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Screening for lung cancer: the early lung cancer action approach
Lung Cancer 35 (2002) 143– 148
www.elsevier.com/locate/lungcan
Screening for lung cancer: the early lung cancer action approach Claudia I. Henschke *, David F. Yankelevitz, James P. Smith, Olli S. Miettinen, for the ELCAP Group 1 Weill Medical College of Cornell Uni6ersity, New York, NY 10021, USA Received 18 April 2001; accepted 29 August 2001
Keywords: Lung cancer; Screening; Pooling of data; Computed tomography (CT); Early diagnosis
1. Introduction Suddenly, screening for lung cancer has become a hot topic. Researchers are initiating projects to study it; the public is demanding it; and medical institutions are offering it. The sudden activity is also prompting reconsideration of the still-nihilistic North American public policies on lung-cancer screening. Out of the Fourth International Conference on Screening for Lung Cancer, held in February 2001 and only 16 months after the first one, arose a unanimous recommendation to quickly publish the current protocol of the International Early Lung Cancer Action Program (I-ELCAP) initiated by a resolution of the third Conference. The purpose here is to do just that, though only upon first outlining the origins of this initiative and also specifying its aims and broadest principles.
2. Origins In 1992, a group of chest radiologists (CIH, DFY), pulmonologists (including DML, JPS), oncologists and a thoracic surgeon (NKA) from Cornell University Medical Center, now Weill Medical College of Cornell * Corresponding author. Tel.: + 1-212-746-2529; fax: +1-212-7462811. E-mail address: [email protected] (C.I. Henschke). 1 ELCAP Group: Claudia I. Henschke, PhD, MD, radiologist, principal investigator; Nasser K. Altorki, MD, thoracic surgeon; Daniel M. Libby, MD, pulmonologist; Dorothy I. MacCauley, MD, radiologist; Olli S. Miettinen, MD, PhD, epidemiologist; Mark W. Pasmantier, MD, oncologist; James P. Smith, MD, pulmonologist; David F. Yankelevitz, MD, radiologist.
University, together with a statistician (M. Kimmel) from Rice University, convened in a ski resort to outline to each other their respective research interests with a view to finding a common ground; and they invited an epidemiologist (OSM) from McGill University to assist in this search. The search was successful: screening for lung cancer turned out to be a shared interest, notably as the advent of helical CT imaging held promise for early diagnosis and, thereby, for enhanced curability of this highly fatal disease. This inspiration led to the initiation, in 1993, of the Early Lung Cancer Action Project (ELCAP) which experimentally screened a cohort of 1000 high-risk persons. In it, investigators from New York University Medical Center joined the Cornell group. This collaborative effort led to the publication, in 1999, of its overall design and baseline screening results [1]. The report showed CT-based imaging’s great superiority over traditional radiography in the initial testing, and that the false-positive test results that are common in baseline —though not repeat [2] —screening could be managed with no notable excess of biopsies or thoracotomies when following the ELCAP protocol. That ELCAP report, in turn, inadvertently led to considerable public and professional interest in the practice of CT-based screening for lung cancer; and within Cornell it led to two carefully-considered initiatives: the planning and fund-raising for a project experimentally to screen 10,000 high-risk persons in what got to be called the New York ELCAP (NY-ELCAP), and the International Conferences on Screening for Lung Cancer [3]. The latter initiative also was an outgrowth of the Cornell team’s already extensive role in helping other investigator groups in various institutions initiate research projects patterned after the original ELCAP,
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including sharing with them its web-based management and data-recording system and its associated teaching files. Integral to this international collaboration is pooling of the data, which represents the final element in what is now being launched as the I-ELCAP, 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 that in the original ELCAP, as is to be expected in this novel and rapidly evolving area of medical technology and its requisite evaluation towards the knowledge-base of future practice.
3. Aims At any given time, the I-ELCAP focuses on the then-most-promising regimen of early (pre-symptomatic) diagnosis of lung cancer; and in respect to any such regimen, the first-order aim is to determine how early the diagnoses are achieved [4– 6]. This is a matter of determining the distribution of the diagnosed cases according to indicators such as stage and size, and status as to symptoms and signs, jointly considered. The diagnostic distribution is considered separately for baseline and for post-baseline diagnoses, and as for the latter, separately for interim (symptom-prompted) and screen-prompted diagnoses. The diagnostic subclassification is further refined by other prognostic indicators, notably cell type and, for the earliest diagnoses, CTbased measures of the tumor’s rate of growth. Focus is on diagnoses in the practice-relevant sense of intervention-guiding, pre-surgical diagnosis. For each of the diagnostic– prognostic categories, the broad aim is to determine their respective degrees of significance. This involves determining their associated case-fatality rates without and with intervention (in the absence of competing causes of death), together with the respective timings of fatal outcomes. Implied by these are the category-specific proportions of overdiagnosed cases, curability rates for progressive cases, and the time lags to deaths preventable by early intervention. With sufficiently detailed diagnostic– prognostic categories, these parameters presumably are general over various regimens of early 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, and also that specific to screen-detected cases—both of these for genuine, progressive cases of lung cancer. They also imply the timing of the deaths prevented by screening-associated early intervention. An ancillary aim is to assess the frequency— prevalence —of cases diagnosable by the regimen, the way
this depends on the risk indicators involved in the definition of indications for the screening (at baseline and subsequently).
