| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Early Stage Lung Cancer: New Approaches to Evaluation and Treatment |
Author's Affiliation: Weill Medical College of Cornell University, New York, New York
Requests for reprints: Claudia I. Henschke, Department of Radiology, New York Presbyterian Hospital, 525 East 68th Street, Box 586, New York, NY. Phone: 212-746-2529; Fax: 212-746-2811; E-mail: chensch{at}med.cornell.edu.
 |
Abstract |
|---|
 Top Abstract Screening for Lung CancerOngoing ProjectsOpen DiscussionReferences |
|---|
Pursuit of early diagnosis is defined by a regimen of screening. This regimen starts with the initial screening test. If this test is positive, a well-defined diagnostic algorithm is followed to rule in the diagnosis of cancer. If the test result is negative or the diagnostic algorithm does not lead to a diagnosis of cancer, the person is referred to the next routinely scheduled screening as defined by the regimen. The regimen for the first, baseline screening may be different from that for the subsequent repeat screenings.
Application of the screening regimen produces screen-diagnosed cases of cancer in each cycle of screening. A cycle starts with the performance of the initial test and the subsequent diagnostic work-up and ends before the next routinely scheduled rescreening. Any malignancy diagnosed as a result of a recommendation for biopsy is attributed to the cycle during which the nodule was first reported. Any case of cancer diagnosed as a result of symptoms prompting the work-up after a negative result of screening is called an interim-diagnosed cancer of that cycle.
These screen- and interim-diagnosed cases of cancer characterize a particular regimen of screening. Such characterization can be summarized by aggregating these diagnosed cases into a frequency distribution by relevant prognostic factors (e.g., stage, size, and histology). This frequency distribution is what we call the diagnostic distribution under the particular screening regimen. Typically, the diagnostic distribution under the baseline regimen is provided separately from the diagnostic distribution under repeat screening. The screening cases from different repeat cycles of screening are pooled.
These are general principles in screening for cancer; we now apply them to lung cancer screening.
|
Screening for Lung Cancer |
|---|
|
TopAbstractScreening for Lung CancerOngoing ProjectsOpen DiscussionReferences |
|---|
In ELCAP, the regimen of screening started with the initial low-dose CT (1). In that initial study, we defined a positive result of the low-dose CT to be one to six noncalcified nodules. If none were identified, the result was negative and the person was referred to the first annual repeat screening 1 year later. The baseline screening of 1,000 persons initially produced 27 screen-diagnosed (1) and 2 interim-diagnosed endobronchial lung cancers identified before the first annual repeat screening (2). Of the 27 screen-diagnosed lung cancers, 26 (96%) were respectable. The diagnostic distribution under baseline screening of these screen-diagnosed cases by stage and size was given in ref. (1).
A positive result of annual repeat screening was defined as any growing noncalcified nodule, regardless of size (2). Among the 1,184 instances of annual repeat screening, 7 were diagnosed with lung cancer; no interim-diagnosed cancers were identified in this cycle of repeat screening.
Important components of the ELCAP diagnostic algorithm included assessment of nodule growth and CT-guided fine-needle aspiration, particularly for nodules 15 mm or less. Growth was assessed by comparison of the CT images obtained at different times, both visually and by image-analytic techniques (4–7). If growth was consistent with malignancy, fine-needle aspiration was recommended. Both growth and fine-needle aspiration are important components of a program of CT screening for lung cancer, as they serve to limit unnecessary surgery.
Since the initial results of ELCAP were published, helical CT scanning has rapidly advanced from the single-slice scanner to 4-, 8-, 16- and soon, even more slice scanners. Using these multislice scanners, images of <1 mm slice thickness can be obtained in a single breath-hold, as compared with 10 mm slice thickness using single-slice scanners. As resolution has been markedly improved, it is not surprising that many more nodules are being detected, most of them well below 5.0 mm. Accordingly, the definition of positive result on baseline screening required updating.
A new type of nodule, a subsolid one, was identified on CT screening tests (8). Subsolid nodules had not been recognized on chest radiographs, nor was their importance understood initially in CT screening. Upon review of the ELCAP results, we found that subsolid nodules, consisting of either part-solid or nonsolid ones, had a higher malignancy rate than solid ones and that part-solid nodules had about a 3-fold higher malignancy rate.
As a result of these new findings and the advances of CT scanning, the definition of a positive result of screening has been changed from one to six noncalcified nodules to one or more noncalcified solid or part-solid nodules 5.0 mm or larger or a nonsolid nodule 10.0 mm or larger (without solid or part-solid nodules 5.0 mm or greater; ref. 9). Using this updated definition, the percentage of positive results on the baseline, low-dose screening is reduced to around 10% without any increase in the false-negative rate. The definition for positive results on annual repeat screening has remained unchanged.
Definition of the particulars of the screening regimen, starting with the initial low-dose CT test to the diagnosis of lung cancer, is critical to understanding the diagnostic distribution achieved under the particular regimen. Another regimen of screening will produce a different diagnostic distribution; thus, when comparing the results of studies, the differences in regimens must be understood. Also, it should be realized that the diagnostic distribution can be obtained to any desired accuracy by performing a baseline and single repeat screening with a sufficient number of screenees.
Comparison of two screening regimens or any component of the regimens, such as different screening tests, requires determination of their respective diagnostic distributions. The ELCAP provides such an example, as baseline screening was done using both chest radiography and CT scan on all study participants. The two resulting diagnostic distributions were provided by stage and size in the initial publication in 1999 (1). Comparison of these two distributions showed the superiority of CT imaging over chest radiography in identifying cancerous nodules in the lungs.
