LCS: A Win With NELSON; Shared Decision-Making Takes a Tumble

Expert Critique

FROM THE ASCO Reading Room

Mariela N. Macias MD, MS Sharp Rees-Stealy Medical Group

Lung cancer is responsible for the majority of cancer-related deaths worldwide, partly due to detection in later stages when treatments become palliative. Therefore, lung cancer screening has the potential to decrease cancer-related mortality if detection leads to early stages of diagnosis. In the National Lung Screening Trial (NLST), there was a 20% lung cancer survival advantage to the intervention group using low-dose computer tomography (CT) versus chest radiographs (CXR). Most cancers were detected at earlier stages. Although, there have been negative European studies such as the Italian DANTE study, even the negative studies have detected at least 60% of the cancers as early stage in the low-dose CT groups.

Most recently, results from the NELSON study showed a 26% lung cancer mortality reduction in the intervention group with low-dose CT versus observation. Post-hoc analysis of female participants showed an even greater reduction in lung cancer mortality of 29-61%. Based on these results, it’s expected that European society recommendations for screening will now have sufficient data to support low-dose CT, as will the U.S. Preventive Services Task Force and the American Academy of Family Medicine physicians.

We in the medical community have been slow to adopt these lung cancer screening recommendations, with only about 5% of the eligible population currently being screened. Partly this is due to physicians balancing the risks versus benefits. It was estimated that about a 20% false-positive rate can lead to invasive procedures and possible physical and financial harms to our patients. In addition, the logistical constraints of shared decision-making discussions have been part of the slow adaptation of our screening guidelines to offer low-dose CT to current and former smokers (?years) with ?30 of more pack years of smoking history from the ages of 55-75.

It should also be emphasized that screening should be offered to individuals who are clinically stable and without competing terminal comorbidities, as well as emphasize interventions for smoking cessation as part of shared decision-making discussions.

Differences in protocol that led to decreases in false positives in the NELSON study were using the following measurement variables: volumetric and density versus diameter. Perhaps, these can be adopted in the U.S. if it would mean reducing the burden of false positives.

It would be interesting to continue to gather data on the money saved using screening low-dose CT leading to curative procedures versus our age-matched locally advanced and metastatic patients that utilized newer, effective, but financially draining treatments such as targeted tyrosine kinase inhibitors and immunotherapy. The Milliman studies in cost-effectiveness showed that low-dose CT screening costs are comparable to those of other cancer screening modalities such as colonoscopies and mammography.

Full Critique

In wrestling, a half Nelson hold is considered one of the easiest moves to lock down an opponent, by threading a hand under the other person's arm and locking the hand on their neck. A full Nelson, however, is considered illegal because of the excessive pressure on the opponent's neck.

At the 2018 World Conference on Lung Cancer in Toronto, the full NELSON was in full effect and that was a good thing – findings from the NELSON trial showed that low-dose CT (LDCT) lung cancer screening (LCS) in asymptomatic men at high risk for lung cancer led to a 26% reduction in lung cancer deaths at 10 years of study follow-up.

"These findings show that CT screenings are an effective way to assess lung nodules in people at high risk for lung cancer, often leading to detection of suspicious nodules and subsequent surgical intervention at relatively low rates and with few false positives, and can positively increase the chances of cure in this devastating disease," said NELSON investigator Harry J. De Koning, MD, PhD, of Erasmus MC in Rotterdam, the Netherlands, in a statement. "It is the second largest trial in the world, with an even more favorable outcome than the first trial, the NLST [National Lung Screening Trial], showed. These results should be used to inform and direct future CT screening in the world."

But when it comes to LCS shared decision-making (SDM), which is mandated by the Centers for Medicare & Medicaid Services (CMS) for coverage, clinicians seem to be doing a half-hearted half Nelson given the underwhelming SDM uptake, according to one study. Related research wrestled with the downstream costs in the LCS process.

Andrea Borondy Kitts, MS, MPH, a lung cancer and patient advocate consultant, and a patient outreach and research specialist at Lahey Hospital and Medical Center in Burlington, Massachusetts, joined the Reading Room to discuss the pros, cons, and practical implications in this edition of our continuing LCS update.

NELSON on Top

NELSON was a population-based, controlled trial that enrolled 15,792 individuals (ages 50-74), who were randomized 1:1 to either LDCT LCS at baseline, and at years 1, 3, and 5.5 after randomization (study arm). The patients in the control arm were not offered LCS at all.

Participants' records were linked to multiple national Dutch registries with 100% coverage regarding cancer diagnosis, date of death, and cause of death. An expert panel reviewed 65% of cases. The follow-up period was a minimum of 10 years for 93.7% of enrolled participants who were still alive.

According to the results, there was an 86% average LCS compliance rate encompassing 29,736 scans. In 9.3% of the participants, additional CT scans were performed within 2 months to estimate nodule volume doubling time, which led to an overall referral rate of 2.3% for suspicious nodules.

