Yield and Complications of Endobronchial Ultrasound Using the Expect Endobronchial Ultrasound Needle

Fatima Ghazal¹, Sandrine Hanna², Christy Costanian³, Shashank Nuguru⁴, and Khalil Diab²

¹Department of Internal Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT USA

²Department of Medicine, Division of Pulmonary and Critical Care Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC USA

³Department of Biostatistics, The Lebanese American University Gilbert and Rose-Marie Chagoury School of Medicine, Byblos, Lebanon

⁴Department of Medicine, Division of Pulmonary and Critical Care Medicine, Wellstar Kennstone, Atlanta, GA USA

Abstract 

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) stands as the gold standard for sampling the mediastinum and possesses the capability to detect a diverse range of disease processes. The EBUS needle industry has been experiencing rapid advancement, characterized by numerous companies either enhancing existing needles or introducing innovative ones. The majority of EBUS studies to date have predominantly utilized the Olympus^TM Vizishot needles, which are constructed from stainless steel. In this paper, we focus on the evaluation of a cobalt chromium needle, namely the Expect^TM EBUS needle, with a specific emphasis on its diagnostic efficacy and any associated complications. It is important to note that our investigation is conducted independently, and we do not provide a comparative analysis with other needle types available in the market.

Methods: This is an institutional review board-approved retrospective analysis of all patients who have undergone an EBUS-TBNA lymph node sampling using the Expect^TM needle between August 2016 and September 2017 at the IU Health University Hospital. Comparisons of clinical characteristics by complications, diagnosis, needle gauge, and lymph node size were performed using chi-square test and Fisher’s exact test.

Results: 75% of the 102 included patients had their procedures done with the 22-gauge needle which were majorly performed in the setting of suspected intrathoracic malignancy followed by sarcoidosis and lymphoma. 99% of the patients had no complications after their procedures which were almost all diagnostic with two cases of bronchoscope damage. Mutational analysis was successful with both the 22 and 25-Gauge needles.  

Conclusion: In this paper, we demonstrate that the Expect^TM 22 and 25-gauge needles are safe and effective when used for EBUS-TBNAs through the Olympus^TM EBUS bronchoscope for the evaluation of intrathoracic lymphadenopathy.

Introduction

The treatment of lung cancer has been evolving rapidly over the past several years. It is of utmost importance to secure an accurate pathological diagnosis and to adequately stage lung cancer patients prior to any treatment decision. One of the primary determinants of cancer staging is lymph node tumoral involvement which makes accurate pre-operative assessment essential. The utility of endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) is now firmly established in sampling mediastinal lymph nodes and has become the gold standard method in place of mediastinoscopy in terms of cost-effectiveness, accuracy, and safety (1,2). More importantly, the use of EBUS-TBNA has been particularly important in upstaging tumors, especially in presumed N0 or N1 disease on initial imaging (3-6). Furthermore, in the era of targeted cancer treatment, it has also shown success in tissue sampling for molecular analysis, such as programmed death ligand-1 (PD-L1) analysis and other mutations (7-10).

Endobronchial ultrasound has become the gold standard for lung cancer diagnosis and staging, and its use and adoption has increased rapidly over the years. Indeed, the market share of endobronchial ultrasound needles has been growing recently with multiple companies expanding on older needles or producing new ones. Most endobronchial ultrasound studies have utilized the Olympus^TM (Center Valley, PA) Vizishot needles, which are stainless steel needles (11-13). Our aim in this paper is to examine another type of needle, the Expect^TM endobronchial ultrasound needle (Boston Scientific, Marlborough, MA), looking at its diagnostic yield and rate of complications when used for EBUS-TBNA. This is a cobalt chromium needle with a sharp tip that has a unique locking mechanism and method of entry into the lymph nodes.

Our primary outcome is to assess the yield and specimen adequacy at different nodal stations using this specific needle. We evaluated its yield in the diagnosis and staging of lung cancer and other mediastinal diseases. The secondary objective of our study is to look at procedure-related complications pertaining to both the patients and the bronchoscope itself using the Expect^TM needle.

Materials and Methods 

Patients

From August 2016 to September 2017, we reviewed our database of patients older than 18 years of age with mediastinal lymphadenopathy whether associated with a suspected, or confirmed lung cancer or other causes, who were referred to the Indiana University Health University Hospital for a diagnostic workup using the Expect^TM 22 and 25-gauge needles. Electronic health records were reviewed for demographic information, including age, gender, pre-procedure diagnosis, smoking status, associated comorbidities, radiographic findings with either computed tomography (CT) scan and/or Positron Emission Tomography (PET), location and size of the enlarged lymph nodes as well as their clinical course. The study was approved by the Indiana University institutional review board (study number:1610932969).

Procedure

All cases were performed in the operating room of Indiana University Health University Hospital under general anesthesia using an I-gel^TM manufactured by Intersurgical (Berkshire, United Kingdom). The cases were performed by the same interventional pulmonologist in the presence of a pulmonary fellow. Prior to the procedure, a CT scan of the chest and reports of prior imaging (including PET scans) were available for a final review of the lymph nodes. Those lymph nodes to be sampled were selected based on appropriate lung cancer staging in cases of suspected lung cancer, or for diagnosis of other benign and malignant mediastinal nodal diseases. After introduction in the trachea, the bronchoscope was advanced to the main carina and the lymph nodes were examined sequentially. For all visualized lymph nodes, an EBUS image was obtained with the sizes measured prior to nodal puncture. After selection of the lymph node to be sampled, the airway mucosa was punctured under continuous ultrasound guidance using the either the 22-gauge or 25-gauge Expect ^TM endobronchial ultrasound needle (Boston Scientific, Marlborough, MA). The stylette is typically pulled out several centimeters prior to puncture to expose the sharp tip of the needle, then entry into the lymph node is established. Ten actuations are done and the lymph nodes are sampled on a slide in the presence of rapid onsite cytologic evaluation. Each lymph node is sampled at least 3 times. Further sampling for cell block is done based on the cytologist’s recommendations.

Statistical Analysis

Descriptive statistics were used to analyze clinical characteristics and outcomes. Comparisons of clinical characteristics by complications, diagnosis, needle gauge, and lymph node size were performed using chi-square test and Fisher’s exact test, when needed. In all cases, a two-tailed p-value of 0.05 or less was considered statistically significant. All data were analyzed using STATA 13.0.

Results

A total of 102 patients were included in the analysis. Most of the patients were older than 70 years of age (more than 70%) with almost 30% aged between 51-60 years. 40% of patients were former smokers while 35% were current smokers. More than 75% of patients had their procedure performed using the 22-gauge needle and the rest using the 25-gauge needle. A lymph node size of ≥ 8mm was selected in 78.4% of cases. The most common indications for bronchoscopy were diagnosis and staging of lung cancer with mediastinal adenopathy in 61.8% of the cases, followed by sarcoidosis and lymphoma rule out in 31%., followed by work-up of mediastinal lymphadenopathy with or without lung nodules in the setting of active extra-thoracic malignancy. The overwhelming majority of patients had no complications after their procedures (99%) which were almost all diagnostic. There were only two cases of bronchoscope damage which happened when the needle was entered without the stylette.

All diagnostic procedures had no complications except one procedure complicated by a pneumomediastinum which was the only non-diagnostic case. Table 1 explores the proportion of procedures done using the 22-gauge and 25-gauge needles by diagnosis, in which all patients (100%), had adequate tissue sample for molecular testing.