4. Principles Some of the principles of the I-ELCAP were already set forth in the two preceding sections. Added in this section are the admissibility criteria for contributing membership in this program, pertaining to research groups and their institutions. They are to: 1. Implement the regimen of early diagnosis specified below (subject risk profiles and intervention policies may vary; cf. below). Commitment to at least one repeat screen on each subject is required. 2. Submit to the Coordinating Center the institutional documents approving the screening and participation in the I-ELCAP, be committed to conform to the stated requirements, and be amenable to Coordinating Center auditing of adherence to those requirements. 3. ‘Register’ with the Coordinating Center each successive instance of baseline screening, and be committed to full documentation of this and also of all repeat screenings. 4. Identify, and document, each instance of interim diagnosis of lung cancer, including its symptoms and signs (if any). 5. Document the reason(s) for discontinuation of screening. 6. Document the timing and nature of the intervention(s), if any, in each instance of diagnosed lung cancer, including interim-diagnosed cases. 7. Follow each diagnosed case of lung cancer, interimdiagnosed cases included, until fatal outcome or, in the absence of evidence of spread, for up to 10 years; and document that follow-up. 8. Deploy the ELCAP web-based management system for CT screening for lung cancer, and in this framework submit the research data including images as well as pathology specimens to the Coordinating Center for review. 9. Conform to all other policies of the I-ELCAP, notably those concerned with quality assurance. It deserves note that among the contributors to I-ELCAP could very well be the Coordinating Centers of randomized controlled trials (RCTs) contrasting CT screening with either no screening or some other type of screening. Here, the relevant contributions would derive from the CT screening arm of such a trial. Of course, all of the requirements above would have to be satisfied. Yet further principles will come up, some only implicitly, in the Protocol section that follows.
C.I. Henschke et al. / Lung Cancer 35 (2002) 143–148
5. Protocol, as of October 2001
5.1. Subject admissibility The participating investigator groups are free to set their own criteria for both entry into the screening and termination of this. Insofar as they wish to maximize the screening’s presumptive benefit to the screenees, they are advised to accent screening in the fifth and sixth decades of age [3] and, of course, on persons with the highest levels of risk. On the other hand, study tends to be more efficient when accenting higher ages. There is flexibility in the admissibility criteria because, while it bears on the frequency with which cancer is diagnosed, it presumably has no bearing on the distribution of diagnosed cases according to indicators of how early the diagnosis is and other prognostic indicators pertaining to the diagnosed cases. Critical to admissibility in both baseline and repeat screening is, by definition, freedom from symptoms and signs suggestive of lung cancer in high-risk persons: worsening cough, hoarseness, chest pain, hemoptysis, and/or unexplained loss of weight.
5.2. Diagnostic regimen The initial screening-test is based on CT imaging, and the imaging itself is identical between baseline and repeat screenings. A multi-slice helical CT scanner (General Electric Lightspeed, Milwaukee, WI; Siemens Volume Zoom, Erlangen, Germany; or equivalent) is preferably used, at low-dose setting (GE: l20 kVP, 40 mA with 6:1 pitch, 1.25 mm slice thickness and 0.5 s rotation; Siemens: 120 kVp, 20 mA with a 7:1 pitch at 1 mm slice thickness and 0.5 s rotation). In a single breathhold, contiguous slices from the thoracic inlet to the adrenal glands are obtained. The use of contrast material is not involved. Although multi-slice scanners are preferable, as they provide higher-resolution images for the initial screening-test and thus simplify the subsequent diagnostic work-up, single-slice helical (spiral) CT scanners may be used —again at low-dose setting and obtaining the images at the thinnest collimation and lowest pitch in a single breathhold. The resulting images are read by a radiologist in the institution at issue, expert at interpreting chest CT. The reader is aware that the images derive from the initial low-dose screening-test for early diagnosis of lung cancer and also whether at issue is baseline or repeat screening. The reader views the images as they are displayed on a high-resolution monitor at their typical window and level settings with maximal magnification, scrolling through the images one at a time. For purposes of assessing size, however, the following settings will be used: lung windows 1500, −650; mediastinal windows 350, 25.
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Another reading, without knowledge of the initial reading, is done by a ‘central’ reader who is a dedicated chest radiologist and experienced in CT screening at the Coordinating Center, Weill Medical College of Cornell University for a specified number of screenings. The ‘site’ radiologist receives the ‘central’ reading report (from the Coordinating Center), with discrepancies, if any, highlighted on the Dual Reading Report. In case of discrepancies, the ‘site’ radiologist may find it necessary to change the site report; and in this event, the updated final report is also submitted to the Coordinating Center. Record is kept (in the Coordinating Center) of all reports. As a matter of good practice, the ‘site’ radiologist sends the final report to the subject and to his/her referring physician. In both baseline and repeat screening, the reader’s first concern is to identify all non-calcified nodules visible in the initial images. A nodule is any focal non-linear opacity, whether ‘solid’ or a ‘focal translucency’ (previously termed ‘ground-glass opacity’). A nodule is called non-calcified if it fails to meet the usual criteria for benign, non-calcified nodules. Thus, a nodule less than 5 mm in diameter is non-calcified if it appears uniformly less dense than the ribs (on bone and lung windows); a nodule 5–20 mm in diameter is non-calcified if less than 50% of it is ‘calcified’, calcification does not correspond to a classical benign pattern (complete, central, lamellated, popcorn), and/or the edge is spiculated (to some extent at least); and a nodule over 20 mm in diameter is non-calcified unless it is completely calcified. Diameter is the average of length and width. At baseline the result of the initial screening test is: negati6e if there are no non-calcified nodules, or more than six of them with the largest one less than 5 mm in diameter; positi6e if there are 1–6 non-calcified nodules, or more than six of them with the largest one 5 mm in diameter or larger. When a single-slice scaner is used, a ‘positive’ result of the initial screening test, as just defined, is only tentative. The tentatively positive result of the initial screening test immediately leads to a diagnostic CT scan of the entire chest, except (1) when recommending antibiotics, the diagnostic CT scan of the entire chest is performed 1 month after the initial screening test or (2) if all nodules are less than 5 mm in size, the diagnostic CT scan of the entire chest may be performed 6 months after the initial screening test. The diagnostic CT is obtained at 5 mm slice thickness using the lowest possible pitch in a single breathhold. Also, HRCT (1 mm slice thickness) images of each nodule are obtained using the lowest possible pitch to scan the entire nodule in a single breathhold. The HRCT images are obtained at maximum resolution (GE: targeted field of view of 9.6 cm; Siemens: 10