Detection rates across the rounds varied from 0.8% through 1.1%, and 69% of screen-detected lung cancers were detected at Stage 1A or 1B. A total of 261 lung cancers (52 interval cancers) were detected before the fourth round of follow-ups, the researchers reported.

In a subset of analyzed patients, surgical treatment was three times significantly more prevalent in the study lung cancer patients than in control-arm patients (67.7% vs 24.5%, P<0.001).

In total, 934 participants died in the control arm versus 904 in the study arm.

In the smaller subset of women, there was a larger reduction in lung cancer mortality compared with the men, with the rate-ratio of dying from lung cancer varying from 0.39 and 0.61 in different years of follow-up. "A (non-significant) 41.8% lung cancer mortality reduction has been achieved in the small subset of 2,382 Dutch women," the authors wrote.

"Arguably, the plenary presentation of the mortality results from the NELSON trial was one of the highlights of the 2018 WCLC," said Borondy Kitts. "Results from the second randomized, controlled clinical trial showing a large mortality benefit for LDCT LCS have the potential to influence clinical practice globally."

She pointed out that regions that have been waiting for the NELSON results will now start implementing LCS programs. For instance, Europe has an 18-month implementation plan, and in November 2018, the l'Intergroupe Francophone de Cancérologie Thoracique (IFCT) and Société d'Imagerie Thoracique (SIT) issued a press release recommending rapid implementation of LCS in France.

"The U.S. Preventive Services Task Force (USPSTF) is currently in the process of a systematic review of the evidence for an update to their LCS recommendation. NELSON results have the potential to shift the task force recommendation from a 'B' grade to an 'A' grade, thereby influencing LCS uptake and access," she explained. "In turn, that may persuade medical societies to recommend LCS, and may change CMS requirements for SDM, clinician referral, and maintenance of an LCS registry."

It remains to be seen if the American Association of Family Practitioners (AAFP), which currently does not recommend LDCT LCS, claiming that there is insufficient evidence, changes its recommendation.

The NELSON results may also lead to recognition of the large benefits of LCS for women, and potentially increase recommendations for women to enter LCS programs, as well as inform the development of tailored interventions to increase LCS uptake.

Finally, the inclusion of younger people with lighter smoking history in NELSON, versus NLST, may lead to changes to current eligibility criteria, and include other populations shown to be at high risk, she said.

Shared Decision-Making: A Non-Starter?

James Goodwin, MD, of the University of Texas Medical Branch in Galveston, and colleagues, analyzed Medicare data from January 2015 through December 2016 to determine the percentage of enrollees who received an LDCT LCS and underwent an SDM visit. The team used logistic regression to estimate the odds of patients engaging in SDM before LCS screening and the relative risk of undergoing LCS after SDM.

Among more than 19,000 enrollees, 20% underwent LCS in 2016, but only 9% had a separate SDM visit on the day of LCS or in the previous 3 months. After an initial increase, the monthly percentage of enrollees who had LCS with an SDM plateaued at about 10%.

Goodwin's group found that characteristics tied to lower odds of SDM before LCS included:

• Black race vs white race: odds ratio 0.76 (95% CI 0.59-0.97)
• Female sex: OR 0.88 (95% CI 0.79-0.98)
• Higher education (highest vs lowest quartile of education): OR 0.81 (95% CI 0.68-0.96)
• U.S. region: OR 4.46 (95% CI 3.27-6.08) in mountain region; OR 1.92 (95% CI 1.41-2.60) in Pacific region

Among the more than 2,000 people who underwent SDM from January through October 2016, 60.8% underwent LCS in the following 3 months. Once again, black race (risk ratio 0.81, 95% CI 0.66-0.97) and female sex (RR 0.93, 95% CI 0.86-0.99) were associated with significantly lower LCS after SDM.

"Several factors may contribute to this finding, including the recentness of the mandate [CMS requirement for SDM established in 2015], lack of training in SDM, and competing priorities for clinicians," Goodwin and colleagues noted. "In addition, SDM may have occurred as part of another medical encounter."

They concluded that SDM may have "rapidly evolved from an abstract concept to mandated implementation, but the clinical community has not adopted the CMS mandate for an SDM visit" before LCS.

Rita Redberg, MD, editor of JAMA Internal Medicine, questioned the value of LCS, noting that in the study by Goodwin's group there was a high percentage of patients who chose not to be screened after SDM visits, likely reflecting "the high false-positive rate, high chance of incidental findings, and subsequent need for invasive procedures and small chance of benefit."

"These data suggest that the current use of resources for lung cancer screening should be reexamined and efforts should be refocused on smoking cessation and smoking prevention to prevent lung cancer and improve health," Redberg stated.

Borondy Kitts pointed out that, per Goodwin and colleagues, "low percentages of SDM discussions may have been due partially to underreporting, as these discussions may be occurring as part of clinical visits for other reasons. In addition, the CPT codes for both LCS and the SDM visit were confusing when first implemented after the CMS recommendation in early 2015, so discussions may have occurred but not have been billed."

