Leading cause of cancer mortality ... The American Cancer Society estimates 169,500 new cases of lung cancer will be ... Non-small Cell Lung Cancer, By Stage ... – PowerPoint PPT presentation
In the United States the second most common cancer in men and women
Leading cause of cancer mortality
Accounts for more deaths from than cancer than breast prostate and colorectal cancer combined
3 Common and Lethal
The American Cancer Society estimates 169500 new cases of lung cancer will be diagnosed in 2001
Overall 5-year survival remains poor approximately 15
ACS anticipates 157400 deaths from lung cancer in 2001
4 Estimated U.S. Cancer Deaths10 Leading Sites by Gender 2001 5 Age-adjusted cancer death rates by siteUS males 1930-1997 6 Age-adjusted cancer death rates by siteUS females 1930-1997 7 Prognosis of Non-small Cell Lung Cancer By Stage 8 Table 4. Current guidelines for lung cancer screening Adapted from Mandel J Weinberger S. Screening for lung cancer. UpToDate 2000 81-2. Mandel J Weinberger S. Screening for lung cancer. UpToDate 2000 81-2. 9 Presentation overview
History of lung cancer screening
Trials of the 1950-60s
National Cancer Institute Cooperative Early Lung Cancer Project
Mayo Lung Project
Memorial Sloan-Kettering
Johns Hopkins
Czechoslovakian Trial
Lost interest
10 Presentation Overview Cont.
Renewed interest and new directions
Chest radiographs
Computed tomography
PET
Biomarkers
Fluorescence bronchoscopy
Conclusions and recommendations
11 (No Transcript) 12 (No Transcript) 13 Screening Principles
Successful cancer screening program
needs to detect disease in the preclinical stage
when it is amenable to curative treatment
reduce mortality by preventing progression of disease
14 Lung cancer screening
A successful randomized trial of screening for lung cancer
Enhances detection of lung cancers particularly asymptomatic early stage cancers in the study group when compared to a control group during the screening phase
As the trial progresses the number of lung cancers in the two groups should equalize as asymptomatic early stage cancers undetected in the control group grow spread and present as symptomatic advanced stage cancers
If treatment is more effective for asymptomatic early stage cancers compared with symptomatic more advance lung cancers fewer deaths would be expected in the screened group compared to non-screened controls
Model assumes that the bulk of early stage lung tumors progress to lethal disease without detection and early treatment and assumes that early detection reduces mortality
15 Screening mortality and survival
No randomized controlled trial has demonstrated that lung cancer screening leads to a reduction in disease-specific mortality
Mortality vs. survival
Mortality(death rate) cancer deaths / patients screened expressed as deaths per 1000 persons screened per year
Survival patients alive following cancer diagnosis / cancers detected expressed as a percentage over time
16 Screening
Mortality can be influenced by selection bias in nonrandomized trials however in a RCT a statistically significant mortality reduction is considered proof of screening effectiveness or at least best evidence for efficacy
17 Screening bias
All other measures of outcome can be affected bias including
Selection bias error in patient assignment between groups that permits a confounding variable to arise from study design rather than by chance alone usually eliminated by randomization
Lead-time bias mistakenly attributing increased survival of patients to a screening intervention when longer survival is only a reflection of earlier detection in the preclinical phase of disease
Length-sampling bias Slow growing tumors are detectable longer than fast growing ones and will be preferentially identified by any early diagnosis strategy. Fast growing tumors with shorter survival will be left for routine diagnosis.
Over-diagnosis a portion of detected cancers may have remained indolent and undetected because of patient death from other causes
18 Early early trials
In the 1950s and 1960s a number of uncontrolled and nonrandomized controlled studies were performed to evaluate combinations of chest x-ray and sputum cytology screening at various time intervals ranging up to once every 6 months
Three nonrandomized uncontrolled trials
Philadelphia Pulmonary Neoplasm Research Project
Veterans Administration Lung Cancer Screening Study
South London Lung Cancer Study
Two randomized controlled trials
North London Cancer Study
Kaiser Foundation Health Plan Study
19 Early early trials cont.
All of these studies failed to demonstrate a statistically significant mortality benefit from lung cancer screening.