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cm) and they are reconstructed using the high-frequency spatial algorithm. The use of contrast material is not involved. The criteria for non-calcified nodules given above are applied to these HRCT images, and based on this classification, the result of the initial test is definitively positive or negative as defined above. The reader documents whether the result of the initial test at baseline is negative or positive; and if positive, the reader also documents each of the 1– 6 non-calcified nodules, or the six largest such nodules in case of more than six of them in total. Specifically, for each of these nodules of record at baseline, the reader documents the location, size (length, width), whether solid or translucent, calcifications and edge type. On repeat screenings, interest among the identified non-calcified nodules focuses on the ones that have grown in size since the previous screen. To determine whether growth has occurred, the reader compares the current images with the corresponding previous ones, displayed side-by-side with the current images. Of course, a nodule that is seen in the current images but not in the juxtaposed previous ones has grown since the previous screen. Growth is defined as any increase in the length or width of a solid nodule or focal translucency or in the solid component of a focal translucency [7,8]. On repeat screening, the test result is negative or positive by criteria fully analogous to those at baseline, except that tallied are non-calcified nodules with interim growth. With this same proviso, the documentation of repeat-screen nodules of record is analogous, except that documentation of the rate of growth is added. When the result of the initial low-dose CT screeningtest is negative, whether at baseline (by baseline criteria) or on repeat screening (by repeat-screening criteria), the pursuit of early diagnosis stops, and the next screening-test is scheduled— for a time 12 months after the current one (even if the current one is a repeat screen not 12 months after the previous one). When the result is positive, further diagnostic work-up immediately ensues. In the further work-up detailed below, HRCTs are to be obtained using consistently the same dose setting (kVp, mA) with 1 mm slice thickness through the entire nodule, at the lowest possible pitch, in a single breathhold. The initial images must be well above the nodule and the final ones well below it, to ensure that the entire nodule is covered by this set of images as this is critical for accurate assessment of growth. The images are obtained at maximum resolution and they are reconstructed using the high-frequency spatial algorithm. The use of contrast material is not involved. The localization of the nodule(s) prior to obtaining the HRCT images is done using low-dose CT imaging. At baseline, the work-up varies according to the size of the largest nodule of record (defined above):
1. If the largest nodule is less than 5 mm in diameter, then HRCT of the nodules of record is performed 6 months after the screening test; and given no growth in any of these nodules, the work-up stops (see below). If growth is manifest, then biopsy of those nodules is immediately carried out. 2. If the largest nodule is 5–9 mm in diameter, then HRCT of the nodules of record is performed within 3 months after the screening test; and given no growth in any of these nodules, but some of them remaining, the HRCT is repeated 6 months after the screening-test. If no growth is manifest in any of the remaining nodules, the work-up stops. If growth of any of the nodules is manifest at either 3 or 6 months, then biopsy is immediately carried out. 3. If the largest nodule is 10 mm or larger in diameter, then immediate action on the nodules of record in this size range is to ensure. There are three options for this: 3.1. One option is immediate biopsy of each of these nodules. 3.2. Another option is an immediate 2-week course of broad-spectrum antibiotics followed by an HRCT, limited to these nodules, 1 month after the test. Further work-up depends on the HRCT result: – For these nodules showing complete resolution, the work-up stops. – These nodules not showing even partial resolution are immediately biopsied. – These nodules showing partial resolution are followed with another HRCT 3 months after the initial screening test. If complete resolution of all nodules is manifest, then the work-up stops. Remaining nodules showing growth are immediately biopsied. For remaining nodules not showing growth, HRCT is repeated 6 months after the screening test: – For these nodules showing further resolution, the work-up stops. – These nodules showing no further resolution or showing growth are immediately biopsied. 3.3. Yet another option is to immediately perform a contrast-enhancement CT, a PET scan, or some other equivalent test. Further work-up depends on the result: – If the result is positive, then no. 3.1 or no. 3.2 above is followed. – If the result is negative, then HRCT of the nodules of record is performed within 6 months after the screening-test; and given no growth in any of these nodules, the work-up stops. If growth of any of the nodules is manifested within 6 months, then biopsy is immediately carried out.
C.I. Henschke et al. / Lung Cancer 35 (2002) 143–148
If associated with the large nodules (10 mm or more in average diameter) there are others less than 10 mm in average diameter, they are worked up according to no. 1 or no. 2 above, whichever applies. When the regimen at baseline does not lead to the diagnosis of malignancy, repeat screening is scheduled, as was noted, for 12 months subsequent to the baseline screening-test. Similarly, when in the first repeat screening malignancy is not diagnosed, the second repeat screening is scheduled to follow 12 months subsequent to the first one, etc. Also, if Stage I or II malignancy is diagnosed, screening is continued with the next repeat screening scheduled 12 months after diagnosis. At repeat screening, a positive result of the screening test routinely leads to an immediate 2-week course of broad-spectrum antibiotics, followed by an HRCT of the nodules of record at 1 month after the screening test. Further work-up depends on the HRCT result in respect to resolution and growth of the nodules of record on repeat screening (defined above): 1. If all of these nodules have completely resolved, then the work-up stops. 2. Among the nodules of record that persist, any nodule 5 mm in diameter or larger is immediately biopsied. For the remaining nodules of record (if any), the HRCT, limited to the remaining nodules of record, is repeated at 3 months after the initial test. Given complete resolution of all nodules, the work-up stops. Any nodule showing growth (over the 3 months) is immediately biopsied. If there are any remaining nodules of record, the HRCT is repeated 6 months after the initial test. The result is dealt with as at 3 months, including as for scheduling another HRCT, only in this instance at 12 months; and if need be, yet another HRCT is scheduled at 24 months. With any one of these successive HRCTs, the assessment of growth is based on this in comparison with the HRCT at 1 month. The CT assessment of growth, including rate of growth [7,8] is done centrally based on the electronic image-transmission provided for in the web-based ELCAP management system. As the biopsy procedure, CT-guided percutaneous transthoracic fine-needle aspiration (FNA) is to be preferred, as this is a 1-h outpatient procedure. If this is not feasible, transbronchial needle or forceps biopsy, or video-assisted thoracoscopic (VAT) biopsy is used. The biopsy specimens are described and classified into diagnostic–prognostic categories. The slides are submitted to the Coordinating Center for independent reading by the Pathology Panel, and representative slides are digitized for viewing within the ELCAP Management System. The diagnosis of this expert panel is the definitive one and used for study purposes only; it is documented on the study forms at the Coordinating Center.
