Introduction

This chapter describes the outcomes of the baseline and follow-up CT scans, and documents any lung cancers that were identified. As all trial participants will be followed up over 10 years for health and mortality outcomes, it is possible here to give only an early indication of the outcomes for trial participants. This chapter should therefore not be regarded as giving complete information on the trial participants – only that information available to autumn 2014. It is therefore not possible to draw any definitive conclusions from the current data regarding the long-term effectiveness of lung screening.

Methods

Detailed methods regarding technical aspects of CT scanning/reading are given in the previous chapter. In brief, the trial participants who had been randomised to the intervention arm were given an appointment to attend for a single thoracic CT scan at either LHCH or Papworth Hospital. Scans were double-read by a radiologist at the local site (LHCH or Papworth) and a radiologist at the central site (Royal Brompton Hospital). Where necessary, arbitration was performed by an expert radiologist at the central site.

Any lung nodules identified on the CT scan were classified into four categories. Full details of these categories and the formal care pathway are shown in the previous chapter (see Figure 12). In summary, nodule categorisation and subsequent care was as follows:

• No nodules or category 1 (benign) nodules No further action required.
• Category 2 (small, probably benign) nodules Follow-up CT scan at 12 months.
• Category 3 (larger, potentially malignant) nodules Follow-up CT scan at 3 months and 12 months.
• Category 4 (higher chance of malignancy) nodules Immediate referral to MDT.

For category 2 or 3 nodules, the VDT of the nodule was calculated from the follow-up scan (at 3 or 12 months). The VDT was used to assess the likelihood of malignancy.

The UKLS protocol specified clear criteria for referral to the local lung cancer MDT. These were designed to select those at sufficiently high risk of lung cancer to justify further investigation. The subjects referred included those with a high risk of malignancy at baseline CT scan (category 4 nodules regarded as suspicious for lung cancer) and those of categories 2 and 3 with nodules that displayed a VDT of < 400 days. In addition, the protocol specified action for SOFs. These included abnormalities detected that required further action, either urgent, such as the finding of a cancer from another primary site, or less urgent, such as a likely pneumonia, requiring further imaging follow-up or treatment.

Computed tomography scan readers were required to make recommendations as per protocol wherever possible. However, radiologists were also at liberty to vary their recommendations on clinical grounds, if, in the opinion of both the local and central readers and local MDT chest physician, the CT scan appearances were not adequately covered by the protocol.

Details of subjects requiring follow-up for any of the criteria set out in the protocol were recorded in the UKLS database by the local investigators and from the GPs’ records. For lung cancer, stage, pathology and treatment offered were recorded.

Results

A total of 4061 high-risk individuals consented to take part in the RCT. Six of these were not randomised because they had undergone a recent thoracic CT scan (so were not eligible; n = 3), changed their mind about participating (n = 1) or had no randomisation partner at the same hospital (n = 2). The remaining 4055 high-risk individuals were randomised into two groups. Following randomisation, 2028 individuals were assigned to the screening arm, and were offered a thoracic CT scan. Thirty-four of these individuals were not scanned. The most common reasons for this were that the individual withdrew following consent or a scan was felt to be inappropriate as a result of a change in his/her health. A total of 1994 individuals therefore underwent a baseline CT scan (see Figure 2). Details of individuals in both arms of the trial are shown in Table 8; the characteristics of people in both trial arms were very similar with respect to all factors considered.

TABLE 8

Demographic, risk and medical characteristics of n = 4055 individuals who were randomised to the UKLS intervention (CT screen) and control (non-screen) trial arms

Figure 14 shows the outcome of the initial LDCT in a total of 1994 subjects. There were 979 (49.1%) subjects with either clear scans or category 1 nodules that were considered benign or who had a probability of malignancy that was too low to justify further investigation and follow-up, as per protocol.

FIGURE 14

Diagnostic tree showing outcomes of 1994 baseline scans. a, One of these individuals had a third 3-month follow-up scan before referral to MDT; b, one person discharged from category 4 MDT at baseline also had several category 3 nodules – so was (more...)

A total of 1015 (50.9%) participants had category 2–4 nodules. There were 479 (24%) subjects who had category 2 nodules, and who were therefore recommended for a 12-month repeat scan (see Figure 14). Of these, 474 subjects’ repeat CT scans were clear (no significant growth; VDT > 400 days), and the remaining five subjects (0.8%) were referred to the MDT. One of these subjects was diagnosed with cancer (which was resected) and four were discharged or are under follow-up with a presumed likely benign lesion.