Small cohorts with limited follow-up periods limiting demonstration of small-moderate improvements or longer-term benefits in mortality
20 NCI Cooperative Early Lung Cancer Group
In 1971 the National Cancer Institute (NCI) sponsored three large-scale long-term randomized controlled trials created to determine
whether a program of lung cancer screening might lead to earlier detection that is to finding a larger proportion of lung cancers at a localized potentially curable stage and whether with appropriate treatment this would result in a substantial reduction of lung cancer deaths in the screened group.
21 NCI Cooperative Early Lung Cancer Group cont.
Specifically the trials sought to establish if detection of early lung cancer could be improved by the addition of sputum cytology to routine chest x-ray and if lung cancer mortality could be reduced by this screening and appropriate therapy.
The trials completed in 1984 were conducted at Mayo Clinic Johns Hopkins Medical Center and the Memorial-Sloan Kettering Cancer Center and the participating institutions were designated the Cooperative Early Lung Cancer Group.
22 Mayo Lung Project
From late 1971 to mid-1976 enrolled
10933 male volunteers
Age 45 years or older
At least one pack per day cigarette use in the previous year
Referred for participation by their primary care physician during routine physical examination
All participants were offered an initial prevalence screen including chest x-ray and sputum cytology.
23 Mayo Lung Project Prevalence 24 Mayo Lung Project
91 prevalent cancer patients removed from the initial volunteers
978 patients ruled ineligible because of serious underlying medical problems and predicted life expectancy of less than 5 years
653 volunteers refused participation
Remaining 9211 participants were randomized to two groups screening and control
Screening group participants received chest x-ray and sputum cytology examination every 4 months for 6 years
Control group participants were advised to seek annual chest x-ray and sputum cytology standard Mayo advice at the time and no reminders were sent
Study group was followed for a total of 9 years 6 years of screening and 3 years of follow-up observation.
25 MLP Incidence and Mortality 26 MLP Staging and 5-year survival 27 MLP Late stage cancers nonresectable cases and number of deaths 28 MLP Extended follow-up 29 Memorial Sloan-Kettering
From 1974 to 1978 enrolled
10040 male volunteers
Age 45 years or older
At least 1 pack per day cigarette use currently or in the preceding year
On initial intake all participants received PA and lateral chest films and pooled sputum cytology
30 Memorial Sloan-Kettering
Following the initial prevalence screen
5072 men randomized to the chest x-ray only group
4985 men randomized to the dual-screened group
Both groups received annual chest x-rays.
The dual-screened group additionally received 3-day pooled sputum cytology every 4 months.
31 Memorial Sloan-KetteringIncidence 32 M S-K Conclusions
There was no statistically significant difference in early stage lung cancers identified 5-year survival or mortality between the dual-screen group and the chest x-ray only group
Sputum cytology even as often as q4 months does not improve mortality compared to CXR alone
33 Johns Hopkins
Uncanny-ly similar to Memorial Sloan-Kettering
From 1973 to1977 enrolled
10387 male volunteers
Age 45 years or older
At least one pack per day smoking history in preceding year
Volunteers were randomly allocated to two groups
Control or single-screen group received annual radiographic screening only
Dual-screen group received annual radiography plus annual sputum cytologic examination
34 Johns Hopkins Incidence
Lung cancer detected in 396 participants
194 in the dual-screen group
202 in the control group
Over half (51) of the cancers identified were detected incidentally by chest x-ray or sputum cytology performed outside of the screening protocol
Compared with clinical diagnosis by symptoms screening by both chest x-ray and sputum cytology identified a greater proportion of the lung cancer cases at an earlier stage
Addition of sputum cytology improved detection of squamous cell lung cancer but did not effect disease-specific mortality
35 NCI Cooperative Lung Conclusions
Demonstrated improvements in stage distribution resectability and survival in screened groups
No improvement in disease-specific mortality with screening
Cooperative authors recognize the potential effects of bias lead-time length-sampling and over-diagnosis
Role of control contamination screening non-compliance
However they hedge
It is probable that some patients who had lung cancers detected by screening would have died of their malignancies had they not been detected at earlier stages.
