when age was controlled (p = 0.05). We suggest that prior to performing an exploratory laparotomy in a given patient, the necessity of the procedure be weighed against its potential hazards.

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.