Concern has been building for years about the tremendous pressures that oncology specialists face, including long hours, caring for seriously ill patients, performance standards, reimbursement challenges, and staffing issues. Now, the coronavirus disease 2019 (COVID-19) pandemic has added another burden, with growing evidence of its negative effects on the well-being of many cancer care providers.

Recent survey findings suggest the pandemic has had a significant impact on the global oncology workforce. Practicing oncologists and hematologists are showing signs of emotional exhaustion. For example, approximately half of the oncologists recently surveyed by Cardinal Health have experienced more burnout at work since the pandemic began. In a survey Cardinal Health conducted with a similar group of oncologists in 2018, less than a quarter said they frequently experienced stress at work or symptoms of burnout.

The most recent Cardinal Health survey found the increased feelings of burnout were not related to a heavier workload. Instead, loss of face-to-face patient interactions was cited as the top factor contributing to physician burnout during the pandemic, although reduced patient volumes and practice financial loss were also commonly cited (

Figure. Factors Contributing to Doctors’ Feelings of Burnout

Organizations have a responsibility to support the well-being of their workforce, and a supportive environment can be developed and enhanced through community collaboration.

"Organizational programmatic initiatives are vital for empowerment of oncologists to grapple with the morally distressing situations encountered during and well after COVID-19 to bolster moral resilience, and professional satisfaction of workforce for the long term,” Fay J. Hlubocky, PhD, MA, of the University of Chicago Medicine, and colleagues wrote in an editorial in 

Burnout is Not Just a Problem in the United States

As studies show, physician burnout is a global issue. Recently, the European Society for Medical Oncology Resilience Task Force released the results of 2 surveys conducted last year to determine the impact of the pandemic on burnout, job performance, and well-being in the global oncology workforce.

The first survey was conducted from April 16, 2020, to May 3, 2020, and involved 1520 oncology specialists from 101 countries. Among respondents, 38% stated that they had experienced feelings of burnout and 78% had felt increased concern for their personal safety since the onset of the pandemic.

The follow-up survey, which was done from July 16, 2020, to August 6, 2020, found that the proportion of respondents reporting feelings of burnout had increased to 49%, and the proportion at risk of distress had increased from 25% to 33% between the 2 surveys.

“COVID-19 has changed our world. The entire oncology community has been facing rapid changes to help ensure the safety of our [patients with] cancer whilst maintaining care,” lead author Susana Banerjee, MBBS, PhD, MA, FRCP, a consultant medical oncologist and research lead for the Gynaecology Unit at The Royal Marsden in London, England, said during a press conference in advance of the European Society for Medical Oncology Virtual Congress 2020.

“These changes include patient management plans, the way we deliver care, and our daily working practice, taken together with our personal situations outside of work,” she said. “The impact of COVID-19 on well-being has the potential for serious negative consequences on work, home life, and patient care.”

In another recent survey of practicing oncologists at Cancer Care Ontario in Canada, 72% of respondents reported high levels of burnout. Investigators found factors that led to this development include a poor culture of wellness at work, inefficiencies of the practice, and personal resilience.

Additionally, findings from several studies were presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program (ASCO 2020). In a study from Spain, investigators sought to gauge the impact of professional burnout among residents and oncologists in the first 5 years of their careers. Of the 243 respondents, more medical oncology residents (28.24%) showed a burnout profile than young oncologists (19.79%).

The highest burnout profile (35.71%) was observed in second-year residents. There was a significant correlation between not having a good work/life balance and adequate vacation time and the burnout score.

“Young oncologists are a special risk population due to high workload, academic pressure, and specific factors related to cancer care,” Elena Elez, MD, PhD, of the Gastrointestinal Tumor Unit, at the IOB Institute of Oncology at Vall d’Hebron University Hospital in Barcelona, Spain, said in an interview with 

. “Medical oncologists deal with complex situations, given the particulars of the discipline with a high emotional impact on patients and families.”

In another study, the Russian Society of Clinical Oncology conducted a survey of 389 doctors aged 26 to 73 years (67% women), including chemotherapists (47.5%) and surgeons (28%), who work in cancer institutions in different regions.

 Overall, 72% of participants had signs of emotional burnout.