36 NCI Cooperative LungRecommendations 1984
1. If screening for lung cancer is to be carried out it should be done within the framework of general health care that is in the private practitioners office HMO or general medicine clinic.
2. The chest x-ray is the most sensitive method for detection of lung cancer currently available.
3. Sputum cytology is the most effective and specific method of detecting early squamous cell lung carcinoma. Patients with positive sputum cytology in the setting of radiologically occult malignancy have good 5 year survival.
4. Data do not indicate if prolonged survival in prevalent cases of lung cancer represented decreased mortality from disease or reflects one or more screening artifacts.
37 (No Transcript) 38 (No Transcript) 39 (No Transcript) 40 Czechoslovakian Lung Cancer Study
Began in Czechoslovakia in 1976
Designed to evaluate semi-annual screening by chest x-ray and sputum cytology
6364 males ages 40-64 with a greater than 20 pack year history of tobacco abuse were screened with PA chest x-ray and 24-hour sputum cytology to identify prevalent cases
41 Czech study cont.
After the prevalence screen remaining participants were randomized to a screening group or a control group
3172 randomized to screening received PA chest x-ray and sputum cytology every 6 months for 3 years
3174 randomized to control received a single screening chest x-ray at the end of the 3 year trial
All participants received annual chest x-ray for an additional 3 years following the screening period
42 Czechoslovakian Lung Cancer Study
Prevalence
Initial screen identified 19 cancers 9 squamous cell carcinomas and 7 small cell lung cancers
Overall prevalence was 3/1000 examinations
5-year survival for prevalent cases was 25
43 Czechoslovakian Lung Cancer Study
During the three year screening period 55 confirmed lung cancers were identified
36 cases were identified in the screening group. 26(75) cancers found in asymptomatic participants
19 cases were identified in the control group. 4 (25)found incidentally or at autopsy
Following the screening period annual CXR surveillance revealed an additional 35 cases of lung cancer in the screening group and 38 cases in the control group
Overall mortality after nine years was 3.6/1000 person/years in both the screened and control groups
44 Randomized control trials summary 45 RCT summary cont.
Four RCTs collectively screened 37724 participants
All studies demonstrated improvements in stage distribution resectability and survival in screened groups
No improvement in disease-specific mortality with screening
46 (No Transcript) 47 (No Transcript) 48 (No Transcript) 49 (No Transcript) 50 (No Transcript) 51 Interest lost found
With failure to demonstrate mortality benefits from screening all major advisory organizations adopted recommendations against screening for lung cancer
Research funding waned
Butwith emergence of new diagnostic and therapeutic modalities new interest in lung cancer screening arose in the mid-1990s
52 New directions in early lung cancer detection
Chest x-ray reexamined
PLCO
Low-dose spiral CT
ELCAP
PET
Biomarkers
hnRNP expression
Fluorescence bronchoscopy
53 Chest x-ray reexamined PLCO
The National Cancer Institute is readdressing the use of periodic chest x-ray screening in the Prostate Lung Colorectal and Ovarian Cancers Trial (PLCO)
Currently in progress PLCO seeks to enroll 150000 Americans age 55-75 for randomization to various screening or no screening strategies
14 years follow-up planned
54 Computed Tomography
In the 1990s a number of population-based trials demonstrated increased sensitivity of CT scan for the detection of resectable lung cancer vs. CXR
Majority of reports come from Japan where a government sponsored screening program with CXR and sputum cytology has been in place since mid-1980s. The addition of low-dose spiral CT to screening programs there lead to higher detection rates of early stage non-small cell lung cancers.
A number of studies are currently underway to evaluate the use of low-dose spiral CT for early lung cancer detection.
