Screening study finds high prevalence of early-stage lung cancer among smokers with HIV

Using low-dose computed tomography to screen selected people living with HIV who smoke, led to early lung cancer diagnoses at younger ages than normally seen in the general population, according to findings from the ANRS EP48 HIV CHEST study reported last week at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), in Seattle, USA.

During follow-up of the screening, there were no serious adverse events due to diagnostic procedures and more than half of the lung cancers detected by screening were surgically curable (stage 1a) according to Alain Makinson of University Hospital Montpellier who presented the study results during a thematic discussion session on cancer.

Lung cancer has been one of the most common non-AIDS-defining cancers in people living with HIV and it is seen at higher frequencies than in the general population. As noted by other presentations at the conference, a high rate of smoking among people with HIV is responsible for most of the increased risk, but HIV-related immune deficiency also appears to contribute.

Lung cancer has a very high rate of mortality because it can develop without noticeable symptoms and usually remains undiagnosed until it has advanced to a stage where it can no longer be cured.

However, studies have shown that low-dose computed tomography (CT) scans can detect early-stage non-small cell lung cancer lesions that are more responsive to treatment or surgery. Clearly, it would not be cost effective to perform scans on everyone, but a large multicentre study in the US, the National Lung Screening Trial (NLST), showed that using low-dose CT to screen those at highest risk reduced lung cancer-related mortality by 15-20% and overall mortality by 7%.

The screening protocol followed in the NLST is now recommended by the American Cancer Society: low-dose CT three times per year for high-risk individuals, defined as adults aged 55 to 74 years old, in fairly good health (sicker patients may have more abnormalities in their scans and are more likely to be harmed by diagnostic procedures) who are either still smoking or smoked within the last 15 years, with a smoking history of at least 30 pack-years (number of packs smoked per day multiplied by the number of years of smoking – people who smoke one pack a day for 30 years, or two packs a day for 15 years, would have a smoking history of 30 pack-years).

However, Makinson pointed out that further studies are needed to evaluate low-dose CT screening in different populations – particularly among smokers with HIV who are at higher risk of developing lung cancer. He noted that other studies have suggested that people living with HIV might develop lung cancer at an earlier age and with less of a smoking history.

The ANRS EP48 HIV CHEST study

In order to assess the feasibility and efficacy of low-dose CT for people living with HIV and to identify what might be the best screening criteria to achieve early lung cancer diagnosis in this population, Makinson and colleagues performed a prospective study in 14 clinical centres in France.

The study included people living with HIV aged 40 years or older, with a history of smoking within the last three years, a history of 20 or more total pack-years, a CD4 cell nadir (lowest-ever level) of less than 350 cells/mm³ and a current CD4 count above 100 cells/mm³.

Only a single round of low-dose CT screening was performed for all trial participants. If a significant nodule was found on the CT – defined as a solid or partly solid nodule >5mm or a non-solid nodule >8mm – or if there was an endobronchial image or significant adenopathy (swollen lymph nodes), participants received follow-up CT or an immediate diagnostic work-up, as recommended by the International Early Lung Cancer Action Program Algorithm. Follow-up continued for two years.

The study enrolled 442 participants. A majority were men and the median age was 50 years. The median current CD4 count was 574 cells/mm³, the median nadir CD4 count was 168 cells/mm³ and 90% had a viral load below 50 copies/ml.

The researchers found that 94 participants (21%) had a significant image on low-dose CT screening that required follow-up. Over the course of the next 24 months, 18 diagnostic procedures were performed for 15 people (3.4%). There were no adverse events reported from these procedures.

Ten lung cancers were diagnosed in the study, nine of which were detected by the low-dose CT screen; the other was a small-cell lung cancer which can develop very rapidly and probably emerged after the baseline screen. Nine of the lung cancer cases were proven histologically and one was a very probable lung cancer that was treated as such with stereotaxic radiotherapy. (Among the other patients undergoing diagnostic procedures, a mucosa-associated lymphoid tissue lymphoma, an Abrikossoff tumor and a mycobacterial infection were identified.)

Of the nine lung cancer cases detected by screening, six were diagnosed at an early treatable stage. Most were adenocarcinomas and one was a stage 1a squamous cell lung cancer. These six participants could quite possibly have died prematurely if this screening trial had not been conducted. In the other three cases that were diagnosed later, the local clinicians had delayed performing diagnostic procedures – in two cases for more than 66 weeks after the baseline CT scan.

Only 38 study participants did not complete the study. One withdrew consent, 32 were lost to follow-up and five died (two of lung cancer, one of sudden death, one in an accident and one of a lung infection).

Makinson noted that one concern had been that low-dose CT screening for people with HIV might yield a very large number of significant images – which would require either expensive on-going follow-up or diagnostic procedures – but the proportion of significant images was similar (slightly lower, actually) to those in the NLST, and the total number of invasive diagnostic procedures was low.

Most of the cases of lung cancer were diagnosed in people under age 55 (though none were under age 45), so "lung cancer screening criteria that target only those between the ages of 55 to 74 years would miss substantial numbers of cancers in people living with HIV, at least in those with low CD4 nadir counts," Makinson said.

Discussion

This presentation was one of the most hotly debated during the thematic discussion, partly because of concerns about 'false positive' images and the costs of CT scanning. While the rate of false-positives was low in this study, it excluded people with very low current CD4 cell counts who might be expected to have more significant images due to lung infections, etc. However, in this study only a single baseline scan was performed and follow-up scans were only done for those with a significant image (unlike the NLST protocol that involved periodic screening). How often repeat scanning might be necessary in the entire population is yet to be determined.

Other doctors at the discussion session were unsure about aspects of the screening criteria – such as the appropriate age (perhaps screening should start at 45 years of age) or the smoking pack-year cut-off. The median number of pack-years was 30 in the French trial, however three of the diagnosed cases occurred in participants with less than 30 pack-years. Makinson agreed that some of the criteria might be fine-tuned.

Others expressed concerns about the robustness of the data in support of low-dose CT screening, particularly given that 30% or 40% of these cancers that are treated may recur – even when surgically resected with clear margins – in people living with HIV. Some felt that a randomised controlled study would be necessary to demonstrate a survival benefit.

"I'd be glad to do a randomised controlled trial in [people with] HIV, but if you want to prove increased survival, you would have to enrol thousands of patients and that is something very difficult," Makinson concluded.