“The questionnaires did not show any fundamental differences in the development of symptoms of emotional burnout syndrome in male and female oncologists,” said Tatiana Semiglazova, MD, PhD, ScD, of the Department of Innovative Methods of Therapeutic Oncology and Rehabilitation of the National Medical Research Centre of the Ministry of Health of the Russian Federation in St Petersburg. “At the same time, people over 65 years old with extensive work experience are least susceptible to emotional burnout syndrome. Perhaps this indicates professional adaptation,” she concluded in an interview.

Burnout Affects Oncology Physician Assistants

Although much of the focus on workplace stress has been on specialists, concerns also have been voiced about other cancer care providers. In a study presented at ASCO 2020, investigators conducted a survey to determine whether physician assistants (PAs) in oncology have experienced changes in the rates of burnout.

Findings showed a significant increase in the rate of burnout for PAs in oncology, from 34.8% in 2015 to 48.7% in 2019.

 “This increase in the rate of burnout was not only statistically significant but profoundly concerning given the negative outcomes for providers, patients, and the health care system associated with burnout,” explained lead author Eric D. Tetzlaff, MHS, PA-C, DFAAPA, advanced practice clinician and physician assistant in the Department of Hematology/ Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“All occupations and work settings are at risk for workers to suffer from burnout and the essential elements of burnout remain the same regardless of the work setting or occupation,” he said in an interview. 

According to Tetzlaff, additional research is needed to better understand the factors associated with fairness and workload. “As an example, workload is not simply defined as the number of patients seen, as we did not find a difference in burnout based on the number of patients seen per week, but there was a difference in burnout based on the number of hours worked per week,” he explained.

Because burnout is such a prevalent phenomenon, methods for prevention and management are needed to maintain the well-being of the global clinician population, experts say. Unfortunately, current methods for addressing burnout haven’t been very effective. 

One meta-analysis involving more than 1500 physicians found that physician-directed interventions often were associated with “small benefits.” Organization-directed interventions that combined structural changes, fostered communication, and cultivated a sense of teamwork tended to be the most effective.

“The most effective strategies also allow providers to engage in the meaningful and satisfying work that initially led them to pursue a career in medicine,” Tetzlaff noted. “If we can increase the provider engagement with patients by decreasing the administrative burdens and increasing the practice efficiencies, I believe that not only will we see a decrease in provider burnout but also improved patient care, patient satisfaction, and patient outcomes.” 

Organizations should measure burnout in a way to identify the system-level issues that are driving burnout and attempt to correct them, wrote Hlubocky, in the editorial in JCO Oncology Practice (

“Too often, interventions focus on the individual alone (eg, mindfulness, resiliency). which have the unintended consequence of blaming the individual or putting the responsibility for managing burnout on the individual,” Tetzlaff said. “There needs to be a far greater emphasis on system-level concerns that are supplemented by efforts that focus on the individual.”

Tetzlaff emphasized the importance of seeking help when experiencing symptoms of burnout. “We need to continue to have open and honest dialogues about burnout and work to decrease the negative stigmas associated with burnout,” he said. “Burnout in no way should be considered a reflection on the individual as a personal weakness.” 

Recognizing the impact of burnout, ASCO in February 2021 released a 5-year plan designed to enhance the well-being of oncology care providers.

 The goal is broaden the resources available and promote research of provider needs. Among the goals, ASCO will promote education and policy solutions centered on well-being and begin to incorporate well-being initiatives within its volunteer and professional development programs. The organization also plans to publish and disseminate information specific to well-being and burnout, as well as highlight areas of research.

Hlubocky FJ, Symington BE, McFarland DC, et al. Impact of the COVID-19 pandemic on oncologist burnout, emotional well-being and moral distress: considerations for the cancer organization’s response for readiness, mitigation, and resilience. 

. Published online February 8, 2021. doi:10.1200/OP.20.00937

Oncology Insights December 2020. Cardinal Health. December 2020. Accessed February 15, 2021. http://bit.ly/3rWJsuX

Burki TK. Burnout among cancer professionals during COVID-19. 

. 2020;21(11):1402. doi:org/10.1016/S1470-2045(20)30584-2

Banerjee S, Lim KHJ, Kamposioras KV, et al. The impact of COVID-19 on oncology professionals: initial results of the ESMO resilience task force survey collaboration. 