Table 1. Needle Gauge by Yield or Diagnosis

*SCLC, Small cell lung cancer; **NSCLC, Non-small cell lung cancer

75-80% of lung cancer diagnoses were obtained using a 22-gauge needle, while the rest were obtained using a 25-gauge needle. 88.9% of cases with metastatic malignancy from outside the lungs were diagnosed using a 22-gauge needle. All cases of granulomatous disease (100%) and most cases of reactive lymphadenopathy were diagnosed with the 22-gauge needle. At Indiana University, reactive lymphadenopathy diagnosis was based on rapid on-site assessment and indicated the presence of adequate specimen with lymphocytes at our centre. Pneumomediastinum as a complication occurred in the only non-diagnostic case using the 22-gauge needle. Transvascular needle aspiration was performed successfully in two cases; one diagnosing small cell lung cancer and the second diagnosing reactive lymphadenopathy. There was no significant difference in the diagnostic yield by the two needle gauges (98.75 vs 100%); most procedures were performed using the 22-gauge needle. There was no significant difference in yield between lymph nodes less than 8 mm in size and those greater than 8 mm in size, although most lymph nodes studied were greater than 8 mm in 89% of the cases. Hence in almost all the cases, mutational analysis was adequate using both the 22 and 25-gauge needles.

Discussion

To our knowledge, this is the first study assessing the yield and complications of the Expect ^TM needle with EBUS. Previous studies had assessed the yield of this needle with endoscopic ultrasound (14). The results of our study show that the Expect needle demonstrated good diagnostic yield in lymph node sampling during the evaluation of mediastinal lymphadenopathy for either suspected primary thoracic, metastatic malignancy or non- malignant disease processes. As the use of the EBUS technique has become the gold standard preferred over mediastinoscopy in the management of lung cancer and evaluation of mediastinal lymphadenopathy since the end 2000s, more EBUS related techniques are being evaluated and studied to enhance their diagnostic accuracy (15-19). Indeed, overwhelming evidence has proven the lower number of complications of this technique compared to surgical mediastinoscopy while yielding very good results.

In a review of biopsy needles for mediastinal lymph node sampling, Colella et al. (20) reviewed characteristics of an ideal needle, which mostly consisted of high level of resistance, flexibility and echogenicity for better visualization under ultrasonography. There are multiple needles in the market currently trying to meet these standards. These include the Procore^TM needle and the SonoTip Topgain^TM needle. The Expect^TM needle used in this study meets some of these characteristics, mostly attributable to the chromium-cobalt (CoCr) alloy it is made of. From a series of experimental needle trials, Keehan et al. (21) showed that the chromium-cobalt alloy was 24% harder than the tested Stainless Steel 304 (SS) indicating that these needles are more likely to conserve their sharpness and resist blunting (21). They also demonstrated greater kinking resistance and tensile properties than the SS needles. Moreover, it was shown that the needle was easily visualized on ultrasound and that upon withdrawal from the endoscope, there was less deformation of the needle itself. All of these aforementioned properties are particularly important, as several types of needle-related complications have been reported such as the release of metal particles into lymph nodes, breakage of the needles with possible migration and infectious sequelae (22-25).

As for the diagnostic properties investigated in this study, there was no significant difference between the 22 and 25-gauge needle sizes, although the 22-gauge needle was used in the majority of the cases. The overwhelming majority of prior studies have not reported significant superiority of a particular needle size though most were conducted comparing the 22 and 21 needle sizes (26-28). In a recent 2019 study published by Di Felice et al. (29) comparing the 22 and 25-gauge needle sizes, no significant difference was noted between their sample adequacy and diagnostic accuracy. Similarly, another 2021 study published by Sakaguchi et al. (30) showed that while the diagnostic yields of the 22 and 25-gauge sizes may be comparable in lung cancer, that of the 22-gauge is superior in the diagnosis of sarcoidosis. While no particular needle size in the evaluation of lung cancer is certainly favoured, the need for increasing tissue sampling for molecular studies, immunophenotyping and next-generation sequencing has supported the use of larger needles (31-32).

On that same note, as the treatment of advanced non-small cell lung cancer (NSCLC) has revolutionized with targeted therapies based on driver mutations positivity, more attention is drawn to maximize the yield of EBUS guided biopsies for tissue sampling (33-36). Using EBUS for this purpose is now well established especially for EGFR and ALK mutations testing (37-41). More recent studies have also supported the role of EBUS-guided TBNA samples for PDL-1 testing which draws more attention to enhance this technique as it becomes gold standard in both cancer diagnosis and management. In our study, we demonstrate that using the Expect^TM needle provides adequate samples for these tests (anaplastic lymphoma kinase (ALK), receptor tyrosine kinase -1 (ROS-1), epidermal growth factor receptor (EGFR), programmed death ligand -1 (PDL-1)), particularly useful when sent for adenocarcinoma.

As for the complication rate, it was low and similar to what has been previously described in the literature (42). Indeed, the only complication (pneumomediastinum) occurred in the one non-diagnostic case. Most of the literature supports a rate of adverse events of less than 1%. In a metanalysis including more than 9000 EBUS-FNA cases, von Barthled et al. (43) found a rate of serious adverse events of 0.05%. These comprised infectious complications as sepsis and mediastinal abscess formation, pneumothorax, and hypoxemia. Another Japanese survey that also evaluated the complications related to bronchoscope damage, described a low complication rate as well. The rate of needle breakage was reported at 0.2% while the rate of bronchoscope damage at 1.33% (42). This is similar to our rate of bronchoscope damage which was 0.98%.

Our study has several limitations. It is a retrospective review, and therefore, prone to the errors associated with such reviews. It also does not provide a head-to-head comparison with other needles. The absence of a control group in this research poses a challenge in estimating the potential clinical befits of utilizing the “expect” needle compared to various other types, including the Olympus^TM needles (Vizishot and Vizishot 2). It is a single-centre study involving one interventional pulmonologist, and therefore, is operator-dependent and centre-dependent. Its strengths are that it is a rare evaluation of the needles currently on the market, and it paves the way for upcoming multi-center collaborative studies evaluating newer needles.

Conclusions

EBUS-guided biopsies have emerged as the preferred method for diagnosing and managing non-small cell lung cancer (NSCLC), prompting the exploration of various techniques for this purpose. We present evidence supporting the safety and efficacy of Expect^TM 22- and 25-gauge needles when employed for EBUS-TBNAs through the Olympus^TM EBUS bronchoscope in the assessment of both benign and malignant intrathoracic lymphadenopathy. This contributes to the expanding body of EBUS literature, as novel techniques and needle options are continually being investigated and utilized. Nonetheless, the selection of the appropriate needle for EBUS entails numerous considerations. While effectiveness and the risk of complications remain paramount, factors such as the operator’s familiarity with the needle, its availability, and cost has substantial influence in decision making process.

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Cite as: Ghazal F, Hanna S, Costanian C, Nuguru S, Diab K. Yield and Complications of Endobronchial Ultrasound Using the ExpectTM Endobronchial Ultrasound Needle. Southwest J Pulm Crit Care Sleep. 2024;28(6):81-89. doi: https://doi.org/10.13175/swjpccs020-23 PDF

June 2022 Pulmonary Case of the Month: A Hard Nut to Crack

Daniel Gergen MD¹

Anne Reihman MD¹

Carolyn Welsh MD^1,2

¹Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Colorado, Aurora, Colorado USA

²Eastern Colorado Veterans Affairs Medical Center, Aurora, Colorado USA

History of Present Illness: A 54-year-old man presented to clinic with chronic cough, dyspnea on exertion, unintentional weight loss, and night sweats. Seven months before, he developed dyspnea on exertion and symptoms did not improve with inhalers. Four months prior to presentation, he was treated for presumed community-acquired pneumonia of the right lower lobe. Neither symptoms nor chest radiograph improved with multiple courses of antibiotics. In the four weeks prior to presentation his symptoms progressed to the point that he was unable to walk in his house without significant dyspnea.