55 What is low-dose spiral CT
Takes 15-30 seconds to perform
Allows complete chest imaging in one breath hold using wide slices
Radiation exposure equivalent to mammography
Can detect lesions as small as 2mm
56 Computed tomography ELCAP
ELCAP Early Lung Cancer Action Project
On-going study begun in 1992
Single cohort non-comparative design
Aims to establish a cure rate based on lung tumor size to be used subsequently to assess other screening protocols or novel tests
Compared with a randomized controlled trial this design is less costly and allows more rapid acquistion of data
57 ELCAP
Enrolled 1000 symptom-free volunteers from New York Hospital-Cornell University and NYU Medical Center hospitals associated physicians offices
60 years of age or older
Both men and women!!
10 pack-year history of cigarette abuse or greater
No prior history of malignancy no contraindications to thoracic surgery.
58 ELCAP
All participants underwent PA and lateral chest radiographs and low-dose helical CT
Positive results were defined as CT evidence of 1 or greater non-calcified nodules.
When nodules were identified parameters were recorded including number of nodules size location (lobe and distance from pleura) shape (round non-round) edge (smooth non-smooth) and benign calcification (present or absent.)
59 ELCAP
Patients with CT evidence of non-calcified pulmonary nodules underwent standard-dose high resolution diagnostic CT scan of the chest
If standard CT demonstrated benign calcifications in a nodule with smooth edges nodule was classified as benign
Suspicious nodules were evaluated according to ELCAP protocol
months. If no growth noted _at_ 24 months the lesion was considered benign.
6-10mm biopsy recommended. If contraindications to biopsy exist follow-up serial CTs as described above.
11mm biopsy strongly recommended
60 ELCAP RESULTS (brief) 61 ELCAP Conclusions
Compared with CXR low-dose CT greatly increases the likelihood of detection of small non-calcified nodules and thus of lung cancer at earlier more curable stages
CT vs CXR
detected 3x as many non-calcified nodules
4x as many malignant tumors
6x as many stage I cancers
62 ELCAP Conclusions
High false positive rate of 233 suspicious nodules only 27 malignant tumors were confirmed. Only 4 patients underwent biopsy for benign disease and no biopsy complications were noted.
Risks of cumulative radiation likely low
Cost-effectiveness
63 (No Transcript) 64 PETPositron Emission Tomography
Utilizes metabolic activity of a pulmonary lesion to provide information about the malignant potential of a pulmonary nodule
Allows imaging of structures by virtue of their ability to concentrate specific molecules that have been labeled with a positron-emitting isotope
In evaluation of solitary pulmonary nodules some studies suggest a 95 sensitivity and 70 specificity for the detection of malignancy
65 (No Transcript) 66 (No Transcript) 67 Biomarkers Introduction
Screening with conventional sputum cytology failed to decrease mortality as demonstrated in the Johns Hopkins and Memorial Sloan-Kettering trials.
However new techniques and immunostaining for biomarkers promises much greater sensitivity for sputum cytology evaluation.
68 Biomarkers
Lung cancer results from an interaction between genetic predisposition and environmental causes.
Exposure of the respiratory epithelium to carcinogens triggers mutation in specific genes proto-oncogenes and tumor suppressor genes. Once epithelial cells undergo malignant transformation cell proliferation depends on tumor promoters cellular growth factors.
Several genetic abnormalities have been identified in association with lung cancer (table13.) Mutations and molecular products can be identified from sputum and tissue samples using polymerase chain reaction (PCR) and other techniques in molecular biology.
69 Biomarkers cont. 70 Prospective Detection of Preclinical Lung Cancer Results from studies of heterogeneous nuclear ribonucleoprotein A2/B1 overexpression
Lung Cancer Early Detection Working Group a cooperative NCI-sponsored group
Earlier studies identified potentially useful lung CA biomarkers expressed in archieved sputum
Initiated to address
Does hnRNP A2/B1 overexpression correctly detect preclinical lung cancer
Does overexpression precede dysplastic morphological changes in sputum epithelial cells
71 hnRNP overexpression study cont.