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The early-diagnosis regimen (above) is to be suitably communicated, in the informed consent context, to each subject. If, however, the subject or physician subsequently elects not to follow this regimen, the actual work-up must be carefully documented. In the framework of the I-ELCAP protocol for early diagnosis of lung cancer and study of the significance of the diagnosed malignancies, there is opportunity for the conduct of ancillary studies on variants of this: various non-CT initial tests can be deployed parallel with the CT test, and this provides for studying their relative sensitivity for one and their value as add-ons for another. Such tests might be based on ‘biomarkers’ among others.
5.3. Characterization of diagnosed cancers Central to the I-ELCAP is detailed, careful characterization of the diagnosed malignancies according to descriptors of how early is the diagnosis, and according to other indicators of the prognostic significance of what has been diagnosed. Principal among these descriptors/indicators is the Stage of the disease at diagnosis, that is, at the time when prognosis with and without early intervention becomes a concern. Relevant to this is the Stage in terms of its pre-operati6e (clinical–operational) definition. The protocol, for purposes of the I-ELCAP, expressly defines the pre-operative staging criteria, notably for distinguishing between Stages I and II–IV. Stage I: no chest CT manifestations of metastases in the mediastinum, axillae, adrenals, liver, spleen, or visualized bones; negative palpation of lymph nodes in the axillae, neck, and groin; and freedom from symptoms (worsening cough, hoarseness, chest pain, hemoptysis, and unexplained loss of weight). Continual monitoring and on site quality assurance is directed to this aspect of the program. Closely related to the pre-operative Stage of the disease is the size of the tumor, notably within Stage I. Quality assurance in respect to this descriptor of the diagnosed malignancies is internal to the Coordinating Center, as the study data from the images are derived centrally. Two definitions of size will be deployed. One of these has to do with the ‘diameter’ involved in the present regimen of early diagnosis presented above: the average of the nodule’s length and width. In the analyses, however, an alternative to this will also be used: nodule volume determined automatically using the software that has been developed at Weill Cornell. Closely related to size is the tumor’s growth rate. The study data for this descriptor of the malignancies will also be derived centrally—and on the basis of automated volumetry. The pathology data, both final pathologic diagnoses, and also pre-surgical by biopsy are, again, for study purposes derived centrally—by the Pathology Panel.
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5.4. Inter6ention regimen When lung cancer has been diagnosed by the experimental regimen of early diagnosis, that diagnosis creates a situation not inherently one of medical research but of medical practice. The I-ELCAP protocol of research naturally does not dictate decisions of practice. However, since the concern in the Program is to learn from the intervention practices, close documentation of the intervention(s) is required. Also important to carefully document is the occurrence of any complications of the intervention(s), notably surgical death (within 28 days) and other serious complications. With select subtypes of diagnosis, some institutions may wish to participate in randomized controlled trials designed to address the relative merits of different interventions.
5.5. Quality assurance In the I-ELCAP, quality assurance is a central concern. It begins with unfailing application of the criteria for data-contributing institutions’ admissibility for collaboration (above), and it is served by the built-in web-based ELCAP management system. Additional elements in it are the Coordinating Center’s activities in terms of central reading of images and pathology material for study purposes and in training the participants and humanly monitoring their performance (thus supplementing what the management system accomplishes electronically)— and taking corrective actions, as needed. The radiologists in the participating institutions, apart from having continual access to the electronic teaching files imbedded in the management system, are invited to the Coordinating Center for training sessions provided by its chest radiologists, highly experienced in the use of CT in the various phases and situations that are involved in early diagnosis of lung cancer. This training is concentrated in the time before subject intake begins, but also will be available subsequently, as needed. The pathologists in the participating centers are also invited to the Coordinating Center for discussions and training. In addition, as noted above, I-ELCAP has organized a central Pathology Panel of experts for the central reading of the ‘slides’, for study purposes and to supplement training as needed.
The study coordinators in each of the participating institutions are trained by the senior supervisor of the coordinators at the Coordinating Center. At the onset, and as indicated later, the Coordinating Center arranges site visits to the participating institutions to assess comprehension of various aspects of the study protocol and compliance with these; and where problems are identified, remedial actions are taken—in the extreme a matter of discontinuation of the collaboration. The site visit team typically consists of representatives from the Coordinating Center and some of the other participating institutions.
5.6. Outcome determination Every effort must be made to assure complete followup of the diagnosed cases of lung cancer. The beginning of this is documentation of all information that may bear on this, Social Security number included. And where the local efforts fail, the Coordinating Center will assist in locating the person or identifying his/her death, as well as in documenting whether manifestations of spread (perhaps death from lung cancer) have occurred.
References [1] Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99 – 105. [2] Henschke CI, Naidich DP, Yankelevitz DF, et al. Early Lung Cancer Action Project: initial findings from annual repeat screening. Cancer 2001;92:153 – 9. [3] International Collaboration to Screen for Lung Cancer. Proceedings of the First, Second, Third and Fourth International Conferences on Screening for Lung Cancer. New York, NY (Website:http://ICScreen.med.cornell.edu). [4] Miettinen OS. Screening for lung cancer. Radiologic Clinics of North America 2000;38(3):479 –86. [5] Miettinen OS, Yankelevitz DF, Henschke CI. Screening for cancer: what needs to be studied, and how? (Submitted). [6] Miettinen OS, Henschke CI. CT screening for lung cancer: coping with nihilism. Radiology (in press). [7] Yankelevitz DF, Gupta R, Zhao B, Henschke CI. Repeat CT scanning for evaluation of small pulmonary nodules. Radiology 1999;212:561 – 6. [8] Yankelevitz DF, Reeves AP, Kostis WJ, Zhao B, Henschke CI. Determination of malignancy in small pulmonary nodules based on volumetrically determined growth rates. Radiology 2000;217:251 – 6.