There were 472 subjects (23.6%) who had category 3 nodules and therefore underwent a 3-month interval CT scan. Following the 3-month repeat scan, 53 (11.2%) subjects were discharged and 19 (4.0%) were referred to the MDT (two of these had cancer). Nineteen subjects underwent a further 3-month interval CT scan. This was part of a protocol amendment that was introduced to account for new nodules appearing on the 3-month interval CT scan; the concern was that potentially fast-growing cancers might be missed. Following the second 3-month interval CT scan, three subjects were discharged, one subject was referred to the MDT, and one subject underwent a further 3-month repeat scan before referral to the MDT; neither of these had cancer. The remainder comprised 14 subjects who underwent a 6-month CT scan (to complete a 12-month interval from the first CT scan). All of these CT scans have been completed with no malignancy detected. Following the first 3-month interval CT scan, 381 (80.7%) subjects were protocolled for a further 9-month interval CT scan; this resulted in 357 being discharged with no malignancy detected and 24 being referred to the MDT, five of whom had cancer. Thus, a total of 45 individuals initially classed as category 3 (9.5%) were referred to the MDT. Of these, 11 were thought to have cancer and 34 were discharged or are under surveillance for a likely benign diagnosis. One subject (with metastatic cancer) had chemotherapy and 10 had surgery. Altogether, 10 of 50 (20%) subjects referred to the MDT (who had category 2 or 3 nodules at baseline) had confirmed lung cancer.

Sixty-four subjects were referred to the MDT immediately following the baseline scan (see Figure 14). Thirty-one of these were discharged or are under MDT surveillance for nodules with a presumed benign diagnosis, and 33 were thought to have cancer and underwent further investigations. Five subjects had chemoradiotherapy and 28 had surgery, of whom 27 had histopathologically confirmed cancer. Thus 32 of 64 subjects (50%) referred to the MDT with category 4 findings at baseline had confirmed lung cancer.

Table 9 summarises the number of screened individuals assigned to each category, and the numbers referred to the MDT and identified cancers in each category.

TABLE 9

Overall numbers of individuals in each nodule category, numbers referred to the MDT and number of lung cancers diagnosed

Thus, 1952 of 1994 (97.9%) participants completed screening in the trial with no cancer found. Forty-two (2.1%) individuals were diagnosed with lung cancer.

Diagnostic work-up and false-positives

In the UKLS, we defined false-positives or rate of recall as those requiring further diagnostic investigation more immediately than a repeat annual screen, but who transpired on such investigation not to have lung cancer.

Overall, 951 of 1994 (47.7%) of subjects underwent at least one further CT scan after the initial screen. This comprised 479 subjects in category 2 who underwent a 12-month interval CT scan and 472 in category 3 (see Table 10). In addition, at the time of reporting, a further 414 CT scans have been carried out as per protocol (see Figure 14).

TABLE 10

Details of cancers diagnosed

It should be noted that a repeat CT scan at 3 months for category 3 nodules was mandated by the protocol. There were a total of 536 subjects (i.e. 472 category 3, 64 category 4) with nodules requiring a repeat scan. Of the 64 category 4 individuals, 41 were found to have lung cancer.

Owing to our failsafe policy reflecting the single-screen design (i.e. follow-up of category 2 individuals), there were a further 479 individuals for whom a repeat screen was recommended at 12 months, only one of whom was found to have a confirmed cancer.

The referral rate to the MDT was low and there were relatively few people with benign disease who had invasive tests. One hundred and fourteen (5.7%) were referred to the MDT of whom 72 (3.6% of the total; 72/1994) did not have cancer.

For complete clarity, the proportion of false-positive tests is now provided in two ways, which allows an appreciation, in a patient-centred approach, of the variable impact on the subject in a trial or the patient in a programme. A ‘false-positive’ that mandates referral to the lung cancer MDT will usually be associated with significant psychological distress, and additional more or less invasive investigations with, in some cases, definitive treatment. An individual with a false-positive so defined is thus more likely to suffer harm than one defined in a different way; that is, those subjects who are recalled solely for further CT imaging to clarify the nature of a nodule. The latter is best termed ‘interval imaging rate’ and may, in screening programmes, merely mean continuing in the programme rather than referral to the MDT. For this reason, all category 3 lesions without cancer are reported separately as false-positives warranting interval imaging. Category 2 findings are not classified as false-positives warranting recall, as the cancer rate was found to be so low in this study that interval imaging would not be recommended.

Thus, on examining the number of UKLS participants referred to the MDT clinic, the false-positive rate is 3.6% (114 – 42/1994 = 3.6), whereas the interval imaging rate for the category 3 nodules is 23.2% (472 – 9/1994).

In total, 114 of 1994 (5.7%) participants were referred to the MDT, of whom 42 (2.1% of all screened) had lung cancer.

Details of cancer diagnoses

Of the 42 cancers with a confirmed diagnosis, 27 were diagnosed at LHCH, and 15 at Papworth Hospital. Twenty-five diagnoses were adenocarcinoma, 12 were squamous cell carcinoma, three were small cell carcinoma, one was a typical carcinoid and one was of unknown type (this patient was treated with palliation alone).