Prospective case-cohort design
Monitored Chinese tin workers over age 40 with annual sputum cytology and immunocytochemistry
Blinded investigators at Johns Hopkins analyzed sputum samples from participants with clinically detected and confirmed non-small lung cancers and from age-matched controls
72 Immunodetection of preclinical primary lung cancer by hnRNP overexpression hnRNP test characteristics
Primary lung cancer risk 56/62850.9
Sensitivity82 (CI 68-92)
Specificity65(CI 50-78)
Relative risk1480/432 3.4
73 Biomarkers conclusions
May be possible to use biomarkers to identify an early clonal phase of progression of lung cancer in high-risk populations enabling cancer detection earlier than visualization by spiral CT.
May be used to complement spiral CT to sensitivity and specificity for malignancy.
May be used to identify targets for treatment allowing chemical radiation or pharmacological targeting of minute primary lung cancers.
74 Contemporary Screening for Lung Cancer Pre-malignancy and Malignancy Project
Recruitment underway now
Multicenter randomized controlled trial
Aims to address whether a screening program using lung cancer associated molecular markers in sputum combined with low-dose helical CT can improve lung-cancer specific survival in individuals at high risk for lung cancer.
75 Contemporary Screening for Lung Cancer Pre-malignancy and Malignancy Project cont.
With enrollment participants will undergo chest x-ray and sputum cytologic evaluation to select out prevalent cases of lung cancer prior to randomization. Enrollees without evidence of lung cancer will be randomized to screening and control groups.
Screening group will undergo sputum (cytologic and biomarker evaluation) and radiographic (chest x-ray and low dose spiral CT) at 6 month intervals. The control group will undergo no screening but will complete annual health questionnaires.
NC Baptist/Wake Forest University Medical Center is one of thirteen participating institutions for this study.
76 Fluorescence Bronchoscopy
Undergoing early multi-center trials for screening in smokers with established obstructive lung disease and abnormal sputum cytology
Utilizes differences in the fluorescence properties of normal and abnormal bronchial epithelium to identify dysplasia and metaplasia
77 Fluorescence bronchoscopy
Demonstrated ability to enhance detection of severe dysplasia and carcinoma in situ over white-light bronchoscopy
May be most useful in localization of sputum cytology positive CXR/CT (-) malignancies and in determination of endobronchial involvement by malignancy
Technology and technique remain under development
Anticipate improved sensitivity and specificity with future systems
78 Conclusions
No randomized controlled trial to date has demonstrated reduced mortality from a lung cancer screening program
Trials demonstrate improvement in stage at diagnosis resectability and survival with screening programs
No evidence to support the use of chest x-ray or sputum cytology for routine lung cancer screening in asymptomatic patients
79 Conclusions cont.
New diagnostic techniques may prove promising for use alone or together in early lung cancer detection
Low-dose spiral CT looks promising for detection of early stage lung cancer however high false positive rate could lead to unnecessary morbidity and mortality in disease-free patients
80 Conclusions conclude
PET and biomarkers may improve sensitivity and specificity of other diagnostic tests especially CT
Not sure what to expect from fluorescence bronchoscopy sounds neat
81 Should you screen
1. Does the burden of disability from the disease warrant action
2. Are at-risk populations well-defined
3. Does early diagnosis really lead to improved clinical outcomes (in terms of survival function and quality of life)
4. Are the cost and accuracy of the screening test acceptable
5. Can you manage the additional clinical time required to confirm diagnosis and provide long-term care to those who screen positive
6. Will patients in whom an early diagnosis is achieved comply with subsequent recommendations and treatment regimens
Adapted from Sackett et al. Clinical Epidemiology. A Basic Science for Medicine. 1991 391.
82 Recommendations
At this time would hold on screening of asymptomatic high-risk patients
Could consider lowering your threshold for screening in patients with documented airflow obstruction
Lung Health Study found a 1 cancer mortality at 5 years in patients with COPD
Eagerly await the results of pending trials (that do indeed include women)
83 Recommendations cont.
Anticipate screening will have greater mortality benefit as lung cancer therapy advances
Above all emphasize to patients that the greatest reduction in lung cancer mortality comes from smoking cessation
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