www.elsevier.com/locate/lungcan
Screening for lung cancer: the early lung cancer action approach Claudia I. Henschke *, David F. Yankelevitz, James P. Smith, Olli S. Miettinen, for the ELCAP Group 1 Weill Medical College of Cornell Uni6ersity, New York, NY 10021, USA Received 18 April 2001; accepted 29 August 2001
Keywords: Lung cancer; Screening; Pooling of data; Computed tomography (CT); Early diagnosis
1. Introduction Suddenly, screening for lung cancer has become a hot topic. Researchers are initiating projects to study it; the public is demanding it; and medical institutions are offering it. The sudden activity is also prompting reconsideration of the still-nihilistic North American public policies on lung-cancer screening. Out of the Fourth International Conference on Screening for Lung Cancer, held in February 2001 and only 16 months after the first one, arose a unanimous recommendation to quickly publish the current protocol of the International Early Lung Cancer Action Program (I-ELCAP) initiated by a resolution of the third Conference. The purpose here is to do just that, though only upon first outlining the origins of this initiative and also specifying its aims and broadest principles.
2. Origins In 1992, a group of chest radiologists (CIH, DFY), pulmonologists (including DML, JPS), oncologists and a thoracic surgeon (NKA) from Cornell University Medical Center, now Weill Medical College of Cornell * Corresponding author. Tel.: + 1-212-746-2529; fax: +1-212-7462811. E-mail address: [email protected] (C.I. Henschke). 1 ELCAP Group: Claudia I. Henschke, PhD, MD, radiologist, principal investigator; Nasser K. Altorki, MD, thoracic surgeon; Daniel M. Libby, MD, pulmonologist; Dorothy I. MacCauley, MD, radiologist; Olli S. Miettinen, MD, PhD, epidemiologist; Mark W. Pasmantier, MD, oncologist; James P. Smith, MD, pulmonologist; David F. Yankelevitz, MD, radiologist.
University, together with a statistician (M. Kimmel) from Rice University, convened in a ski resort to outline to each other their respective research interests with a view to finding a common ground; and they invited an epidemiologist (OSM) from McGill University to assist in this search. The search was successful: screening for lung cancer turned out to be a shared interest, notably as the advent of helical CT imaging held promise for early diagnosis and, thereby, for enhanced curability of this highly fatal disease. This inspiration led to the initiation, in 1993, of the Early Lung Cancer Action Project (ELCAP) which experimentally screened a cohort of 1000 high-risk persons. In it, investigators from New York University Medical Center joined the Cornell group. This collaborative effort led to the publication, in 1999, of its overall design and baseline screening results [1]. The report showed CT-based imaging’s great superiority over traditional radiography in the initial testing, and that the false-positive test results that are common in baseline —though not repeat [2] —screening could be managed with no notable excess of biopsies or thoracotomies when following the ELCAP protocol. That ELCAP report, in turn, inadvertently led to considerable public and professional interest in the practice of CT-based screening for lung cancer; and within Cornell it led to two carefully-considered initiatives: the planning and fund-raising for a project experimentally to screen 10,000 high-risk persons in what got to be called the New York ELCAP (NY-ELCAP), and the International Conferences on Screening for Lung Cancer [3]. The latter initiative also was an outgrowth of the Cornell team’s already extensive role in helping other investigator groups in various institutions initiate research projects patterned after the original ELCAP,
0169-5002/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 1 ) 0 0 4 1 6 - 0
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C.I. Henschke et al. / Lung Cancer 35 (2002) 143–148
including sharing with them its web-based management and data-recording system and its associated teaching files. Integral to this international collaboration is pooling of the data, which represents the final element in what is now being launched as the I-ELCAP, 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 that in the original ELCAP, as is to be expected in this novel and rapidly evolving area of medical technology and its requisite evaluation towards the knowledge-base of future practice.
3. Aims At any given time, the I-ELCAP focuses on the then-most-promising regimen of early (pre-symptomatic) diagnosis of lung cancer; and in respect to any such regimen, the first-order aim is to determine how early the diagnoses are achieved [4– 6]. This is a matter of determining the distribution of the diagnosed cases according to indicators such as stage and size, and status as to symptoms and signs, jointly considered. The diagnostic distribution is considered separately for baseline and for post-baseline diagnoses, and as for the latter, separately for interim (symptom-prompted) and screen-prompted diagnoses. The diagnostic subclassification is further refined by other prognostic indicators, notably cell type and, for the earliest diagnoses, CTbased measures of the tumor’s rate of growth. Focus is on diagnoses in the practice-relevant sense of intervention-guiding, pre-surgical diagnosis. For each of the diagnostic– prognostic categories, the broad aim is to determine their respective degrees of significance. This involves determining their associated case-fatality rates without and with intervention (in the absence of competing causes of death), together with the respective timings of fatal outcomes. Implied by these are the category-specific proportions of overdiagnosed cases, curability rates for progressive cases, and the time lags to deaths preventable by early intervention. With sufficiently detailed diagnostic– prognostic categories, these parameters presumably are general over various regimens of early 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, and also that specific to screen-detected cases—both of these for genuine, progressive cases of lung cancer. They also imply the timing of the deaths prevented by screening-associated early intervention. An ancillary aim is to assess the frequency— prevalence —of cases diagnosable by the regimen, the way
this depends on the risk indicators involved in the definition of indications for the screening (at baseline and subsequently).