Review of systems: 10-pound unintentional weight loss and six weeks of night sweats.

Past Medical History, Social History and Family History: The patient had a 15-pack-year smoking history and quit 15 years prior to presentation. He had no other past medical history, surgical history, family history, nor medications.

Physical Examination: Vital signs were normal on presentation. Physical exam showed faint wheezing and decreased breath sounds over the right posterior lung fields.

Radiography: Chest radiograph demonstrated dense opacification in the superior segment of the right lower lobe (Figure 1).

Figure 1. Initial chest radiography. A: PA view. B: Lateral view.

What are diagnostic possibilities at this time?

1. Lung abscess
2. Lung cancer
3. Foreign body with post-obstructive pneumonia
4. Tuberculosis
5. 1 and 3
6. All the above

Cite as: Gergen D, Reihman A, Welsh C. June 2022 Pulmonary Case of the Month: A Hard Nut to Crack. Southwest J Pulm Crit Care Sleep. 2022;24(6):89-92. doi: https://doi.org/10.13175/swjpccs024-22 PDF

A Population-Based Feasibility Study of Occupation and Thoracic Malignancies in New Mexico

Claire R. Pestak, MPH ^1,2

Tawny W. Boyce, MS, MPH ¹

Orrin B. Myers, PhD ⁴

L. Olivia Hopkins^, MD ³

Charles L. Wiggins, PhD ^1,2,3

Bruce R. Wissore, JD, PhD, MA, MS, MS ^3,6

Akshay Sood, MPH, MD ^3,5

Linda S. Cook, PhD ^1,3

¹UNM Comprehensive Cancer Center, University of New Mexico, MSC 07-4025,
1 UNM, Albuquerque, NM, 87131, USA

²New Mexico Tumor Registry, University of New Mexico, MSC 11 6020, 1 UNM, Albuquerque, NM, 87131, USA

³Department of Internal Medicine, University of New Mexico School of Medicine, MSC 10 5550, 1 UNM, Albuquerque, NM, 87131, USA

⁴Department of Family and Community Medicine, University of New Mexico School of Medicine, MSC 09-5040, 1 UNM, Albuquerque, NM, 87131, USA

⁵Miners Colfax Medical Center, Raton, NM, 87740, USA

⁶Southwestern Illinois College, Belleville, IL, 62221, USA

Abstract

Background

Occupational exposures in mining and oil/gas extraction are known risk factors for thoracic malignancies (TMs). Given the relatively high proportion of these industries in New Mexico (NM), we conducted a feasibility study of adult lifetime occupational history among TM cases. We hypothesized a higher proportion of occupational TM in NM relative to the estimated national average of 10-14%.

Methods

We identified incident TM cases through the population-based New Mexico Tumor Registry (NMTR), from 2017- 2018. Cases completed a telephone interview. An adjudication panel reviewed case histories and classified cancers as probable, possible, or non-occupational related, taking into account the presence, duration, and latency of exposures. We characterized recruitment and describe job titles and exposures among those with occupational TMs. We also compared the distributions of industry between those with and without occupational TM.

Results

The NMTR identified 400 eligible TM cases, 290 of which were available to be recruited (n=285 lung/bronchial cancer; n=5 mesotheliomas). Of the latter, 60% refused and 18% were deceased, 9% had invalid addresses, 11% were unable to be reached by telephone, and 3% were too ill to participate. The 43 cases who completed an interview held 236 jobs. A total of 33% of cases were classified as probable occupational TM and 5% as possible occupational TM.

Conclusions

High rates of early mortality and refusals were significant barriers to study participation. Nonetheless, the proportion of probable occupational TMs greatly exceeded the estimated national average, highlighting the need for further study of occupational TM in the state.

Editor's Note: See The Best Laid Plans of Mice and Men for accompanying editorial.

Introduction

Lung cancer and mesothelioma are the most common thoracic malignancies (TMs). Lung cancer is the second most common cancer in the United States (US) and in New Mexico (NM) and the leading cause of cancer death (1). Mesothelioma is relatively rare but has a specific association with occupational exposure to asbestos. For this paper, lung cancer and pleural mesotheliomas are combined as TMs. Despite some treatment advances (2,3), five-year relative survival is less than 20% for all TM (4).

The strongest risk factor for lung cancer is cigarette smoking (5). Other established risk factors for TMs include exposure to asbestos, uranium, radon gas, and other cancer-causing agents in the workplace, radiation therapy to the lungs, and a family history of lung cancer (6-8). The importance of occupation in TMs is emphasized by the Global Burden of Disease (GBD) report indicating that the two main cancers caused by occupational exposures worldwide were lung cancer (274,000 deaths annually) and mesothelioma (27,000 deaths annually) (9). Various estimates attributing occupation to lung cancer include: a 1981 US estimate of 15% for men and 5% for women, or 10% overall (10), a 1987 NM estimate of 14% in men (11); and, a 2003 US estimate for deaths of 8.0%–19.2% for men and 2% for females, or 6.3%-13.0% overall (12,13). Thus we estimated that overall in the US, 10%-14% of TMs could be attributable to occupation.

Historic and current occupational exposures are of particular interest in NM. Mining, in particular uranium mining, was a major operation in NM from 1950-1970. Mining is still an important industry in this region: between 2011 and 2015, the NM mining industry saw a 20% increase in employment for all types of mining (14). NM also has significant employment in the Mining, Quarrying, and Oil and Gas Extraction industry relative to other parts of the Southwest (15). These industries have a greater share of local employment in NM than in the US overall (16). Additionally, NM was the ninth highest natural gas producer in the US in 2018, producing 1.49 million cubic feet of natural gas (17).

Given the historic and current extraction activities in NM, we hypothesized that NM would have a higher proportion of occupational TMs than the estimated national average of 10%-14%. As an initial step in estimating this occupational TM cancer burden in NM, we conducted a feasibility study to obtain adult lifetime occupational histories for TM cases.

Methods

Recruitment and Data Collection 

This feasibility study was approved (#16-306) by the Human Research Review Committee at the University of New Mexico and cases provided signed, informed consent. We identified incident TM cases from February 1, 2017 to February 2, 2018 via the population-based New Mexico Tumor Registry (NMTR), a founding member of the National Cancer Institute’s (NCI) Surveillance Epidemiology and End Results (SEER) Program. Cases were identified by two methods: (1) rapid case ascertainment (RCA) via electronic pathology reports and (2) usual case ascertainment (UCA) via tumor registrars manually collecting data from around the state. Contact with eligible cases involved a three-step process. In step 1, the NMTR contacted treating physicians explaining the study and advising them of their patient’s eligibility allowing the physician to state any objection to patient contact. In step 2, the NMTR contacted the patient (letter and study brochure in English and Spanish) informing them about the study and allowing them to opt-out from further contact. In the special case of no physician of record, patients were contacted after a three month wait period. Patients who refused participation or were deceased were ineligible for study contact. In step 3, for the remainder, contact information was released to study personnel.

