Carolyn M. Dresler

Smoking, the missing drug interaction in clinical trials: Ignoring the obvious

Tobacco use is universally recognized as the foremost preventable cause of cancer in the United States and globally and is responsible for 30% of all cancer-related deaths in the United States. Tobacco use, including exposure to secondhand smoke has been implicated as a causal or contributory agent in an ever-expanding list of cancers, including lung, oral cavity and pharynx, pancreas, liver, kidney, ureter, urinary bladder, uterine cervix, and myeloid leukemia. In addition to and independent of the etiologic effects of tobacco carcinogens in numerous cancers, there is a growing literature on the direct and indirect effects of smoking on treatment efficacy (short-term and long-term outcomes), toxicity and morbidity, quality of life (QOL), recurrence, second primary tumors (SPT), and survival time as summarized below. Oncology health professionals have called for increased advocacy for tobacco control. Despite the critical relevance of smoking to cancer outcomes, most oncology clinical trials do not collect data on smoking history and status unless the malignancy is widely acknowledged as smoking related (e.g., lung or head and neck cancer). Usually, these data are collected only at trial registration. Changes in smoking status during treatment or follow-up are monitored in very few trials and are infrequently reported in sample descriptions or included in analysis plans as a potential moderator of outcomes. Based on mounting evidence that tobacco use affects cancer treatment outcomes and survival, we recommend that smoking history and status be systematically collected as core data in all oncology clinical trials: at diagnosis, at trial registration, and throughout treatment and follow-up to long-term survival or death. We feel that the inclusion and analysis of such data in clinical trials will add important information to the interpretation of outcomes and the development of scientific knowledge in this area. Smoking status has been called another “vital sign” because of its relevance to a patients immediate medical condition. We explain the critical value of knowing the smoking status of every patient with cancer at every visit by providing a brief overview of the following research findings: (a) the effects of tobacco use on cancer treatment and outcome; (b) recent findings on the role of nicotine in malignant processes; (c) some unexpected results concerning tobacco status, treatment, and disease outcome; and (d) identifying key questions that remain to be addressed. We provide a suggested set of items for inclusion in clinical trial data sets that also are useful in clinical practice.

A 32-country comparison of tobacco smoke derived particle levels in indoor public places

Objective: To compare tobacco smoke-derived particulate levels in transportation and hospitality venues with and without smoking in 32 countries using a standardised measurement protocol. Methods: The TSI SidePak AM510 Personal Aerosol Monitor was used to measure the concentration of particulate matter less than 2.5 microns in diameter (PM2.5) in 1822 bars, restaurants, retail outlets, airports and other workplaces in 32 geographically dispersed countries between 2003 and 2007. Results: Geometric mean PM2.5 levels were highest in Syria (372 μg/m3), Romania (366 μg/m3) and Lebanon (346 μg/m3), while they were lowest in the three countries that have nationwide laws prohibiting smoking in indoor public places (Ireland at 22 μg/m3, Uruguay at 18 μg/m3 and New Zealand at 8 μg/m3). On average, the PM2.5 levels in places where smoking was observed was 8.9 times greater (95 CI 8.0 to 10) than levels in places where smoking was not observed. Conclusions: Levels of indoor fine particle air pollution in places where smoking is observed are typically greater than levels that the World Health Organization and US Environmental Protection Agency have concluded are harmful to human health.

Gender differences in genetic susceptibility for lung cancer

In contrast to men, the incidence of lung cancer among women has increased over the past decade. The basis for this increase among female smokers remains unknown. Surgical patients with a diagnosis of lung cancer and control subjects without a history of malignancy completed a smoking questionnaire and donated a blood sample. DNA was extracted from peripheral mononuclear cells and genotyped for polymorphisms in cytochrome P450 1A1 (CYP1A1) (exon 7) and glutathione S-transferase M1 (GSTM1) (null). No gender differences in either age at diagnosis or histological subtype were observed among lung cancer patients. In both patients (n = 180) and controls (n = 163), females smoked significantly less than males. The pack-year history associated with adenocarcinoma was smaller than that for squamous cell carcinoma. No significant association was observed between the GSTM1 null genotype and cancer risk. However, women had a larger cancer risk than men (odds ratio 4.98 vs. 1.37) if they possessed the mutant CYP1A1 genotype. Female cancer patients were significantly more likely than female controls to have both the CYP1A1 mutation and GSTM1 null genotype. The combined variant genotypes conferred an odds ratio of 6.54 for lung cancer in women versus 2.36 for men, independent of age or smoking history. These data suggest that polymorphisms in CYP1A1 and GSTM1 contribute to the increased risk of females for lung cancer.

