1. Holt, Chuck

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Since the introduction of electromagnetic navigation bronchoscopy (ENB) procedures in 2004, physicians have been able to navigate through the lung to biopsy suspicious lung nodules that appear on CT scans without resorting to surgery. The minimally invasive technology provides a 3D map of the lungs and GPS-like guidance of endoscopic tools used to obtain tissue samples of pulmonary lesions for biopsy. Additionally, the ENB procedure eliminates unnecessary surgery for benign disease and invasive procedures like transthoracic needle aspiration.

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Several studies have shown ENB is highly successful in diagnosing and treating patients in the early stages of lung cancer. Research evaluating the effectiveness of ENB for lesions located in the difficult-to-reach peripheral third of the lungs, however, has been inadequate. Such research has been hampered, experts say, by being too small in terms of the number of participants, being conducted in a single setting, and/or including only favorable or "cherry-picked" results.


In response, a team of researchers in 2015 launched NAVIGATE, the largest-ever prospective, multicenter, global, single-arm, pragmatic cohort study of ENB. The study was planned with two follow-up evaluations, one at 12 months and another at the end of 2 years. The first enrolled patient underwent an ENB procedure at Pulmonary and Critical Care Associates of Baltimore in April 2015. Recently, the results of the 12-month follow-up evaluations of 1,215 patients enrolled in the study at 29 medical centers throughout the U.S. were published in the Journal of Thoracic Oncology (2019;14(3):445-458). The data prove that ENB is both safe and effective in the diagnosis of early and advanced lung cancer, the researchers say.


"This is the first large study of its kind proving that what we have been seeing is accurate-that we can navigate to the peripheral third of the lung to obtain appropriate tissue in a safe and effective way, and also stage and prepare for future treatment, in a single procedure. We now need to ask ourselves, 'How can we make diagnoses and staging faster?'" stated Erik Folch, MD, MSc, Chief of the Complex Chest Disease Center and Co-Director of Interventional Pulmonology at Massachusetts General Hospital in Boston, and co-lead investigator of the NAVIGATE study.


Early detection is critical. When patients are diagnosed in the early stages of lung cancer (stage I or II) and receive immediate treatment, their typical long-term survival rate increases from 5 percent at 5 years to 80-90 percent. Still, up to 160,000 people in the U.S. will die from lung cancer this year, making it the deadliest form of the disease, according to the American Lung Association. Among the participants in the NAVIGATE study, 65 percent were diagnosed with stage I or stage II lung cancer.


"There is an epidemic of lung nodules, and there is great difficulty separating benign from malignant for pulmonologists, thoracic surgeons, and radiologists. We use the best existing technologies and we still fall short," Folch told Oncology Times. "Given the survival of patients with lung cancer depends on early identification of malignancy and early staging for referral and treatment, we all must try to shift toward early diagnosis. We have to be aggressive about peripheral lung nodules. And the challenge is, 'How do we get there safely in a population of patients who may have limited pulmonary reserve?'"


Methods & Goals

For the NAVIGATE study, the researchers evaluated ENB cases using the superDimension navigation system. The patented, first-of-its-kind LungGPS technology used enables the ENB procedures.


According to the study abstract, the median lesion size discovered using ENB was 20.0 mm. Fluoroscopy was used in 91 percent of cases (lesions visible in 60%) and radial endobronchial ultrasound in 57 percent. The median planning time was 5 minutes and the procedures were completed in 25 minutes. Among 1,157 subjects who underwent ENB-guided biopsy, 94 percent (1,092) completed navigation and tissue was obtained. Follow-up with the study participants was completed in 99 percent of subjects at 1 month and 80 percent at 12 months, during which the diagnostic yield was 73 percent (J Thorac Oncol 2019;14(3):445-458).


The researchers further report that, of the 1,092 ENB-aided tissue samples collected in the NAVIGATE study, 484 (44%) were malignant and sensitivity, specificity, positive predictive value, and negative predictive value for malignancy were 69 percent, 100 percent, 100 percent, and 56 percent, respectively. ENB-related Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher pneumothoraces (requiring admission or chest tube placement) occurred in 2.9 percent of the cases. While the ENB-related CTCAE grade 2 or higher bronchopulmonary hemorrhage and grade 4 or higher respiratory failure rates were 1.5 percent and 0.7 percent, respectively (J Thorac Oncol 2019;14(3):445-458).