All potential cases in step 3 were mailed documents in both English and Spanish including: an introductory letter, a flyer about benefits counseling, a Frequently Asked Questions sheet, two copies of a Residence and Work History worksheet, a Life Events Calendar, showcards, and two copies of the consent form. One consent form was for the case to sign and keep and the other was signed and returned to the study, along with one copy of the Residence and Work History worksheet. Showcards functioned as a visual aid by listing possible answers to interview questions. The Life Events Calendar functioned as a memory aid to anchor major life events like marriages, births, deaths, relocations, job changes, and other historical events. The Residence and Work History Worksheet gave the cases a time frame to date their paid jobs and occupations, held for at least 6 months, during their adult life and was used for reference during the interview. Work did not have to occur in the state of NM. Study interviewers contacted cases by telephone to answer questions. Those who expressed a willingness to participate were asked to complete and return the worksheets/consent form and to schedule an interview.

Consenting cases completed the same structured telephone interview with an embedded script that obtained information on demographics, lifestyle factors, medical history, reproductive history (women only) and adult lifetime occupational history. For each and every job held for six months or longer from age 18 years onwards, the cases provided job title, city and country of job location, job status (full-time/part-time), job duties, exposure information on relevant agents (18) (a list of more than 30 relevant exposures was provided to cases) including the duration of each exposure, and age at start and end of the job. All cases were asked all job-related questions providing a detailed and specific work history for each individual. Data were recorded in Research Electronic Data Capture (REDCap) database (19). Cases received a small merchandise card in appreciation. All potential cases and surviving family members were given an optional referral to a benefits counselor regardless of their self-reported exposures or determination by the Data Adjudication Committee (DAC).

Determination of Occupational TM

De-identified occupational history summaries were reviewed by the DAC to determine if each case was attributable to occupational exposures, as summarized below. The DAC was composed of three voting members: a pulmonologist with expertise in occupational pulmonary diseases associated with the coal and uranium mining industries; a preventive medicine specialist with expertise in occupational health who works in the Center for Occupational Environmental Health Promotion; and, an attorney with expertise in the medicolegal definitions for causation in the occupational setting. A non-voting member (CRP) served as the committee Chair to tally votes and mediate further discussion if necessary.

This expert panel independently reviewed the de-identified individual job histories for each case, and considered exposures that had a latency of at least 10 years, exposure durations of at least one year, and exposure intensity through self-reported frequency of exposure on the job. To aid in assessment, each panel member was provided a summary table of the known strength of the association between relevant exposures and TM occurrence (available upon request) (20-27). After independent review, the panel would meet to discuss and vote on classification. If all three DAC members found sufficient evidence for relevant occupational exposure, the case was classified as a probable occupational TM. If at least one DAC member found insufficient evidence for relevant occupational exposure, the case was classified as a possible occupational TM. If all DAC members found insufficient evidence for relevant occupational exposure, the case was classified as non-occupational TM. Smoking history for each case was provided to the DAC, but occupational cancer was decided independent of smoking, except in the case of asbestos exposure where a synergistic relationship is well supported by the published literature (28). Because of the participant burden and the high likelihood of misclassification, we did not collect information on environmental tobacco smoke or biomass/coal smoke for each job reported in this study. A letter was sent to each case with the DAC’s determination.

Analysis

After the determination of occupational TM status by the DAC, each job title for each case was coded to an industry using the NIOSH Industry and Occupation Computerized Coding System (NIOCCS) (29). Each job title was submitted, and using the "Census 2010/NAICS 2007/SOC 2010" coding scheme, the most appropriate 2010 Industry Census Code provided by the industry and occupation output was selected. If the industry was unclear based on the job title alone, the work history was reviewed for the company name, job duties, or other relevant notes. In these situations, once an industry was selected, the industry was independently verified by another study team member. The possible 269 industry categories in the 2010 census system were further summarized into 20 North American Industry Classification System (NAICS) sectors (30).

Results

Of the 400 eligible cases initially identified via the NMTR, 110 (28%) were not released to study personnel for the following reasons: 33 (30%) refused to have their information released to investigators; 47 (43%) were deceased; 23 (21%) had no physician of record and were in the 3-month wait period; four (4%) had an invalid address; two (2%) were subsequently determined to be ineligible, and one case (1%) was determined to have a duplicate record in the NMTR. The remaining 290 eligible cases were invited to join the study, of which 285 had lung cancer and 5 had mesothelioma. Over-all, refusals (60%) and deaths (18%) were the two major reasons for non-participation in the interview, but cases also had invalid addresses (9%), were unable to be reached by telephone (11%), or were too ill to participate (3%). Of the 43 cases, 98% agreed to future tumor tissue testing and medical record reviews.

Demographic characteristics of cases are detailed in Table I.

Table I. Demographics of Thoracic Malignancies (TM) cases

Among the cases, 51% were women, 70% were Non-Hispanic White, 86% were >60 years of age, 19% reported a parent had lung cancer. In terms of insurance and benefits, 95% had some type of health insurance, but only 9% had sought compensation through Social Security Disability, Worker's Compensation, or the Veterans Administration before the study. Medical Histories of cases are detailed in Table II.

Table II. Medical History of Thoracic Malignancies (TM) cases.

Among the cases, 49% were overweight/obese. Both smoking (72% current/former cigarette smokers) and non-malignant respiratory diseases (40% reporting pulmonary fibrosis, COPD, or chronic bronchitis) were common.

Cases reported 236 jobs representing 20 NAICS sectors, and 14 (33%) were classified as probable and 2 (5%) as possible occupational TM. Among the probable occupational TM cases, 11 (79%) were men, and both the possible occupational TMs were men. The 14 cases with a probable occupational TM self-reported one or more of the following occupational exposures: aluminum production (n=1), arsenic (n=1), asbestos (n=7), cadmium (n=1), coal-tar (n=1), diesel (n=7), ether (n=5), nickel (n=2), paint (n=1), radiation (n=1), silica (n=9), and soot (n=2). The joint distribution of these cases by job title and exposure category is shown in Figure 1.

Figure 1. Relevant Self-Reported Exposures by Job Titles per Industry Sector for the Cases with Occupationally Related Thoracic Malignancies*

*Exposures deemed to be causal by the Data Adjudication Committee.

The study population only included those who were diagnosed and captured by the NMTR from February 1, 2017 to February 2, 2018 (n=400). Case identification at the NMTR, especially for cancers like TMs where there may not be a pathology report, may be ascertained more than a year after diagnosis. A NMTR query in March 2020 for diagnoses in the same time period noted above yielded more than double the number of TM cases (n=913). Thus we had the opportunity to compare those identified early (n=400) and up to two years later (n=513) as well as those released to the study for contact (n=290) with those whose names were not released for study contact (n=110) by selected demographic and histological characteristics (Table III).

Table III. Summary of the characteristics of the lung cancer and mesothelioma cases diagnosed between 2/1/17 – 2/2/18 for the OCTOPUS Study. Data source New Mexico Tumor Registry (NMTR).

There were differences in age between the 400 cases identified during the study period (50% for those 70 years and older) and the 513 cases identified later (57% for those 70 years and older) (p<0.05) and rurality between the 400 cases identified during the study period (23% rural) and the 513 cases identified later (44% rural) (p<0.001). Apart from the obvious difference in death as this was a criteria for not releasing contact to the study, a difference in histology was noted for those released to the study (77% non-small cell carcinoma) and those not released (66% non-small cell carcinoma) (p<0.05).