Pathological staging of cancers was completed for 35 of 42 cancers: 17 were T1aN0 (one Nx), six were T1bN0, two were T2aN0, two were T2bN0, two were T1aN1, three were T2aN1, two were T1–2N2 and one was T3N0. Clinical staging was recorded for a further seven cancers (Table 10). Thus, 67% of the screen-detected cancers that have so far been staged (28/42) were identified at stage 1. Details of all individuals referred to the MDT with a cancer diagnoses are shown in Table 10.

Demographics of people diagnosed with lung cancer

Of the 42 individuals with a screen-detected lung cancer, 32 were men and 10 were women (i.e. 1.8% of all individuals screened, for both genders). The mean age at trial recruitment for the cancer patients was 66.9 years (median 67 years; range 55–75 years). This was similar to the mean age of all those screened (67.1 years). Seventeen of 42 (40.4%) people with a confirmed cancer were from the most deprived IMD quintile (Q1), five (11.9%) were from Q2, nine (21.43%) from Q3, four (9.5%) from Q4, and seven (16.7%) from the least deprived IMD quintile (Q5).

Predictors of subjects requiring further investigations

Variables from questionnaire 1 (see Appendix 3) were used in both univariate and multivariate logistic regression analyses to establish which factors were associated with participants requiring follow-up scans or investigations (i.e. category 2–4 individuals; n = 1015) compared with individuals with clear scans (category 1; n = 979). In the univariate analysis, both female gender [odds ratio (OR) 1.25, 95% confidence interval (CI) 1.02 to 1.53; p < 0.032] and a previous history of respiratory disease (OR 1.25, 95% CI 1.05 to 1.49; p < 0.012) were associated with requiring further scans. In the multivariate analysis, a previous history of respiratory disease (OR 1.28, 95% CI 1.06 to 1.54; p < 0.009) was associated with requiring further scans.

Further work-up by multidisciplinary team

Table 11 shows the further investigations and procedures that have so far been completed for subjects referred to the MDT. Only 8.6% of subjects who did not have confirmed cancer had needle biopsies and 4.3% had surgery. These are the two procedures most associated with complications. Overall, of 114 subjects referred to the MDT, 11 subjects (15.3%) without confirmed cancer had either a biopsy or surgery and nobody had both. This includes one subject with likely lung cancer. Thus, only 0.55% of subjects screened underwent semi-invasive or invasive tests for benign disease.

TABLE 11

Work-up by MDT

Treatment

Table 10 shows the treatment received by subjects with lung cancer. Reflecting the early stage, 35 of 42 subjects (83.3%) had surgery as their primary treatment. Of these, eight also had chemotherapy and one had radiotherapy. Chemotherapy was the primary treatment in three patients and radiotherapy was offered to two subjects who declined surgery. Treatment was palliative (supportive care) in two subjects.

Incidental findings

To date, over the course of the UKLS screening trial, 128 SOFs have been identified on the CT scans by the trial radiologists. Most of these findings related to thoracic disease, but 17 extrathoracic SOFs were also identified. Individuals with a SOF on scan were referred for further investigations and treatment to a relevant specialist or MDT, or their own GP. Details of the thoracic and extrathoracic SOFs are shown in Tables 12 and 13, respectively.

TABLE 12

Clinically significant thoracic incidental findings, for which a supplementary radiology report was sent to the GP or appropriate MDT

TABLE 13

Clinically significant extrathoracic incidental findings, for which a supplementary radiology report was sent to the GP or appropriate MDT

Significant other findings were managed locally in Liverpool or Papworth. For any incidental findings that were identified before 9 December 2013, the participants’ GPs were contacted by UKLS and asked to provide follow-up and outcome data. The results from both Liverpool and Papworth are detailed below. Follow-up information for incidental findings arising after 9 December 2013 has not yet been requested, hence the figures below do not include all of the incidental findings detailed above (see Tables 12 and 13).

In the Liverpool cohort, 55 SOFs were identified, and the patients’ primary care physician informed. Seventeen different conditions were identified, including eight abdominal conditions. Thoracic conditions included pneumonia (n = 18), pulmonary fibrosis (n = 8), pleural thickening (n = 5), bronchiectasis (n = 3), lymphadenopathy (n = 3), severe emphysema (n = 3), lobar collapse (n = 2), oesophageal thickening (n = 2), mediastinal mass (n = 2), thyroid mass (n = 1) and thoracic aortic aneurysm (n = 1). Abdominal abnormalities included adrenal lesion (n = 2), abdominal aortic aneurysm (n = 2), cirrhosis of the liver (n = 1), splenomegaly (n = 1), renal mass (n = 1) and pancreatic cyst (n = 1). Further information on these patients was identified from secondary care records and 31 responses from primary care for follow-up data. Although the vast majority of pneumonias were managed in primary care, at least 22 of the others were referred to secondary and tertiary care for further investigation and management.