 2020;31(suppl 4):S1142-S1215. Abstract LBA70. doi: 10.1016/annonc/annonc325

Singh S, Farrelly AC, Chan C, et al. Assessing burnout among oncologists in Ontario, Canada. 

 2020;38(suppl 29):41. doi:10.1200/JCO.2020.38.29_suppl.41

Elez E, Cebria A, Bosch-Barrera J, et al. Identifying burnout in young oncologists: the sooner the better. 

. 2020;38(suppl 15):11010. doi:10.1200/JCO.2020.38.15_suppl.11010

Semiglazova T, Safina S, Tsimafeyeu I, et al. Results of emotional burnout study among oncologists in Russia. 

. 2020;38(suppl 15):11011. doi:10.1200/JCO.2020.38.15_suppl.11011

Tetzlaff ED, Hylton HM, Ruth K, Hasse Z, Hall MJ. Burnout among oncology physician assistants (PAs) from 2015 to 2019. 

. 2020;38(suppl 15):11009. doi:10.1200/JCO.2020.38.15_suppl.11009

Panagioti M, Panagopoulou E, Bower P, et al. Controlled interventions to reduce burnout in physicians: a systematic review and meta-analysis. 

. 2017;177(2):195-205. doi:10.1001/jamainternmed.2016.7674

ASCO oncology clinician well-being task force roadmap. American Society for Clinical Oncology. February 26, 2021. Accessed March 4, 2021. https://practice.asco.org/sites/default/files/drupalfiles/2021-01/Final-Roadmap-Graphic.pdf

Articles

The COVID-19 pandemic has added another burden, with growing evidence of its negative effects on the well-being of many cancer care providers. 

Pandemic Intensifies the Struggle With Burnout in Cancer Field 

Financial issues are among the top concerns burdening patients with cancer.

 Even with insurance, patients often face unpredictable costs, including high co-insurance and deductibles.

 The average annual cost of new medicines continues to trend upward, with the median cost at $149,000 in 2018.

 These high costs can lead to nonadhereance and drug abandonment.

At the same time, patients with cancer and facilities often throw away unused or leftover medications. In fact, according to a 2016 study in the British Medical Journal, an estimated $3 billion in leftover cancer drugs are discarded in the United States every year.

 This is especially true for medications that are based on a patient’s weight and that come in single-dose packages, which have to be discarded. 

One solution to address increased medication waste and access has been the use of drug repositories. So far, 38 states have enacted laws related to the donation and reuse of medication, and 20 states have operational programs.

 Laws in 13 states allow repositories to accept and distribute cancer prescription drugs, and 7 of these have operational programs (Table).

The American Society of Clinical Oncology supports the use of repositories as a way to lower costs and improve access to therapies for oral medications in a closed system.

Table. Operational Drug Repository Programs With Cancer Provisions

A drug repository is a program that receives eligible donated drugs that can then be provided to patients who have a financial need or who are patients of a nonprofit clinic, explained Julie Kennerly-Shah, PharmD, MS, MHA, BCPS, a pharmacist and associate director of pharmacy at the Ohio State University Comprehensive Cancer CenterJames Cancer Hospital (OSUCCC-James) in Columbus, Ohio. 

“There are varying rules from state to state as to which drugs are eligible to be donated to a drug repository program,” said KennerlyShah. “In Ohio, for example, we recently expanded to oral chemotherapy agents that had been in the possession of a patient. But we do not allow injectables.”

According to Doug Englebert, MBA, RPh, a pharmacy practice consultant, at the Wisconsin Department of Health Services, who is involved in the state’s drug repository program, pharmacies and clinics can sign up to participate in the program. “They get placed on our provider list and then any consumer or business can donate medications that fit the criteria, which usually means it’s in a package that’s tamper-evident sealed and that the medication still has viable life in it, so that means usually at least 90 days left on the expiration date,” he explained.

Englebert also noted that certain drugs cannot be used in the program, including controlled substances, such as morphine and high-risk medications that are part of federal monitoring programs. One example of this is lenalidomide (Revlimid), which is an oral medication for multiple myeloma. Because of the risk of birth defects, lenalidomide, a derivative of thalidomide (Thalomid), is monitored through an FDA-required Risk Evaluation and Mitigation Strategy. 