Discussion

This feasibility study was designed to obtain lifetime occupational histories from a population-based sample of TM cases and to determine the proportion of such cases that were likely attributable to occupational exposures. Despite our efforts to recruit these subjects in a timely manner, high rates of early mortality and refusals were significant barriers to study enrollment, indicating that a definitive study is not possible based on these methods. Among those who participated in the study, the proportion of cases with occupational TM (33%) was two to three times higher than prevailing national estimates (10-14%). While this result is intriguing and may warrant further study, we cannot say with certainty if this result is due to the low response percentage and the possible selection bias of having cases that were more likely to have relevant occupational exposures, or if this result truly reflects the occupational exposures in NM.

Recruiting TM cases via a population-based cancer registry is challenging. In total, 25% of eligible cases died before they could be recruited to the study via the NMTR or study personnel. An even higher proportion refused, 52% of eligible cases, in part due to poor health as cancer progressed and to the burden of treatment concurrent with study participation. Such a high refusal percentage could be a source of selection bias in which various occupations were under- or over-represented, but we had no data to address this bias directly. Additionally, the study only included those who were diagnosed and captured by the NMTR from February 1, 2017 to February 2, 2018 (n=400). We noted a substantial difference in rurality between the 400 cases identified for our study (23% rural) and the 513 cases identified later (44% rural). The majority of counties in NM are rural or frontier (26/33) (31). TM cases diagnosed among residents of these areas are less likely to receive health care in facilities that are served by pathology laboratories with electronic reporting; instead cancer registrars visit the facilities to manually abstract medical records leading to a longer reporting timeline. These results imply that rural TM cases were under-represented in our study, and since those with mining and other extraction occupations are more likely to reside and get health care in rural areas, our estimate of 33% occupational TM might be an underestimate.

From the list of more than 30 possible exposures that are known or suspected carcinogens for lung cancer (32), probable occupational TM cases reported exposures to aluminum production, arsenic, asbestos, cadmium, coal-tar, diesel fumes, ether, nickel, paint, radiation, silica, and soot. Limitations of these results include the difficulty of retrospective estimation of the intensity and duration of each of these exposures at each job, and the fact that the study did not have enough cases to conduct an analysis accounting for other exposures such as tobacco use, comorbidities, and socioeconomic factors (33). Further, we did not have information on exposures to indoor smoke in the home from, for example, wood burning stoves.

The U.S. does not have a comprehensive employment and exposure database or an occupational disease mortality surveillance system that could provide more objective and comprehensive occupational information than self-report. In some countries, researchers can link data from national cancer registries and occupational databases to help confirm associations between occupational exposures and cancers (34). Inclusion of an occupational history in medical records could also provide more objective data, but such practices are currently sporadic and non-uniform. While death certificates often record a decedent’s longest or lifetime occupation, no exposure details are included, and access to this minimal data is often restricted in an effort to maintain confidentiality (35). Thus, improvements to the evaluation of occupation and occupational exposures for cancers such as TMs on a population-basis remains a challenge.

Other strengths of our study not indicated above include: our success in ascertaining a detailed adult lifetime occupational history from lung cancer survivors using an English or Spanish interview; inclusion of racial/ethnic minorities; inclusion of both men and women (with 21% of women in our study having a probable occupational TM); no eligibility restriction to a specific industry or exposure; a rigorous procedure via the DAC to establish a probable-occupational, possible-occupational, or non-occupational classification for each case; and offering cases a referral for benefits counseling (65% accepted). The limitations of this study have been discussed above.

This feasibility study suggests that 33% of cases had a probable occupational TM, two to three times the national historical estimate, highlighting the importance of exposures and jobs in the NM population that can lead to occupational TMs. However, a more definitive study is not feasible based on the methods used in this study as the ability to overcome the above-described methodological and recruitment challenges remains a significant barrier to further population-based studies of occupation-related TM in NM and the US.

Acknowledgements: This research utilized the UNM Comprehensive Cancer Center (UNMCCC) Biostatistics Shared Resource, and the UNM Clinical & Translational Science Center, the Surveillance, Epidemiology and End Results Program (SEER) data for New Mexico, and REDCap (DHHS/NIH/NCRR #8UL1TR000041).

Funding: The grant sponsor was the UNM Foundation, a non-profit corporation, organized exclusively for charitable and educational purposes under Section 501(c)(3). CRP, TWB, and LSC and the Biostatistics Shared Resource received support from the UNM Comprehensive Cancer Center (NCI P30 CA118100). CRP and CLW received support by Contract HHSN261201800014I, Task Order HHSN26100001 from the National Cancer Institute.

Institution and Ethics approval and informed consent: The work was performed at the University of New Mexico and the Human Research Review Committee (Federal wide Assurance FWA00003255) approved this study. Study participants provided written informed consent.

Acknowledgements: This research utilized the UNM Comprehensive Cancer Center (UNMCCC) Biostatistics Shared Resource, and the UNM Clinical & Translational Science Center, the Surveillance, Epidemiology and End Results Program (SEER) data for New Mexico, and REDCap (DHHS/NIH/NCRR #8UL1TR000041).

Funding: The grant sponsor was the UNM Foundation, a non-profit corporation, organized exclusively for charitable and educational purposes under Section 501(c)(3). CRP, TWB, and LSC and the Biostatistics Shared Resource received support from the UNM Comprehensive Cancer Center (NCI P30 CA118100). CRP and CLW received support by Contract HHSN261201800014I, Task Order HHSN26100001 from the National Cancer Institute.

Institution and Ethics approval and informed consent: The work was performed at the University of New Mexico and the Human Research Review Committee (Federal wide Assurance FWA00003255) approved this study. Study participants provided written informed consent.

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Cite as: Pestak CR, Boyce TW, Myers OB, Hopkins LO, Wiggins CL, Wissore BR, Sood A, Cook LS. A Population-Based Feasibility Study of Occupation and Thoracic Malignancies in New Mexico. Southwest J Pulm Crit Care. 2021;22(1):23-35. doi: https://doi.org/10.13175/swjpcc057-20 PDF 

July 2018 Pulmonary Case of the Month

Anjuli M. Brighton, MB, BCh, BAO

Mayo Clinic Arizona

Scottsdale, AZ USA

Pulmonary Case of the Month CME Information

Completion of an evaluation form is required to receive credit and a link is provided on the last page of the activity. 

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Anjuli M. Brighton, MB. All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives: As a result of completing this activity, participants will be better able to:

1. Interpret and identify clinical practices supported by the highest quality available evidence.
2. Establish the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
3. Translate the most current clinical information into the delivery of high quality care for patients.
4. Integrate new treatment options for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: University of Arizona College of Medicine at Banner University Medical Center Tucson

Current Approval Period: January 1, 2017-December 31, 2018

Financial Support Received: None

History of Present Illness

An 81-year-old gentleman was admitted for syncope. He had felt unwell for one month. His recent illness started with the “flu”. He had lingering productive cough, low volume hemoptysis and felt very fatigued. After a coughing episode he apparently lost consciousness and was taken to the emergency department.

Past Medical History, Social History and Family History

He has a past medical history of hypertension, glaucoma, diverticulosis and COPD. He was taking only antihypertensives including a diuretic. He has a 30 pack-year history of smoking but quit 10 years ago.