There were 48 SOFs in the Papworth cohort. The GPs of patients with SOFs were contacted by letter and asked to take appropriate action. For five cases with a potentially life-threatening condition the letter was followed up with a telephone call a few days later to ensure that action had been taken. Thoracic conditions included interstitial lung disease (n = 10), severe emphysema (n = 2), pneumonia (n = 16), atypical pneumonia (n = 4), lymphadenopathy (n = 3), posterior mediastinal mass (duplication cyst) (n = 1), thymoma (n = 1) and aortic calcification (n = 4). Abdominal conditions included renal mass (n = 2), adrenal mass (n = 1), hepatic mass (n = 1), abdominal aortic aneurysm (n = 1), biliary dilatation (n = 1) and hydronephrosis (n = 1). In 29 cases, outcomes are known from secondary care records or via the primary care follow-up questionnaire. Of these, the UKLS identified a diagnosis that was already known to the GP in three cases and no further action was taken. In 12 cases the GP treated the patient and in 14 cases the patient was referred to secondary or tertiary care.

Overall, about 5% of patients had a SOF identified. Nearly all of these were previously undiagnosed conditions. Their identification empowered primary care physicians to manage or appropriately refer on, for the patient’s benefit.

Discussion

These preliminary findings from the single screen UKLS study have confirmed several suppositions and hypotheses.

The lung cancer detection rate is 2.1%. This means that the LLP risk assessment model has performed as expected. All subjects had to have a 5-year risk of lung cancer of at least 5%. A > 1% risk on prevalence screening would therefore be expected. Unlike other CT screening studies, LLP avoids the problem of screening people at very low risk, for whom the harms of screening may outweigh the benefit.

The low threshold for imaging follow-up of abnormal findings resulted in 47.7% of subjects needing a follow-up CT scan at 3 months and/or 1 year. This was to be expected, as the UKLS protocol indicated repeat scans for people with category 2 nodules, which accounted for around 50% of nodules. However, only one lung cancer was detected from this category. Nine lung cancers have been confirmed from the group of category 3 nodules. For both of these categories the probability of finding lung cancer in the nodules is below the baseline risk of the population as a whole, and for category 3 (although numbers are too small to draw any real conclusion) it is 1.9%. Two lung cancers were identified by the 3-month interval CT scan, so it could be argued that this step is necessary. However, we are not able to comment on the effect on prognosis of detection of these lung cancers after 3 months rather than after a 12-month interval. Whether or not an annual screen is the best strategy for managing both category 2 and 3 nodules should be determined by reference to other studies with larger numbers and by monitoring outcomes of future screening programmes.

The immediate work-up strategy for the category 4 findings resulted in the greatest number of confirmed lung cancers; 50% of category 4 subjects referred to the MDT had lung cancer. Overall, only 5.7% of subjects were referred to the MDT, which demonstrates the utility of the imaging recall protocol. Furthermore, those subjects who underwent further investigation mostly underwent further imaging with few having minimally invasive or invasive procedures for benign disease. This rate of investigation of benign disease was similar to that found in NELSON³⁷ and the NLST. Active treatment rates were high; 83% of subjects with confirmed lung cancer had surgery, reflecting the high proportion of patients with stage 1 or 2 disease. Of those patients who had surgery for later stage 3a disease, this was detected only at surgery, a feature thought to be associated with a more favourable prognosis.

A variety of significant other findings were detected. These included the detection of other cancers including malignant melanoma and renal carcinoma as well as important benign conditions such as severe emphysema. Not all of these benign diagnoses were known to the subject or their doctor. The detection of these other conditions (especially cancer) may clearly benefit subjects, although it is not possible to measure the effect in this study.

It is important to note how many more cancers appeared to be detected in the lower socioeconomic groups. Although numbers are relatively small there was a marked difference between the socioeconomic profile of the subjects screened (which was similar to the population as a whole) and that of those who had lung cancer. This raises a number of issues that may be important if screening programmes are to begin. As the risk of lung cancer is most strongly related to age and smoking, it is likely that the main reason for the observed rates in the lower socioeconomic groups is that the subjects smoked more. This would be in keeping with the way the LLP_v2 selects individuals at a risk of at least 5% over 5 years. There will be a proportion of people who are at much greater risk by virtue of their smoking habit. This observation also has implications for the recruitment of people into programmes. At selection, we observed that the lower socioeconomic groups were more at risk yet were less likely to participate, and we now know that the same group, when recruited, does indeed have a greater prevalence of lung cancer. This serves to emphasise the importance of effective methods of recruitment of these relatively disadvantaged people into screening programmes if the effectiveness of such programmes is to be maximised.