Some hospitals, such as OSUCCC-James, have coordinators who are dedicated to finding options for patients to access medications. Patients are evaluated for inclusion in manufacturer assistance programs or other sources that may help with medication costs. “Once we exhaust other options, the medication assistance coordinator would present this as an option to the team and to the patient to see if they would be interested in utilizing the drug repository,” Kennerly-Shah said.

In contrast, volunteer-based programs provide lists of participating facilities on a website, for example, from which patients can contact a facility to determine whether there is a need for a donation or whether a product is available that can be redistributed.

Large medical groups with multiple participating sites will often pool donations and designate a single site to manage the dispensing so that patients can more easily determine availability and access to medications in a particular geographic location.

“What they’re doing is packaging the medications in a way that can be tamper evident, they dispense these medications, and they tell the patients to donate them back if they become intolerant and discontinue medications,” Englebert explained. 

“In oncology, it’s very common for patients to change medications or have a dose reduction, and they end up with a surplus of medication that is quite expensive that another patient could significantly benefit from,” Kennerly-Shah said. 

OSUCCC-James worked with the Ohio Board of Pharmacy to create new rules allowing them to take medications that one patient cannot use into the drug repository program and then provide that drug to another patient who is in need, at no cost to that patient. Kennerly-Shah noted that to her knowledge, no donated medications have been deemed ineligible through the inspection process.

Drug repositories are resource-intense commitments. “You need pharmacists to inspect the medication,” Kennerly-Shah explained. “You need a place to store the medication safely. You need a process to identify who should be eligible to receive the donated drug. And then, of course, you need the resources to be able to actually redispense that drug to another patient.” 

Patients are required to have a prescription and records must be kept about the dispensing of any prescription drug.

Some states, such as Wisconsin, do not have a statewide central inventory of medications that are available in the repository program that practitioners or patients can access. Currently, practitioners and patients must connect with local facilities to determine medication availability. A local control model works in some environments, so there hasn’t been a push to evolve into a statewide initiative. There are other challenges as well. It’s often an unreliable source of medications for patients and their physicians.

“Practitioners never know if they will get the product and when they do, they need to have space to store it and it’s a separate inventory,” Englebert said. “It becomes a challenge on the management side a little bit.” 

Larger programs, such as Iowa’s SafeNetRx, have statewide support and a budget. They essentially manage all their medications and dispense out of there. This type of program is used differently than other programs across the country.

Oncologists who may be associated with a large health system or a large academic medical center may benefit from resources that are already in place at the health system to operationalize a repository program. However, smaller practices may experience difficulties due to the resource-intense nature of the process.

“The more patients you see, the higher likelihood that you have a large donation pool as well,” noted Kennerly-Shah. “So, one of the things that we thought very hard about when we were launching was which medications to start with,” she explained. They also considered which medications had a need and which medications had a surplus in the community in which they were likely to receive significant donations.

Kennerly-Shah noted that she hopes to expand to include every oral oncolytic and supportive care medication.

At OSUCCC-James, patients and their caregivers have expressed their gratitude for the opportunity to donate oral chemotherapy medications. Patients deciding to discontinue treatment and transition to hospice have been happy to give that medication to another patient with cancer.

“I’m always humbled by the camaraderie and the sense of oneness that I see from one cancer patient to another and a true desire to help others in the cancer community,” explained Kennerly-Shah. “I just am so impressed with our patient population and how much they’ve embraced this program and desire to help other patients that are going through a similar challenge in life."