Physical Examination

• Normotensive
• Tachypneic
• SpO2 96% on 2L NC
• Afebrile
• Diffuse wheezing, diminished at L base
• Irregularly irregular heart rate

Which of the following are indicated at this time? (Click on the correct answer to be directed to the second of six pages)

1. Chest x-ray
2. Complete blood count (CBC)
3. Electrocardiogram (EKG)
4. 1 and 3
5. All of the above

Cite as: Brighton AM. July 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;17(1):1-6. doi: https://doi.org/10.13175/swjpcc073-18 PDF 

First-Line Therapy for Non-Small Cell Lung Cancer Including Targeted Therapy: A Brief Review

Richard A. Robbins, MD*

Thomas D. Kummet, MD**

*Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

**Sequim, WA USA 

Abstract

Operative removal of non-small cell lung cancer remains the mainstay of therapy. When this is not possible, cytotoxic chemotherapy and/or radiotherapy can be given but are marginally effective in prolonging overall survival. However, with a better understanding of the pathobiology of the lung cancer cells, new targeted therapies have been developed which may produce dramatic responses in selected patients. This brief review will emphasize these newer therapies in this rapidly evolving field.

Introduction

Lung cancer is extremely common and remains by far the most frequent cause of cancer-related death with approximately 154,050 deaths estimated to occur during 2018 (1). Although lung cancer deaths have declined in men, the deaths have risen in women and now account for nearly half of all women’s cancer deaths (1). Unfortunately, the vast majority are diagnosed with advanced, unresectable disease that remains incurable (1). Overall the five-year survival rate is <1% for advanced (stage IVB) disease, while the five-year survival rate for all stages is approximately 15 % (1).

Data linking cigarette smoking to human lung cancer is incontrovertible (2). The risk increases with both the amount of smoking and the duration of smoking (2). Passive or second-hand smoke is also associated with an increase in the risk of lung cancer, although this increase is far lower than that observed with active smoking (2). Smoking cessation clearly decreases the risk of lung cancer (2).

Primary lung cancers can be divided into two main types based on their histology, small cell lung cancer and non-small cell lung cancer (NSCLC) (3). NSCLC constitute about 85% of lung cancers with the rest consisting of small cell and some rarer cancers (3). A basic understanding of the pathobiology of NSCLC has shown that the tumor cells depend on the formation of new blood vessels (angiogenesis), transfer of a phosphate group from ATP to tyrosine on proteins (tyrosine kinase), and regulation of programmed death ligands (checkpoint proteins) (4). Targeted therapy against these pathobiologic processes have shown dramatic effects in some NSCLC patients (4).

NSCLC is divided into 4 stages designated by roman numerals (5). The stages are based on the size of the tumor; whether it has metastasized locally or distally; and use the TNM classification where T designates tumor size; N regional lymph node metastasis; and M distant metastasis. Stages I and II are limited to the chest but stage III has metastasized to the pleura and/or regional lung lymph nodes. Stage IIIA means the cancer has metastasized to lymph nodes that are on the same side of the chest as the cancer (ipsilateral) while stage IIIB signifies metastasis to lymph nodes on the opposite side of the chest (contralateral). Stage IV denotes there are distant metastasis outside the chest. The above is admittedly an oversimplification and there are subtle nuances that define the stages which can be found at the National Cancer Institute website (5).

An overall summary of standard preferred by the National Cancer Institute for NSCLC by stage is shown in Table 1 (6).

Table 1. Standard preferred therapy for NSCLC by stage (6).

Surgery

Operative removal of the lung cancer is the cornerstone of management for patients with early-stage (stages I–II) NSCLC and selected patients with stage IIIA disease (7). Lobectomy is the operation of choice for localized NSCLC based on a randomized trial of lobectomy versus more limited resection (8). Operative intervention should be offered to all patients with stage I and II NSCLC who clinically are medically fit for surgical resection. However, patients may be unable to undergo a lobectomy for a variety of reasons such as: 1. severely compromised pulmonary function; 2. multisystem disease making lobectomy excessively hazardous; 3. advanced age; or 4. refusal of the operation. Some patients who cannot tolerate a full lobectomy but may be able to tolerate a more limited sublobar operation (6). For patients in whom complete tumor resection cannot be achieved with lobectomy, sleeve lobectomy is recommended over pneumonectomy because it preserves pulmonary function (6). In addition, the question of whether video-assisted thorascopic surgery (VATS) is equivalent to thoracotomy for patients with lung cancer comes up often, particularly in patients that are less than ideal surgical candidates. In a series of 741 patients with stage IA NSCLC, 5-year survival was similar but VATS was associated with fewer complications and a shorter length of hospital stay (9).  Therefore, VATS is an optional surgical approach particularly in poorer risk patients.

Radiotherapy

Although lobectomy is the treatment of choice for NSCLC patients with early-stage disease, some are unable to undergo an operation due to reasons listed above. For those patients, radiotherapy can be administered with curative intent, albeit with lower overall survival rates when compared to surgery (10,11).

The radiation oncology community is excited about the potential of stereotactic body radiation therapy (SBRT) (12,13). SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). Although there is no data yet, trials are ongoing comparing SBRT with surgery in early stage NSCLC.

Adjuvant Therapy

Adjuvant chemotherapy. Adjuvant chemotherapy is chemotherapy that is given in addition to either surgical and/or radiation therapy. Data from recent randomized adjuvant clinical trials and a meta-analysis support the use of adjuvant chemotherapy in NSCLC (14). A 5.4% five-year survival benefit was observed in a meta-analysis of five randomized trials compared to observation. Not surprisingly, the survival benefit varied according to stage but the benefit was most pronounced for patients with stage II and IIIA disease. Survival benefit in patients with stage IB disease did not reach statistical significance. Importantly, patients with stage IA disease appeared to do worse with adjuvant chemotherapy, and therefore, is not currently recommended.

Adjuvant radiotherapy. The PORT meta-analysis of 2,128 patients demonstrated that the use of post-operative radiotherapy was associated with a detrimental effect on survival (15,16). The decrease in survival was more pronounced for patients with lower nodal status. The PORT meta-analysis has been criticized for its long enrolment period and use of different types of machines, techniques and radiation doses. Despite these criticisms, three randomized phase III trials support the PORT meta-analysis’ conclusion that the use of post-operative radiotherapy provides no survival benefit (17-19). For patients with N2-positive disease, however, a retrospective analysis demonstrated higher survival for those patients who had received post-operative radiotherapy (20). On the basis of the above studies, most do not recommend routine post-operative radiotherapy with the possible exception of those with N2 disease.

Locally Advanced Disease

About a third of patients with NSCLC present with disease that remains localized to the thorax but may be too extensive for surgical treatment (stage III) (21). Concurrent chemotherapy and radiation therapy is considered the standard therapy for this situation but results in only a modest, although statistically significant, survival benefit compared with sequential administration (21). However, significant toxicity results from this approach and so it is usually offered only to those with good performance status.

Surgery after chemotherapy in patients with N2 disease was tested in two randomized trials. A European trial used three cycles of cisplatin-based chemotherapy, then randomized the patients to surgery or sequential thoracic radiotherapy (22). There was no significant difference in overall survival or progression-free survival. An American trial used a slightly different protocol (23). Patients with N2 disease were given two cycles with concurrent radiotherapy and then randomized to further radiation or surgery. This trial showed a better progression free survival with surgery but no difference in overall survival.