Toward a comprehensive long term nicotine policy

Global tobacco deaths are high and rising. Tobacco use is primarily driven by nicotine addiction. Overall tobacco control policy is relatively well agreed upon but a long term nicotine policy has been less well considered and requires further debate. Reaching consensus is important because a nicotine policy is integral to the target of reducing tobacco caused disease, and the contentious issues need to be resolved before the necessary political changes can be sought. A long term and comprehensive nicotine policy is proposed here. It envisages both reducing the attractiveness and addictiveness of existing tobacco based nicotine delivery systems as well as providing alternative sources of acceptable clean nicotine as competition for tobacco. Clean nicotine is defined as nicotine free enough of tobacco toxicants to pass regulatory approval. A three phase policy is proposed. The initial phase requires regulatory capture of cigarette and smoke constituents liberalising the market for clean nicotine; regulating all nicotine sources from the same agency; and research into nicotine absorption and the role of tobacco additives in this process. The second phase anticipates clean nicotine overtaking tobacco as the primary source of the drug (facilitated by use of regulatory and taxation measures); simplification of tobacco products by limitation of additives which make tobacco attractive and easier to smoke (but tobacco would still be able to provide a satisfying dose of nicotine). The third phase includes a progressive reduction in the nicotine content of cigarettes, with clean nicotine freely available to take the place of tobacco as society’s main nicotine source.

Pleural Cytologies in Lung Cancer Without Pleural Effusions

BACKGROUND Malignant pleural effusions significantly increase the stage of lung cancer with attendant worsening of prognosis. There is a paucity of literature evaluating malignant pleural lavage cytology in patients without pleural effusions. We propose to determine the incidence of malignant pleural cytologies in patients without pleural effusions who undergo curative resection for lung cancer and to identify any predictive risk factors for positive cytology. METHODS Seventy-eight patients underwent curative resection for lung cancer. Lavage was performed before lung manipulation and after resection and cytologically evaluated. RESULTS Twelve pneumonectomies, 64 lobectomies, and 2 wedge resections were performed on 40 men and 38 women with an average age of 65.7 years. Fourteen percent had positive lavage cytology before lung resection with an 11% (6 of 53) incidence in stage I. A significant correlation to adenocarcinoma compared with squamous cell was found (p = 0.03) but not to stage, T or N status, grade, pleural invasion, or preoperative transthoracic needle biopsy. CONCLUSIONS The incidence of positive pleural cytology in otherwise stage I patients is disconcertingly high. Positive cytology may be a prognosticator of a more aggressive tumor biology.

Prognostic value of positive pleural lavage in patients with lung cancer resection.

BACKGROUND Despite an early stage, lung cancer patients often have a poor survival, suggesting inaccurate staging. A pleural lavage demonstrating malignant cells at the time of operation may predict a poorer survival, particularly in patients with otherwise early disease. METHODS Patients, with no preoperative evidence of pleural effusions and undergoing a surgical resection with curative intent, had a preresectional and postresectional lavage to be evaluated by cytology. RESULTS Fourteen percent of patients with stage I disease had malignant cells in their preresectional lavage and had a significantly shorter survival than stage I patients with a negative lavage. Positivity of preresectional lavage was not correlated with nodal status, pleural or lymphatic involvement, or histologic findings. CONCLUSIONS Preoperative pleural lavage should become a standard technique intraoperatively to better characterize and stage patients undergoing lung cancer resections. Patients with malignant cells in their preoperative lavage should be upstaged.

Risk of Second Primary Cancer among Esophageal Cancer Patients: a Pooled Analysis of 13 Cancer Registries