4. Principles Some of the principles of the I-ELCAP were already set forth in the two preceding sections. Added in this section are the admissibility criteria for contributing membership in this program, pertaining to research groups and their institutions. They are to: 1. Implement the regimen of early diagnosis specified below (subject risk profiles and intervention policies may vary; cf. below). Commitment to at least one repeat screen on each subject is required. 2. Submit to the Coordinating Center the institutional documents approving the screening and participation in the I-ELCAP, be committed to conform to the stated requirements, and be amenable to Coordinating Center auditing of adherence to those requirements. 3. ‘Register’ with the Coordinating Center each successive instance of baseline screening, and be committed to full documentation of this and also of all repeat screenings. 4. Identify, and document, each instance of interim diagnosis of lung cancer, including its symptoms and signs (if any). 5. Document the reason(s) for discontinuation of screening. 6. Document the timing and nature of the intervention(s), if any, in each instance of diagnosed lung cancer, including interim-diagnosed cases. 7. Follow each diagnosed case of lung cancer, interimdiagnosed cases included, until fatal outcome or, in the absence of evidence of spread, for up to 10 years; and document that follow-up. 8. Deploy the ELCAP web-based management system for CT screening for lung cancer, and in this framework submit the research data including images as well as pathology specimens to the Coordinating Center for review. 9. Conform to all other policies of the I-ELCAP, notably those concerned with quality assurance. It deserves note that among the contributors to I-ELCAP could very well be the Coordinating Centers of randomized controlled trials (RCTs) contrasting CT screening with either no screening or some other type of screening. Here, the relevant contributions would derive from the CT screening arm of such a trial. Of course, all of the requirements above would have to be satisfied. Yet further principles will come up, some only implicitly, in the Protocol section that follows.
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5. Protocol, as of October 2001
5.1. Subject admissibility The participating investigator groups are free to set their own criteria for both entry into the screening and termination of this. Insofar as they wish to maximize the screening’s presumptive benefit to the screenees, they are advised to accent screening in the fifth and sixth decades of age [3] and, of course, on persons with the highest levels of risk. On the other hand, study tends to be more efficient when accenting higher ages. There is flexibility in the admissibility criteria because, while it bears on the frequency with which cancer is diagnosed, it presumably has no bearing on the distribution of diagnosed cases according to indicators of how early the diagnosis is and other prognostic indicators pertaining to the diagnosed cases. Critical to admissibility in both baseline and repeat screening is, by definition, freedom from symptoms and signs suggestive of lung cancer in high-risk persons: worsening cough, hoarseness, chest pain, hemoptysis, and/or unexplained loss of weight.
5.2. Diagnostic regimen The initial screening-test is based on CT imaging, and the imaging itself is identical between baseline and repeat screenings. A multi-slice helical CT scanner (General Electric Lightspeed, Milwaukee, WI; Siemens Volume Zoom, Erlangen, Germany; or equivalent) is preferably used, at low-dose setting (GE: l20 kVP, 40 mA with 6:1 pitch, 1.25 mm slice thickness and 0.5 s rotation; Siemens: 120 kVp, 20 mA with a 7:1 pitch at 1 mm slice thickness and 0.5 s rotation). In a single breathhold, contiguous slices from the thoracic inlet to the adrenal glands are obtained. The use of contrast material is not involved. Although multi-slice scanners are preferable, as they provide higher-resolution images for the initial screening-test and thus simplify the subsequent diagnostic work-up, single-slice helical (spiral) CT scanners may be used —again at low-dose setting and obtaining the images at the thinnest collimation and lowest pitch in a single breathhold. The resulting images are read by a radiologist in the institution at issue, expert at interpreting chest CT. The reader is aware that the images derive from the initial low-dose screening-test for early diagnosis of lung cancer and also whether at issue is baseline or repeat screening. The reader views the images as they are displayed on a high-resolution monitor at their typical window and level settings with maximal magnification, scrolling through the images one at a time. For purposes of assessing size, however, the following settings will be used: lung windows 1500, −650; mediastinal windows 350, 25.
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Another reading, without knowledge of the initial reading, is done by a ‘central’ reader who is a dedicated chest radiologist and experienced in CT screening at the Coordinating Center, Weill Medical College of Cornell University for a specified number of screenings. The ‘site’ radiologist receives the ‘central’ reading report (from the Coordinating Center), with discrepancies, if any, highlighted on the Dual Reading Report. In case of discrepancies, the ‘site’ radiologist may find it necessary to change the site report; and in this event, the updated final report is also submitted to the Coordinating Center. Record is kept (in the Coordinating Center) of all reports. As a matter of good practice, the ‘site’ radiologist sends the final report to the subject and to his/her referring physician. In both baseline and repeat screening, the reader’s first concern is to identify all non-calcified nodules visible in the initial images. A nodule is any focal non-linear opacity, whether ‘solid’ or a ‘focal translucency’ (previously termed ‘ground-glass opacity’). A nodule is called non-calcified if it fails to meet the usual criteria for benign, non-calcified nodules. Thus, a nodule less than 5 mm in diameter is non-calcified if it appears uniformly less dense than the ribs (on bone and lung windows); a nodule 5–20 mm in diameter is non-calcified if less than 50% of it is ‘calcified’, calcification does not correspond to a classical benign pattern (complete, central, lamellated, popcorn), and/or the edge is spiculated (to some extent at least); and a nodule over 20 mm in diameter is non-calcified unless it is completely calcified. Diameter is the average of length and width. At baseline the result of the initial screening test is: negati6e if there are no non-calcified nodules, or more than six of them with the largest one less than 5 mm in diameter; positi6e if there are 1–6 non-calcified nodules, or more than six of them with the largest one 5 mm in diameter or larger. When a single-slice scaner is used, a ‘positive’ result of the initial screening test, as just defined, is only tentative. The tentatively positive result of the initial screening test immediately leads to a diagnostic CT scan of the entire chest, except (1) when recommending antibiotics, the diagnostic CT scan of the entire chest is performed 1 month after the initial screening test or (2) if all nodules are less than 5 mm in size, the diagnostic CT scan of the entire chest may be performed 6 months after the initial screening test. The diagnostic CT is obtained at 5 mm slice thickness using the lowest possible pitch in a single breathhold. Also, HRCT (1 mm slice thickness) images of each nodule are obtained using the lowest possible pitch to scan the entire nodule in a single breathhold. The HRCT images are obtained at maximum resolution (GE: targeted field of view of 9.6 cm; Siemens: 10
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cm) and they are reconstructed using the high-frequency spatial algorithm. The use of contrast material is not involved. The criteria for non-calcified nodules given above are applied to these HRCT images, and based on this classification, the result of the initial test is definitively positive or negative as defined above. The reader documents whether the result of the initial test at baseline is negative or positive; and if positive, the reader also documents each of the 1– 6 non-calcified nodules, or the six largest such nodules in case of more than six of them in total. Specifically, for each of these nodules of record at baseline, the reader documents the location, size (length, width), whether solid or translucent, calcifications and edge type. On repeat screenings, interest among the identified non-calcified nodules focuses on the ones that have grown in size since the previous screen. To determine whether growth has occurred, the reader compares the current images with the corresponding previous ones, displayed side-by-side with the current images. Of course, a nodule that is seen in the current images but not in the juxtaposed previous ones has grown since the previous screen. Growth is defined as any increase in the length or width of a solid nodule or focal translucency or in the solid component of a focal translucency [7,8]. On repeat screening, the test result is negative or positive by criteria fully analogous to those at baseline, except that tallied are non-calcified nodules with interim growth. With this same proviso, the documentation of repeat-screen nodules of record is analogous, except that documentation of the rate of growth is added. When the result of the initial low-dose CT screeningtest is negative, whether at baseline (by baseline criteria) or on repeat screening (by repeat-screening criteria), the pursuit of early diagnosis stops, and the next screening-test is scheduled— for a time 12 months after the current one (even if the current one is a repeat screen not 12 months after the previous one). When the result is positive, further diagnostic work-up immediately ensues. In the further work-up detailed below, HRCTs are to be obtained using consistently the same dose setting (kVp, mA) with 1 mm slice thickness through the entire nodule, at the lowest possible pitch, in a single breathhold. The initial images must be well above the nodule and the final ones well below it, to ensure that the entire nodule is covered by this set of images as this is critical for accurate assessment of growth. The images are obtained at maximum resolution and they are reconstructed using the high-frequency spatial algorithm. The use of contrast material is not involved. The localization of the nodule(s) prior to obtaining the HRCT images is done using low-dose CT imaging. At baseline, the work-up varies according to the size of the largest nodule of record (defined above):
1. If the largest nodule is less than 5 mm in diameter, then HRCT of the nodules of record is performed 6 months after the screening test; and given no growth in any of these nodules, the work-up stops (see below). If growth is manifest, then biopsy of those nodules is immediately carried out. 2. If the largest nodule is 5–9 mm in diameter, then HRCT of the nodules of record is performed within 3 months after the screening test; and given no growth in any of these nodules, but some of them remaining, the HRCT is repeated 6 months after the screening-test. If no growth is manifest in any of the remaining nodules, the work-up stops. If growth of any of the nodules is manifest at either 3 or 6 months, then biopsy is immediately carried out. 3. If the largest nodule is 10 mm or larger in diameter, then immediate action on the nodules of record in this size range is to ensure. There are three options for this: 3.1. One option is immediate biopsy of each of these nodules. 3.2. Another option is an immediate 2-week course of broad-spectrum antibiotics followed by an HRCT, limited to these nodules, 1 month after the test. Further work-up depends on the HRCT result: – For these nodules showing complete resolution, the work-up stops. – These nodules not showing even partial resolution are immediately biopsied. – These nodules showing partial resolution are followed with another HRCT 3 months after the initial screening test. If complete resolution of all nodules is manifest, then the work-up stops. Remaining nodules showing growth are immediately biopsied. For remaining nodules not showing growth, HRCT is repeated 6 months after the screening test: – For these nodules showing further resolution, the work-up stops. – These nodules showing no further resolution or showing growth are immediately biopsied. 3.3. Yet another option is to immediately perform a contrast-enhancement CT, a PET scan, or some other equivalent test. Further work-up depends on the result: – If the result is positive, then no. 3.1 or no. 3.2 above is followed. – If the result is negative, then HRCT of the nodules of record is performed within 6 months after the screening-test; and given no growth in any of these nodules, the work-up stops. If growth of any of the nodules is manifested within 6 months, then biopsy is immediately carried out.
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If associated with the large nodules (10 mm or more in average diameter) there are others less than 10 mm in average diameter, they are worked up according to no. 1 or no. 2 above, whichever applies. When the regimen at baseline does not lead to the diagnosis of malignancy, repeat screening is scheduled, as was noted, for 12 months subsequent to the baseline screening-test. Similarly, when in the first repeat screening malignancy is not diagnosed, the second repeat screening is scheduled to follow 12 months subsequent to the first one, etc. Also, if Stage I or II malignancy is diagnosed, screening is continued with the next repeat screening scheduled 12 months after diagnosis. At repeat screening, a positive result of the screening test routinely leads to an immediate 2-week course of broad-spectrum antibiotics, followed by an HRCT of the nodules of record at 1 month after the screening test. Further work-up depends on the HRCT result in respect to resolution and growth of the nodules of record on repeat screening (defined above): 1. If all of these nodules have completely resolved, then the work-up stops. 2. Among the nodules of record that persist, any nodule 5 mm in diameter or larger is immediately biopsied. For the remaining nodules of record (if any), the HRCT, limited to the remaining nodules of record, is repeated at 3 months after the initial test. Given complete resolution of all nodules, the work-up stops. Any nodule showing growth (over the 3 months) is immediately biopsied. If there are any remaining nodules of record, the HRCT is repeated 6 months after the initial test. The result is dealt with as at 3 months, including as for scheduling another HRCT, only in this instance at 12 months; and if need be, yet another HRCT is scheduled at 24 months. With any one of these successive HRCTs, the assessment of growth is based on this in comparison with the HRCT at 1 month. The CT assessment of growth, including rate of growth [7,8] is done centrally based on the electronic image-transmission provided for in the web-based ELCAP management system. As the biopsy procedure, CT-guided percutaneous transthoracic fine-needle aspiration (FNA) is to be preferred, as this is a 1-h outpatient procedure. If this is not feasible, transbronchial needle or forceps biopsy, or video-assisted thoracoscopic (VAT) biopsy is used. The biopsy specimens are described and classified into diagnostic–prognostic categories. The slides are submitted to the Coordinating Center for independent reading by the Pathology Panel, and representative slides are digitized for viewing within the ELCAP Management System. The diagnosis of this expert panel is the definitive one and used for study purposes only; it is documented on the study forms at the Coordinating Center.