It is generally accepted that low-dose CT screening leads to early diagnosis of lung cancer in a high percentage of the cases. Based on this evidence, annual CT screening provides for detecting the disease at earlier and presumably more commonly curable stages in a cost-effective manner (10).
|
Ongoing Projects |
|---|
|
TopAbstractScreening for Lung CancerOngoing ProjectsOpen DiscussionReferences |
|---|
Integral to this international collaboration is pooling of the data, which represents the final element in what is now being launched as the International-ELCAP (I-ELCAP; ref. 14), simultaneously with the NY-ELCAP and with a shared set of not only principles but protocol as well. The I-ELCAP protocol represents an update of the original ELCAP protocol, as is to be expected in this novel and rapidly evolving area of medical technology and its requisite evaluation toward the knowledge base of future practice (15, 16).
At any given time, the I-ELCAP protocol focuses on the then-most-promising regimen of early (presymptomatic) diagnosis of lung cancer; and in respect to any such regimen, the first-order aim is to determine how early the diagnoses are achieved (refs. 9, 17; Table 1). The diagnostic subclassification is further refined by other prognostic indicators, notably cell type and, for the earliest diagnoses, CT-based measures of the tumor's rate of growth. The focus is on diagnoses in the practice-relevant sense of intervention-guiding, presurgical diagnosis.
|
The category-specific, fundamental results under these two aims (frequency and significance) imply the overall case-fatality and curability rates associated with the regimen of early diagnosis—both of these for genuine, progressive cases of lung cancer. They also imply the timing of the deaths prevented by screening-associated early intervention.
|
Open Discussion |
|---|
|
TopAbstractScreening for Lung CancerOngoing ProjectsOpen DiscussionReferences |
|---|
Dr. Henschke: I don't think we need to over-resect. There is a fairly high resection rate for benign disease in the literature. However, if you can talk to the individuals and they are willing to wait for 3 or 6 months to see if there's growth, you can then go to a fine-needle aspiration or a VAT (video-assisted thoracoscopic) biopsy. If these steps are followed, there should be few to no cases with benign disease that go to surgery.
Dr. Wood: If there is growth, why does one need a fine-needle biopsy?
Dr. Henschke: Because right now we don't think the growth assessment techniques are mature enough. The imaging for assessing growth needs to be obtained in a standardized way maximizing the resolution of the CT scanner, and the limitations of the image processing techniques need to be better understood. In addition, our surgeon really wants to know the cell type prior to surgery.
Dr. Wood: But what about the margin of error of a negative biopsy?
Dr. Henschke: If it is done correctly and the needle tip is documented as being in the center of the lesion on the CT scan, then there are very few cases in our institution in which malignancy is later documented. All those who have a negative needle biopsy should be followed to assess growth. We have found a few cases in which further growth was documented and cancer was subsequently diagnosed. These were all very small lesions.
Dr. Thomas Lynch: Occasionally we see three or four nodules and wonder if these are metastatic foci or are three isolated primary tumors. What do you think the limit should be for invoking the concept of multiple primary tumors?
Dr. Henschke: In our series of screen-diagnosed cases of lung cancer, we find that about 15% have a second malignancy either identified on CT prior to resection or only identified later in the resected specimen. Typically, the second lesion is very small and quite distant from the other lesion in the same lobe. Currently, these are classified as stage IIIB if the cell type of the lesions is the same. We think this classification needs further study and probably in the context of CT screening needs to be revised.
Dr. Lynch: Up to what? How many?
Dr. Henschke: The better the CT scan, the more nonsolid nodules you'll see. I don't have the answer to that question, but it is something we should really think about.
Dr. James Jett: The multiple nodule issue is a problem in deciding how you are going to proceed, but in our study also 75% of patients with lung cancer resected in the screening trial had another nodule on the CT scan. Now, the majority of those—in fact, all but two—have turned out to be benign nodules. So, because you have multiple nodules, even if you have one that is growing, you don't turn the patient down for surgery. But I think this is an issue in the community, where you forgo surgery when you find multiple nodules in the lungs, assuming that they are metastatic without biopsy.
Dr. Henschke: That has happened in the New York ELCAP where we have many institutions and many different medical settings. As soon as they see another nodule in the lung that may be growing, then it may not even be biopsied.
Dr. Lynch: In your initial paper, you reported operating on 28 patients and found 27 cancers. If we can duplicate that, it would be terrific.
Dr. Henschke: It is a lot of work—patient contact and careful CT evaluation—to get such an outcome. As growth analysis improves, this can be duplicated.
Dr. Wood: As a surgical corollary, surgeons learn that to treat appendicitis effectively, we will occasionally operate on a benign appendix, one that isn't inflamed, but that level of aggressiveness is necessary to adequately treat all the true positive cases of appendicitis. If you are hitting it perfect, with no benign nodule resections, that would suggest you are missing some cases, that some patients are losing the opportunity for cure because in the observation phase they may be developing more advanced disease.
Dr. James Mulshine: That is intuitively appealing; however, as you move from a university center where there is a thoracic focus out to the community environment where 60% to 80% of the lung cancer care in this country is delivered, the Bayesian probabilities change. The person who is making that call isn't necessarily caring for lung cancer all the time, and the downside in terms of operative mortality increases. The problem with screening is that we are dealing with individuals who, if you manage them well, are likely to live another 15 years of healthy life, and in that setting, operative mortality is catastrophic.
Dr. Henschke: These are all important issues, and guidelines for the percentage of benign resections should be developed; such parameters should be reviewed in the context of CT screening so that the percentage remains below an upper limit, hopefully reasonably close to zero.
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractScreening for Lung CancerOngoing ProjectsOpen DiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  H. Schoder and M. Gonen Screening for Cancer with PET and PET/CT: Potential and Limitations J. Nucl. Med., January 1, 2007; 48(1_suppl): 4S - 18S. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