Metastatic Disease

About 40% of patients with NSCLC present with advanced stage IV disease. Until recently, cytotoxic chemotherapy was the cornerstone of treatment for stage IV disease but is now recommended as first line therapy alone only for patients with low or no expression of markers for targeted therapy (24). Unfortunately, in stage IV NSCLC standard cytotoxic chemotherapy alone is minimally effective. A meta-analysis that included 16 randomized trials with 2,714 patients demonstrated that cytotoxic chemotherapy offers an overall survival advantage of only 9% at 12 months compared with supportive care (25). Two-drug chemotherapy (doublets) appears to be superior to either a single agent or three-drug combinations (26). Cisplatin-based doublets are associated with a marginal one-year survival benefit compared with platinum-free regimens (27). Platinum-free regimens can be given as an alternative especially in patients who cannot tolerate platinum-based treatment (24). Although gemcitabine, vinorelbine, paclitaxel or pemetrexed are often added to either cisplatin or carboplatin, the choice of the second drug does not appear to matter in increasing survival (28).

Targeted Therapies

Starting in the early 2000s, NSCLC subtypes have evolved from being histologically described to molecularly defined. The use of targeted therapies in lung cancer based on molecular markers is a very rapidly changing field. At the time this article was being written (February 2018) the information was current but recommended therapies are likely to change with development of new therapies and research. It is important to point out that despite these advances, there remains no cure for stable IV NSCLC. Table 2 represents a summary of targets and targeted therapy along with the American Society of Clinical Oncology (ASCO) recommendations for stage IV NSCLC as of February 2018 (24).

Table 2. Targets and targeted therapies for NSCLC (24).

*Currently not recommended for clinical use by ASCO.

The need for adequate tissue to perform molecular studies creates challenges for pulmonologists doing bronchoscopic procedures. Whereas it was previously adequate to obtain diagnostic material. However, it is now important to obtain adequate tissue to perform additional molecular testing to allow determination of whether targeted therapies are appropriate. Sometimes tissue is inadequate which might necessitate a second procedure if clinically warranted.  

Vascular Growth Factors

Epidermal Growth Factor Receptor (EGFR). The EGFR pathway represents the pioneer of personalized medicine in lung cancer. EGFR is a transmembrane receptor that is highly expressed by some NSCLCs. Binding of ligands (epidermal growth factor, tumor growth factor-alpha, betacellulin, epiregulin or amphiregullin) to the extracellular EGFR domain results in autophosphorylation through tyrosine kinase activity (29). This initiates an intracellular signal transduction cascade that affects cell proliferation, motility and survival (29). Inhibition of ligand and EGFR binding or the activation of tyrosine kinases inhibit the downstream pathways resulting in inhibition of cancer cell growth (29).

Initial studies showed that most patients with NSCLC had no response to the tyrosine kinase inhibitor (TKI), gefitinib, which targets phosphorylation of EGFR (30). However, about 10 percent of patients had a rapid and often dramatic clinical response (30). An explanation for these results occurred with the identification of mutations of the tyrosine kinase coding domain (exons 18–21) of the EGFR gene. Subsequent research linked these mutations to the clinical response to gefitinib (31,32). Although about 10% of Caucasian NSCLC have these mutations, the mutations were observed more commonly in Asian patients, particularly non-smoking women (33). There is now overwhelming and consistent evidence from multiple trials that all the approved EGFR-TKIs (gefitinib, erlotinib, or afatinib) have greater activity than platinum-based chemotherapy as the first-line treatment of patients with advanced NSCLC with activating EGFR mutations (24).  These agents have more favorable toxicity profiles than platinum-based chemotherapy and have demonstrated improvements in quality of life. The choice of which EGFR-TKI to recommend to patients should be based on the availability and toxicity of the individual therapy. Randomized clinical trials are ongoing comparing EGFR-TKIs. The results of these trials may help refine this in the future.

Despite high tumor response rates with first-line EGFR-TKIs, NSCLC progresses in a majority of patients after 9 to 13 months of treatment. At the time of progression, approximately 60% of patients (regardless of race or ethnic background) are found to have a Thr790Met point mutation (T790M) in the gene encoding EGFR (34). The presence of the T790M variant reduces binding of first-generation EGFR-TKIs to the leading to disease progression (34). Osimertinib is an irreversible EGFR-TKI that can bind to EGFR despite the T790M resistance mutations and has recently become clinically available (35). Currently it is recommended for T790M mutations that occur after the first-line EGFR-TKIs have failed (24).

Cetuximab is a monoclonal antibody directed against EGFR itself. In the past, addition of cetuximab to cisplatin doublet chemotherapy in EGFR positive tumors was usual. However, cetuximab has recently been shown to shorten progression free survival with some adverse effects and is no longer recommended (24).

Vascular endothelial growth factor (VEGF). Angiogenesis, the formation of new blood vessels, is a fundamental process for the development of solid tumors and the growth of secondary metastatic lesions. Vascular endothelial growth factor (VEGF) acts to promote normal and tumor angiogenesis. Bevacizumab, a recombinant, humanized, monoclonal antibody against VEGF, was previously recommended as first-line therapy in stage IV NSCLC patients without a contraindication. However, the most recent ASCO guidelines finds insufficient evidence to recommend bevacizumab in combination with chemotherapy as first-line treatment (24).

Other Kinase Inhibitors. Receptor tyrosine kinase 1 (ROS1) and the structurally similar anaplastic lymphoma kinase (ALK) are enzymes that are critical regulators of normal cellular activity. In NSCLC rearrangements of these genes can cause them to act as oncogenes, or genes that transform normal cells into cancer cells. Rearrangements in the ROS1 or ALK genes are found in a small percentage of patients with NSCLC. Crizotinib is a molecule that blocks both the ROS1 and ALK proteins. Crizotinib reduced tumor size in ALK+ or ROS1+ positive patients although the most recent ASCO guidelines consider the evidence only moderate with ALK+ and weak with ROS1+ patients (24,36-8).

Checkpoint Inhibitors. An important part of the immune system is its ability to tell the difference between normal cells and those that are “foreign”. To do this, it uses “checkpoints”, molecules on certain immune cells that need to be activated (or inactivated) to start an immune response (39). NSCLC can use these checkpoints to avoid being attacked by the immune system. Programmed cell death protein 1 (PD-1) is a checkpoint protein on T cells. It normally acts as an “off switch” when it attaches to programmed death-ligand 1 (PD-L1), a protein on some normal (and cancer) cells. Some NSCLCs have large amounts of PD-L1, which helps them evade immune attack. Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against NSCLC cells. In patients with NSCLC with >50% of their tumor cells PD-1+ (tumor proportion score >50%), pembrolizumab, a monoclonal antibody against PD-1, significantly prolonged progression-free and overall survival compared to platinum-based chemotherapy (40). Based on this trial, pembrolizumab is now recommended by ASCO for patients with a tumor proportion score >50% for PD-1 (23). A number of other PD-1 (e.g., nibolumab) and PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab) exist but ASCO recommends only pembrolizumab at this time (39,40). As more of these checkpoint inhibitors are developed and tested this will likely change.

Second and Third-Line NSCLC Therapy

Second and third-line therapy for NSCLC is beyond the scope of this brief review. It is a rapidly evolving field which should include close collaboration between the pulmonologist, oncologist and other members of the patient’s NSCLC treatment team.

After an initial response, lung cancers can become resistant to therapy. One example mentioned above is the development of the T790M mutation in EGFR+ NSCLC.  In selected instances rebiopsy of the primary tumor or metastases can direct a new, effective therapy. Obviously, it is not possible to rebiopsy every NSCLC patient after failure of the initial therapy. However, other techniques are being investigated. One is liquid biopsy where blood is drawn and subjected to molecular techniques to determine a possible cause for tumor resistance.  Multiple liquid biopsy molecular methods are presently being examined to determine their efficacy as surrogates to the tumor tissue biopsy (41).