Background: The objective of this study is to assess the risk of second primary cancers following a first primary esophageal cancer as well as the risk of esophageal cancer as a second primary, following first primary cancers of other sites. Methods: The present investigation is a multicenter study of 13 population-based cancer registries in Europe, Australia, Canada, and Singapore. To assess excess occurrence of second cancers after esophageal cancers, we calculated standardized incidence ratios (SIR) by dividing the observed numbers of second cancers by the expected number of cancers calculated from the accumulated person-years and the age-, sex-, calendar period-, and registry-specific first primary cancer incidence rates. Results: During the study period, 959 cases of second primary cancers occurred after an initial esophageal cancer, resulting in a SIR of 1.15 (95% confidence interval, 1.08-1.22). Second primary stomach cancers were associated with first primary esophageal adenocarcinomas (SIR, 2.13; 95% confidence interval, 1.26-3.37) and second primary cancers of the oral cavity and pharynx (6.68; 5.33-8.26), stomach (1.53; 1.14-2.01), larynx (3.24; 1.88-5.18), lung (1.55; 1.28-1.87), kidney (1.88; 1.18-2.85), and thyroid (2.92; 1.18-6.02) were associated with first primary squamous cell carcinomas of the esophagus. An excess of esophageal cancer as a second primary were observed following first primary cancers of the aerodigestive tract, female breast, cervix, testis, bladder, Hodgkins lymphoma, and non–Hodgkin lymphoma. Conclusion: We observed associations of esophageal cancer with second primary head and neck cancers and lung cancer regardless of years of follow-up, which may suggest that common risk factors play a role in multiple tumor development. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1543–9)

Epidemiology of Lung Cancer: Smoking, Secondhand Smoke, and Genetics

The link between smoking and development of lung cancer has been demonstrated, not only for smokers but also for those exposed to secondhand smoke. Despite the obvious carcinogenic effects of tobacco smoking, not all smokers develop lung cancer, and conversely some nonsmokers can develop lung cancer in the absence of other environmental risk factors. A multitude of genetic factors are beginning to be explored that interact with environmental exposure to alter the risk of developing this deadly disease. By more fully appreciating the complex interrelationship between genetics and other risks the development of lung cancer can be more completely understood.

Is it more important to quit smoking than which chemotherapy is used

Many patients continue to smoke after their diagnosis of cancer. It is a critically important time to work with the patient to have them stop smoking. Many oncologists may underestimate the potential interactions of smoking with their anti-tumor therapy. The detrimental possibilities are examined as they relate to surgery, radiation and most importantly, to chemotherapy. Oncologists must become more active in working with their continuing smokers in order to aid in their response to interventions. Documentation of smoking status is critical to report in future studies that have evaluated therapeutic options.

Effects of inflation volume during lung preservation on pulmonary capillary permeability

UNLABELLED The degree of lung allograft inflation during harvest and storage may affect posttransplantation function. High volume ventilation causes pulmonary vascular injury and increased pulmonary capillary permeability. However, the effect of lung inflation on pulmonary capillary permeability after hypothermic flush and storage is unknown. The current study was designed to examine the effects of hyperinflation and hypoinflation during preservation on pulmonary vascular permeability. METHODS An isolated, ex vivo rabbit lung gravimetric model without the confounding effects of reperfusion was used to determine post pulmonary capillary filtration coefficients (Kf). New Zealand White rabbits (2.75 to 3.15 kg) were intubated and lungs ventilated with room air (tidal volume 25 ml). After sternotomy and heparinization, the pulmonary artery was flushed with low potassium dextran-1% glucose solution (200 ml). The heart-lung block was then excised. Two studies were conducted. For measurement of changes in airway pressure and lung volume during preservation, lungs were inflated to one of four storage volumes (12, 25, 40, 55 ml) with room air, 100% O2, or 100% N2 and stored at 10 degrees C in a sealed container filled with saline solution. During preservation, lung volume and airway pressure were measured at 3, 6, 12 and 24 hours. In the Kf study, lungs were inflated with 100% O2, 50% O2 (with 50% N2), or room air and preserved. After 24 hours of preservation at 10 degrees C, the heart-lung block was suspended from a strain-gauge force transducer and the lungs were ventilated with room air. The pulmonary artery was connected to a reservoir of hetastarch solution (6% hetastarch with 0.9% saline solution). Lung weight gain, airway pressure, pulmonary artery pressure, and left atrial pressure were measured continuously. After a brief flush with hetastarch solution, the reservoir was then elevated to achieve 1.0 to 1.5 mm Hg increments in pulmonary artery pressure. RESULTS The slope of subsequent steady-state lung weight gain was used to determine the Kf. The current study demonstrated the following: (1) changes in lung volume and airway pressure during storage increased with intraalveolar O2 concentration, (2) irrespective of inflation, fraction of inspired oxygen, hyperinflation during lung preservation increased the Kf in a volume-dependent fashion; (3) Kf was increased in lungs stored hypoinflated with room air; and (4) at any inflation volume, the Kf was significantly increased with 100% O2 inflation after 24 hours of preservation. CONCLUSION These results suggest that storage at high lung volume or high inspired oxygen fraction increases pulmonary capillary permeability.