A maximum of 75 subjects per site was allowed to ensure diversity. However, there were no protocol-specified restrictions on the procedural technique, complementary tools, or imaging (planning or surveillance), all of which were subject to the clinician's discretion, but were prospectively captured. The researchers were happy to discover that the small variations in how the procedure was performed in different settings during the study would not impact the yield. "It actually enriches what we know," Folch stated.


Of course, the primary objective of the study remains patient safety. "Can we do this across the board? Can we get excellent results even in advanced disease; in early-stage lung nodules, of course, but also in advanced lung disease? Can we make this available to a large group of pulmonologists and thoracic surgeons?" the researchers asked themselves rhetorically. "And we were very pleased to find that it was even safer than we predicted and that the applicability was even better than we had assumed," Folch noted.


It was also important to address criticisms about the comprehensiveness of past studies of ENB technology, he pointed out. "So we said, 'Fine, we are going to address all of these questions all at once.' It's going to be a large population with multiple centers in multiple countries. And we're not going to select high academic centers where only 15 percent of the U.S. population gets care either if 85 percent receive care in mixed settings or private practices. And our results show that this can be done very well in multiple settings and in a pragmatic fashion. We were also pleased that our results show that the [ENB] procedure could not only be done by more people than expected, but also done well in medical centers, private practices, and mixed settings."


Also lending credibility to the NAVIGATE study, Folch stated, is that the investigators looked at all available ENB cases, as opposed to just those with easily accessible lesions. As a result, the study replicates real-world conditions and demonstrates that ENB has the potential to significantly accelerate lung cancer detection and intervention, he emphasized.


"We need to do better. It is not enough to have a single procedure like a CT-guided biopsy that gives you partial information. We needed a platform that can do multiple things at the same time and do it safely and with a higher level of applicability so that we can do ENB everywhere. It doesn't help the population at large if there is just one person who can do it," Folch explained. "So, with all of these concerns in mind, we said: 'We need to do a large study. We need to make it as practical and pragmatic as possible. We need to let everyone do their best work in academic centers, in private practices, in mixed settings, and hopefully multiple countries.' And that's what we did; that's what NAVIGATE is all about."


Looking Ahead

The final results of the NAVIGATE study will be completed after conducting follow-ups with patients and the end of 2 years, "which will give a chance to show the proof of some of the assumptions we made," Folch noted. "When we diagnose something that is negative or that is non-diagnostic right, we are not certain until we follow it for 2 years. So, the follow-up studies on the NAVIGATE will give us the final denominators and the final numbers.


"In this paper, we made conservative assessments, and we said, 'This is where the true range of the results will lie on yield,'" he continued. "In terms of complications, we already knew that it is very safe and that is not going to change. But in terms of the absolute yield, this is the only paper that follows patients up to 2 years, which gives us a sense of certainty."


What further research needs to be done on this topic after NAVIGATE is completed?


"In terms of the future studies that we are planning, obviously, we think with this platform and other platforms there is great innovation coming," Folch emphasized. "So, once NAVIGATE is finished, or even before it is finished, I think the next steps are comparative studies using other technology. And those are difficult because the technology moves very fast and we need a lot of patients. So, we need to do large studies, we need to do comparative studies, and we need to do a randomized control trial."


And moving forward? "Now, we need to say, 'What other options of treatment can we offer to the patients with early lung cancer who are not surgical candidates?' The current standard is no treatment or localized radiation, but each of those has their own problems," Folch noted.


"So maybe the next step we need to elaborate is [making] local ablation safer and effective?' We are not going to compete with surgery because surgery provides curative intent and very good outcomes for the group of patients who can tolerate the surgery. I think the next step-once we have navigation down to a 't'-is to ask ourselves, 'Can we ablate these peripheral tumors in a safe and effective way?"


Chuck Holt is a contributing writer.