Hendren S, Chin N, Fisher S. Patients’ barriers to receipt of cancer care and factors associated with needing more assistance from a patient navigator. J Natl Med Assoc. 2011 Aug; 103(8): 701-710. doi:10.1016/s0027-9684(15)30409-0

American Cancer Society. The costs of cancer care: addressing patient costs. Published April 2017. Accessed June 8, 2020. https://www.fightcancer.org/sites/default/files/Costs%20of%20Cancer%20-%20Final%20Web.pdf

The IQVIA Institute. Global oncology trends 2019. Published May 30, 2019. Accessed June 8, 2020

American Society of Clinical Oncology. Position statement on drug repository programs. Accessed June 8, 2020. https://www.asco.org/sites/new-www.asco.org/files/content-files/advocacy-and-policy/documents/2020-DrugRepositoryPositionStatement.pdf

Bach P, Conti RM, Muller RJ, et al. Overspending driven by oversized single dose vials of cancer drugs. BMJ. 2016;352:i788. doi.org/10.1136/bmj.i788

National Conference of State Legislatures. State prescription drug return, reuse and recycling Laws. Published October 1, 2018. Accessed May 7, 2020. http://www.ncsl.org/research/health/state-prescription-drug-return-reuse-and-recycling.aspx

Drug Repositories Aim to Solve Access Issues

The Lung Cancer Screening Implementation Guide

 was a product of collaboration among 25 experts from 16 institutions. But it was also a product of both the successes and failures of lung cancer screening (LCS) programs before it.

The new LCS guideline, from the American Thoracic Society and the American Lung Association, was developed on research into the experiences related to previously established LCS programs.

As guideline author Peter J. Mazzone, MD, MPH, of the Cleveland Clinic explained in an interview with MD Magazine®, no one system is right.

“Every site may have a different way to do it, but regardless of how you put the program together, there are certain elements to the structure of the program that are necessary to make sure you’re screening safely,” Mazzone said. “Many different structures of programs are outlined in the guide…[to] highlight all the different things you need to think about and how different programs have addressed those issues.”

Offering and Promoting Smoking Cessation Counseling

Most programs offer smoking cessation counseling as part of a shared decision making (SDM) visit and throughout the program. Some LCS programs also order pulmonary function studies for new patients to provide an overall picture of lung health.

The SDM visits provide time to discuss smoking cessation with patients to help them understand its importance. Resources for smoking cessation can be provided at SDM visits, at the time of the scans, in letters to patients confirming appointments,and in letters to patients with their test results.

According to a US surgeon general 2014 report, individuals who quit smoking experience lower all-cause and cancer-specific mortality.

 Therefore, including smoking cessation counseling in LCS programs provides opportunities to promote smoking behavioral changes, which can affect patient prognosis.

The results of a study from investigators at Mayo Clinic in Rochester, Minnesota, revealed that patients who received positive LCS results were more likely to quit smoking.

 Furthermore, the rate of quitting was directly proportional to the number of positive test findings.

Tracking Tobacco Use and Smoking Cessation

The SDM visit is an opportune time to discuss the patient’s tobacco use status and history. During the visit, health care providers record information related to packs/cigarettes per day/year, years smoked, and years since quitting, if a former smoker. Computed tomography technologists also ask about their current smoking status at each screening.

This information can then be cross-referenced with the patient’s electronic health record (EHR) to encourage follow-up. Based on the information gathered during the SDM, LCS program personnel will follow up with patients through phone- or web-based models or in person during annual visits.

It is also important to track whether smoking cessation counseling is provided in the LCS program. This can be done via documentation in the EHR as part of the order for the scan, via documentation in the LCS database, or through tracking of quality metrics, which may include:

The number of individuals screened for tobacco use and/or the number of individuals who present to an LCS screening site

The number of individuals who received or refused counseling to quit and/or the number of individuals identified as current tobacco users

Resources for Smoking Cessation in LCS Programs

The brief tobacco treatment model, which is consistent with the US Public Health Service’s Clinical Practice Guidelines for Treating Tobacco Abuse and Dependence, focuses on 5 steps: (1) asking patients about tobacco use, (2) advising patients to quit, (3) assessing quit readiness, (4) assisting with quitting, and (5) arranging follow-up. Physicians should provide patients with lists of resources, including links, to help facilitate smoking cessation.

Smoking cessation support can be incorporated into LCS programs in many ways. Resource lists can be included with patient letters; LCS program staff can call current smokers, discuss cessation options, and provide counseling; and LCS programs can offer telephone, in-person, and group counseling, as well as online support groups.

“In my specific program, I’ve found we have advanced practice providers who do these visits. They’ve been trained as smoking cessation counselors. They provide our patients with resources to help them quit and point to resources throughout the community that might be easier for them to access over time,” