Background

Lung cancer is most frequently detected at a stage when it is too advanced to be curable.  Although 5-year survival for stage I cancer that has been resected can be as high as 70%, the overall 5-year survival for lung cancer is only about 12%.  This implies that screening to detect early disease should be able to improve prognosis.  The main randomized trial which looked at this question, the Mayo Lung Project, did not show a significant benefit for screening by chest x-ray, however.

Because CT scanning should be able to detect lung cancer at an earlier stage than conventional radiography, the current trial was designed to look at the effect of low-dose, non-contrast screening CT scans on the ability to detect small, stage I lung cancers.

The Early Lung Cancer Action Project (ELCAP) was not a randomized study, but was designed as a screening and follow-up trial. 1000 participants at high risk for lung cancer were offered baseline screening, starting in 1992, with annual re-screening.  The endpoints were the detection of non-calcified nodules and the clinical outcomes for those patients with nodules, with a particular emphasis on outcome by size and radiographic appearance of the nodules detected.  This paper reports on the results of baseline screening.

Methods

Patients were recruited for screening if they were over 60 years of age, had smoked at least 10 pack-years, had no history of cancer, had no symptoms of lung cancer and would be able to undergo thoracotomy.  A total of 1000 volunteers were enrolled (at New York Hospital and NYU Medical Center).  Baseline information recorded included age, sex, race, smoking history and asbestos exposure.

Screening was performed at baseline (the subject of this report) and is to be repeated annually.

Baseline x-ray and CT scan

Standard PA and lateral chest x-rays were obtained.  Helical low-dose CT scanning of the lungs was performed in a single breath-hold (up to 20 secs), at end inspiration after hyperventilation.  The slice thickness was 10 mm; images were reconstructed in overlapping 5 mm increments.

All x-rays were read by two radiologists who then discussed their findings and came to a consensus reading; if no consensus could be reached, a third radiologist was asked to adjudicate.

X-rays and CT scans were analyzed for the presence and absence of nodules.  Each nodule was characterized by its shape (round or not), edge (smooth or not), size (length and width), location (lobe involved and central vs. peripheral) and by the presence or absence of benign calcifications.

Studies were classified as positive if there were between one and six non-calcified nodules (NCN).  Studies were negative if there were no NCN, and were judged to show diffuse disease if there were more than six NCN.

Recommended follow-up

Patients with positive screening CT scans and/or x-rays were recommended to have standard-dose diagnostic CT scans for better delineation of the lesions.  If the non-calcified nodules seen on screening were confirmed and were non-calcified on the diagnostic CT, further work-up was recommended, depending on the size (average of length and width) of the nodule:

• nodules 5 mm or less: follow up with high resolution CT scans at 3 mos, 6 mos, 12 mos and 24 mos as long as there was no growth.
• nodules 6-10 mm: if possible, CT guided fine needle aspiration biopsy or thoracoscopic biopsy; if not biopsied, CT follow up as for the smaller nodules.
• nodules greater than 10 mm: biopsy by fine needle aspiration, bronchoscopy or thoracoscopy.

The actual decisions about diagnostic and therapeutic procedures were left up to the referring physician and patients. Whether or not the recommendations were followed, the results of all diagnostic procedures and any surgery for resectable tumors were recorded.

Analysis

This paper presents the results of baseline screening (prevalence data) and the stage of malignant nodules by nodule size. It is too early in the protocol to present survival data and data on follow-up screening (incidence data).

Results

Median age was 67;  54% were male; 91% were white. Median number of pack-years smoked was 45. Asbestos exposure was present in14%.

Radiologists agreement

The readers disagreed on the interpretation of the low-dose screening scans in only 31 out of the 1000 scans.  In 28 of these cases, both readers identified abnormalities, but only one reader interpreted them as non-calcified nodules. After adjucation, all were deemed NCN's. None of these nodules turned out to be malignant.

Screening results

On screening CT, a total of 559 nodules were detected, of which 35% had benign calcifications. On standard x-ray, a total of 196 nodules were found, of which 60% had benign calcifications.

CT scanning identified a total of 233 individuals with 1 to 6 non-calcified nodules (23% of the study population). Only 33 of these individuals (14%) also had positive findings on conventional x-rays.  There were 68 individuals with positive results on conventional x-rays; 33 had positive CT scans as mentioned previously, the other 35 had "nodules" that were not confirmed on CT scan (shadow confluence).

Among the 233 individuals with a positive CT screening test, 159 (68%) had one nodule and 43 (18%) had two nodules. The remaining 14% had 3, 4, 5 or 6 nodules. The size of the largest nodule detected in these patients was 2-5 mm in 58%, 6-10 mm in 30%, 11-20 mm in 9% and greater than 20 mm in 2%.  Among the 33 patients whose nodules were also seen on standard x-rays, the sizes were larger overall (2-5 mm - 33%; 6-10 mm - 42%; 11-20 mm - 16% and greater than 20 mm - 9%).