"Interrogating the data in the American College of Radiology LCS Registry to assess SDM discussion may provide more accurate data on the frequency of these discussions as this is one of the required input variables of CMS," she noted.

Both the authors and Redberg cited a 2018 study that showed that SDM for LCS was underused in clinical practice. But that study had a very small sample size (14 conversations among 10 unique clinicians) and did not report on statistical significance. The study also included data from April 2014, almost a year before the CMS requirement for SDM, Borondy Kitts explained.

"Unfortunately, credible peer-reviewed academic sources are miscalculating the false-positive rates for LCS, with rates being reported as high as 98%, as Redberg did," she noted. "These are actually the false-discovery rate -- a metric that is not commonly used for any other cancer screening test. The false-positive rates in current clinical practice LCS using Lung-RADS structured reporting are 7-8%, which is similar to screening mammography."

"Referring clinicians depend on medical journals to provide accurate information. The erroneously reported high false-positive rates are likely contributing to the reported 40% of individuals who declined LCS after having a SDM discussion," Borondy Kitts said.

"Redberg advocating for diverting funds from LCS to smoking cessation based on just two SDM studies with significant limitations seems highly irresponsible when considering the mortality benefits of LCS demonstrated in two randomized, controlled clinical trials, not to mention the heavy toll of lung cancer taking as many lives every year as the next three leading causes of cancer deaths combined (colon, breast, and pancreatic)," she emphasized.

LCS: Grappling with Costs

Complication rates following invasive diagnostic procedures for lung abnormalities in the community setting seemed to be twice as high as those reported in the NLST, according to Ya-Chen Tina Shih, PhD, and colleagues at the University of Texas MD Anderson Cancer Center in Houston.

The estimated complication rate in their study among participants (ages 55-64) was 22.2% versus 9.8% in NLST. The estimated rate of complication was 23.8% among participants (ages 65-77) versus 8.5% in NLST.

The team retrospectively analyzed non-protocol driven community practices in MarketScan Commercial Claims & Encounters and Medicare supplemental databases, a nationally representative sample of nearly 350,000 patients (ages 55-77) who underwent invasive diagnostic procedures from 2008 to 2013.

"The mean incremental complication costs were $6,320 (95% CI $5,863-$6,777) for minor complications to $56,845 (95% CI $47,953-$65,737) for major complications," the researchers reported.

For example, among those ages 65-69, the cost of a minor complication associated with bronchoscopy was $5,573 (95% CI $3,637-$7,508), while the costs for some major complications, such as those associated with surgical diagnosis, could be as high as $56,200.

"Although the NLST demonstrated the effectiveness of [LCS], whether a similar magnitude of mortality benefit will be realized outside the trial setting remains uncertain," Shih's group stated. "The financial burden of postprocedural complications can be great, as our data indicate that considerable costs are associated with the invasive diagnostic procedures and postprocedural complications."

The investigators cautioned, however, that none of the costs reported in the study should be directly interpreted as costs associated with LCS.

Borondy Kitts called attention to two major limitations with this study: It was done before LCS was covered by private insurance and Medicare, and the study cohort did not consist of individuals who met LCS criteria.

"Also, one critical factor missing from the cohort study was smoking history. LCS eligibility criteria are based on age and smoking history, so it is likely many of those included in the study cohort would not be eligible for LCS," she said.

The authors also did not discuss the lack of a protocol for follow-up of the lung abnormalities in the study cohort, she added, noting that "the procedures used, and the outcomes, may have been very different if the Lung-Rads structured reporting and follow-up protocol for LCS screening had been followed."

"To this point, the surgical intervention results from an actual LCS cohort at my institution (a community hospital) are consistent with those in the NLST. Also, it is important to note that the false-positive rate for LCS with Lung-Rads in clinical practice is 7-8% versus 23.3% in NLST, and thus will result in fewer invasive interventions and fewer total number of complications. This needs to be accounted for in any population level assessment of downstream complications and associated costs due to LCS," Borondy Kitts stated.

Read previous articles in this lung cancer screening series:

To Screen or Not to Screen? That is the (Eternal) Question

Update, Part 1: To Screen or Not to Screen? That is the (Eternal) Question

Update, Part 2: To Screen or Not to Screen? That is the (Eternal) Question

Update, Part 3: To Screen or Not to Screen? That is the (Eternal) Question

Update, Part 4: To Screen or Not to Screen? That is the (Eternal) Question

Update, Part 5: To Screen or Not to Screen? That is the (Eternal) Question

Update, Part 6: LDCT Lung Cancer Screening on the Road to World Domination?

'Rewards and Risks' of Lung Cancer Screening (Update, Part 7)

Lung Cancer Screening: Room for Growth (Update, Part 8)

Lung Cancer Screening: Who Gets It and Why?