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The early-diagnosis regimen (above) is to be suitably communicated, in the informed consent context, to each subject. If, however, the subject or physician subsequently elects not to follow this regimen, the actual work-up must be carefully documented. In the framework of the I-ELCAP protocol for early diagnosis of lung cancer and study of the significance of the diagnosed malignancies, there is opportunity for the conduct of ancillary studies on variants of this: various non-CT initial tests can be deployed parallel with the CT test, and this provides for studying their relative sensitivity for one and their value as add-ons for another. Such tests might be based on ‘biomarkers’ among others.
5.3. Characterization of diagnosed cancers Central to the I-ELCAP is detailed, careful characterization of the diagnosed malignancies according to descriptors of how early is the diagnosis, and according to other indicators of the prognostic significance of what has been diagnosed. Principal among these descriptors/indicators is the Stage of the disease at diagnosis, that is, at the time when prognosis with and without early intervention becomes a concern. Relevant to this is the Stage in terms of its pre-operati6e (clinical–operational) definition. The protocol, for purposes of the I-ELCAP, expressly defines the pre-operative staging criteria, notably for distinguishing between Stages I and II–IV. Stage I: no chest CT manifestations of metastases in the mediastinum, axillae, adrenals, liver, spleen, or visualized bones; negative palpation of lymph nodes in the axillae, neck, and groin; and freedom from symptoms (worsening cough, hoarseness, chest pain, hemoptysis, and unexplained loss of weight). Continual monitoring and on site quality assurance is directed to this aspect of the program. Closely related to the pre-operative Stage of the disease is the size of the tumor, notably within Stage I. Quality assurance in respect to this descriptor of the diagnosed malignancies is internal to the Coordinating Center, as the study data from the images are derived centrally. Two definitions of size will be deployed. One of these has to do with the ‘diameter’ involved in the present regimen of early diagnosis presented above: the average of the nodule’s length and width. In the analyses, however, an alternative to this will also be used: nodule volume determined automatically using the software that has been developed at Weill Cornell. Closely related to size is the tumor’s growth rate. The study data for this descriptor of the malignancies will also be derived centrally—and on the basis of automated volumetry. The pathology data, both final pathologic diagnoses, and also pre-surgical by biopsy are, again, for study purposes derived centrally—by the Pathology Panel.
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5.4. Inter6ention regimen When lung cancer has been diagnosed by the experimental regimen of early diagnosis, that diagnosis creates a situation not inherently one of medical research but of medical practice. The I-ELCAP protocol of research naturally does not dictate decisions of practice. However, since the concern in the Program is to learn from the intervention practices, close documentation of the intervention(s) is required. Also important to carefully document is the occurrence of any complications of the intervention(s), notably surgical death (within 28 days) and other serious complications. With select subtypes of diagnosis, some institutions may wish to participate in randomized controlled trials designed to address the relative merits of different interventions.
5.5. Quality assurance In the I-ELCAP, quality assurance is a central concern. It begins with unfailing application of the criteria for data-contributing institutions’ admissibility for collaboration (above), and it is served by the built-in web-based ELCAP management system. Additional elements in it are the Coordinating Center’s activities in terms of central reading of images and pathology material for study purposes and in training the participants and humanly monitoring their performance (thus supplementing what the management system accomplishes electronically)— and taking corrective actions, as needed. The radiologists in the participating institutions, apart from having continual access to the electronic teaching files imbedded in the management system, are invited to the Coordinating Center for training sessions provided by its chest radiologists, highly experienced in the use of CT in the various phases and situations that are involved in early diagnosis of lung cancer. This training is concentrated in the time before subject intake begins, but also will be available subsequently, as needed. The pathologists in the participating centers are also invited to the Coordinating Center for discussions and training. In addition, as noted above, I-ELCAP has organized a central Pathology Panel of experts for the central reading of the ‘slides’, for study purposes and to supplement training as needed.
The study coordinators in each of the participating institutions are trained by the senior supervisor of the coordinators at the Coordinating Center. At the onset, and as indicated later, the Coordinating Center arranges site visits to the participating institutions to assess comprehension of various aspects of the study protocol and compliance with these; and where problems are identified, remedial actions are taken—in the extreme a matter of discontinuation of the collaboration. The site visit team typically consists of representatives from the Coordinating Center and some of the other participating institutions.
5.6. Outcome determination Every effort must be made to assure complete followup of the diagnosed cases of lung cancer. The beginning of this is documentation of all information that may bear on this, Social Security number included. And where the local efforts fail, the Coordinating Center will assist in locating the person or identifying his/her death, as well as in documenting whether manifestations of spread (perhaps death from lung cancer) have occurred.
References [1] Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99 – 105. [2] Henschke CI, Naidich DP, Yankelevitz DF, et al. Early Lung Cancer Action Project: initial findings from annual repeat screening. Cancer 2001;92:153 – 9. [3] International Collaboration to Screen for Lung Cancer. Proceedings of the First, Second, Third and Fourth International Conferences on Screening for Lung Cancer. New York, NY (Website:http://ICScreen.med.cornell.edu). [4] Miettinen OS. Screening for lung cancer. Radiologic Clinics of North America 2000;38(3):479 –86. [5] Miettinen OS, Yankelevitz DF, Henschke CI. Screening for cancer: what needs to be studied, and how? (Submitted). [6] Miettinen OS, Henschke CI. CT screening for lung cancer: coping with nihilism. Radiology (in press). [7] Yankelevitz DF, Gupta R, Zhao B, Henschke CI. Repeat CT scanning for evaluation of small pulmonary nodules. Radiology 1999;212:561 – 6. [8] Yankelevitz DF, Reeves AP, Kostis WJ, Zhao B, Henschke CI. Determination of malignancy in small pulmonary nodules based on volumetrically determined growth rates. Radiology 2000;217:251 – 6.