Diagnostic work-up

According to protocol, the 233 participants with positive screening scans should have had high resolution CT scans.  50 participants did not, 14 for "good" reasons (a previous CT scan was available or the nodules were tiny and appeared benign), and 36 because the physician or insurance plan declined or they were lost to follow up.

The remaining 183 participants underwent the high resolution CT scan. In 54 of these, the non-calcified nodules were not confirmed and in 9 the nodules were so benign appearing that only CT follow-up in one year was recommended.

Among the remaining 120 patients requiring follow-up:

• biopsy was recommended immediately in 16, was performed in 14, and revealed malignant disease in 13 cases.
• biopsy was recommended after growth was documented by subsequent scans in 14, and revealed malignant disease in all 14.
• there has been no growth in 90 participants, 36 of these have been followed up for 2 years.

Malignancies detected

A total of 33 patients underwent biopsy, 30 recommended by protocol, as noted above, and three for reasons not indicated by the protocol (all 3 turned out to be benign).

Of the 30 per-protocol biopsies, 27 were malignant. Thus, 27 out of 233 participants (12%) with positive screening tests turned out to have malignant disease.  Among the 68 patients with positive chest x-rays, 7 cases of malignancy were detected (10%).  All of these 7 cases were picked up by CT screening.  Thus CT screening identified 20 (out of 27) cases that would not have been picked up on routine chest x-ray; the yield of CT screening was 4 times greater than that of conventional chest x-ray.

Screening CT also picked up a further 4 malignancies that were not picked up by chest x-ray but were not NCN's (two endobronchial lesions and two mediastinal lesions) and were thus not counted as positive screening results.

Treatment and stage

Diagnosis of malignancy was made by fine needle aspiration in 18 and thoracoscopy in 9; all were judged to be operable. Of the 27 participants with detected malignancies, 24 underwent lobectomy, one underwent mediastinoscopy which revealed stage IIIB disease, one underwent radiosurgery and one declined treatment. 18 of the 27 had adenocarcinoma, the remainder were a mix of adenosquamous, bronchoalveolar, atypical carcinoid and squamous.

Of the 27 malignancies detected, 23 (85%) were stage I.  Of the 7 malignancies detected by conventional x-ray, 4 were stage I.  Thus CT screening detected 6 times as many stage I tumors as conventional x-ray: 23  vs. 4.

Author's discussion

The authors make a number of points about their study:

• Low-dose CT screening is much more sensitive than conventional x-ray for detecting non-calcified nodules and small lung cancers.  CT detected 3 times as many nodules, 4 times as many malignant tumors and 6 times as many stage I tumors as conventional x-rays.
  
  26 out of 27 patients with malignant disease were operable.  In the Mayo Lung Project study, which utilized conventional x-rays, only about 50% of tumors detected at baseline were operable.
   
•  A main objective of this study is to correlate cure rate with nodule size, but follow-up is too short to give any data on this yet.  However, given the small size of tumors that were detected and prior historical data on cure rates according to tumor size, the authors estimate that 5-year survival should be 60%-80% for patients with tumors detected by low-dose CT.  This is much better than the usual 12% 5-year survival rate for lung cancer.
   
• Contrary to current beliefs, the data presented here demonstrate that the presence of 2-6 non-calcified nodules detected on CT was almost as likely to represent malignant disease (11% were malignant) as the presence of a solitary nodule (12%).
   
• The finding of many cases of NCN's did not lead to a lot of unnecessary biopsies.  Unnecessary biopsies were avoided by the management recommendations which required an increase in size before small nodules were biopsied.  If one disregards the three biopsies done which were not recommended by the guidelines, only one out of the 30 recommended biopsies was for a benign lesion.
   
• An argument that can be raised about a study like this one is that it leads to overdiagnosis, i.e. that it leads to the excision of lesions that would not have caused problems in the long run (very slow-growing malignancies).  The authors argue that, using precise measurements of nodule size, the growth rate (doubling time) of the lesions that were excised does not support this hypothesis.
   
• As data accumulates from this study, it will enable more targetted diagnostic approaches to small nodules (based on the characteristics of those nodules that turn out to be malignant) and the evaluation of novel therapeutic approaches to these nodules.
   
• Detailed cost-effectiveness analyses will be conducted, but the authors note that screening CT scans should be only slightly more expensive than conventional x-rays and treatment of early lung cancer is cheaper than treatment of more advanced disease.