Future Directions

The combination of a variety of existing therapies for NSCLC is being evaluated. These will likely yield revised recommendations for therapy. In addition, a variety of therapies, both existing for other cancers, or newer therapies in development are being tested.  These include both monoclonal antibodies and biologic inhibitors (Table 3).

Table 3. Potential new targeted therapies for NSCLC (42,43).

The numbers of pathways and drugs being tested is very impressive and the clinical responses can be dramatic in some patients. One might be tempted to conclude that these therapies might result in a “cure” for NSCLC. However, most of these mutations occur in a small minority of NSCLCs. Furthermore, even if initially successful, resistance to targeted therapies may quickly develop limiting their clinical usefulness in NSCLC.

Targeted therapies may also have potential as adjuvant therapies. In support of this concept, a recent phase 3 study compared durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy (44). The progression-free survival was 16.8 months with durvalumab versus 5.6 months with placebo (p<0.001). It seems likely that more trials using targeted therapy earlier in cancer therapy will be done.

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31. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-39. [CrossRef] [PubMed]
32. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-500. [CrossRef] [PubMed]
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35. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629-40. [CrossRef] [PubMed]
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Cite as: Robbins RA, Kummet TD. First-line therapy for non-small cell lung cancer including targeted therapy: A brief review. Southwest J Pulm Crit Care. 2018;16(3):157-67. doi: https://doi.org/10.13175/swjpcc038-18 PDF 

January 2016 Pulmonary Case of the Month

Kathryn E. Williams, MB

Karen L. Swanson, DO 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 64-year-old man was seen in June 2015 with a nonproductive cough.

Past Medical History, Social History and Family History

He has no significant past medical history. He is a former smoker. Family history is positive for coronary artery disease

Physical Examination

Decreased breath sounds over the right hemithorax with dullness to percussion. Otherwise, the physical exam is unremarkable.

Radiography

A chest radiograph was performed (Figure 1).

Figure 1. Initial PA chest radiograph.

The chest radiograph shows which of the following? (Click on the correct answer to proceed to the second of five panels)

1. There is a large mass in the right upper lobe
2. There is a loculated pleural effusion
3. There is volume loss in the right upper lobe
4. 1 and 3
5. All of the above

Cite as: Williams KE, Swanson KL. January 2016 pulmonary case of the month. Southwest J Pulm Crit Care. 2016;12(1):1-5. doi: http://dx.doi.org/10.13175/swjpcc158-15 PDF 

November 2015 Pulmonary Case of the Month

Kristal Choi, MD

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 66 year-old woman was admitted to neurology with acute-onset dysarthria, right facial droop, and right-sided hemiparesis as a stroke alert. She also had a nonproductive cough and intermittent dyspnea for 4 months.

Past Medical History, Social History and Family History

• She has a history of hypertension and hyperlipidemia. 
• She smoked 1-2 packs/day for 15 years but quit 35 years ago. She drinks two glasses of wine per day.
• There is a family history of bowel and breast cancer.

Physical Examination

• Vital signs: T 36.8, HR 81, BP 129/75, RR 18, O2 sat 93% RA
• General: No acute distress. Awake and alert.
• Heart, abdomen, and lungs: No significant abnormalities
• Neurological: Mild right-sided nasolabial fold flattening.  Evidence of ptosis o the right eyelid. Hemiparesis on the right, the arm greater than leg. Sensation intact. Dysmetria on the right upper and lower extremities.

Laboratory Evaluation

• CBC: Hemoglobin 11.9 g/dL, white blood cells (WBC) 7,900 cells/mcL, platelets 290,000 cells/mcL
• Basic metabolic panel: Na+ 139 mEq/L, K+ 4 mEq/L, Cl- 100 mEq/L , bicarbonate 22 mEq/L, creatinine 0.7 mg/dL

Radiography

A head CT angiogram (CTA) was performed (Figure 1).

Figure 1. Representative images from CTA of the head.

Which of the following should be done next? (Click on the correct answer to proceed to the second of six panels)

1. Administer an intravenous injection of tissue plasminogen activator (TPA)
2. Administer detachable coils (coiling or endovascular embolization) or stereotactic radiosurgery
3. Begin an anti-convulsant and dexamethasone
4. 1 and 3
5. All of the above

Cite as: Choi K, Wesselius LW. November 2015 pulmonary case of the month. Southwest J Pulm Crit Care. 2015;11(5):200-8. doi: http://dx.doi.org/10.13175/swjpcc134-15 PDF

December 2013 Pulmonary Case of the Month: Natural Progression

Robert W. Viggiano, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 68 year old woman was seen for increased back pain in April 2012. In 2000 she had a right lower lobe lung resection for low grade adenocarcinoma, bronchoalveolar type, nonmucinous. Her mass was 2.6 cm in maximal dimension extending to but not invading the pleura. There were clear surgical margins but involvement of one bronchial node. Multiple mediastinal nodes were negative. She had back pain for many years and yearly CTs were negative for metastatic disease.

PMH, SH, FH

Other than the above there was no significant past medical history, social history or family history.

Medications

• Non-steroidal anti-inflammatory drugs for pain
• Nitrofurantoin for chronic urinary tract infections

Physical Examination

There was tenderness to palpation over the mid-thoracic spine and evidence of a previous thoracotomy.

Laboratory

Her complete blood count (CBC), urinanalysis, liver function tests, and calcium were all within normal limits.

Radiology

An x-ray of the chest is interpreted as unchanged from previous x-rays. 

At this point which of the following radiologic testing is not indicated?

1. Bone scan
2. CT scan of the chest
3. Magnetic resonance imaging
4. Serial chest x-rays
5. Thoracic PET scan

Reference as: Viggiano RW. December 2013 pulmonary case of the month: natural progression. Southwest J Pulm Crit Care. 2013;7(6): . doi: http://dx.doi.org/10.13175/swjpcc155-13 PDF

December 2013 Pulmonary Case of the Month: Natural Progression

Robert W. Viggiano, MD 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 68 year old woman was seen for increased back pain in April 2012. In 2000 she had a right lower lobe lung resection for low grade adenocarcinoma, bronchoalveolar type, nonmucinous. Her mass was 2.6 cm in maximal dimension extending to but not invading the pleura. There were clear surgical margins but involvement of one bronchial node. Multiple mediastinal nodes were negative. She had back pain for many years and yearly CTs were negative for metastatic disease.

PMH, SH, FH

Other than the above there was no significant past medical history, social history or family history.

Medications

• Non-steroidal anti-inflammatory drugs for pain 
• Nitrofurantoin for chronic urinary tract infections

Physical Examination

There was tenderness to palpation over the mid-thoracic spine and evidence of a previous thoracotomy.

Laboratory

Her complete blood count (CBC), urinanalysis, liver function tests, and calcium were all within normal limits.

Radiology

An x-ray of the chest is interpreted as unchanged from previous x-rays. 

At this point which of the following radiologic testing is not indicated? (click on correct answer to move to next panel)

1. Bone scan
2. CT scan of the chest
3. Magnetic resonance imaging
4. Serial chest x-rays
5. Thoracic PET scan

Reference as: Viggiano RW. December 2013 pulmonary case of the month: natural progression. Southwest J Pulm Crit Care. 2013;7(6):318-27. doi: http://dx.doi.org/10.13175/swjpcc155-13 PDF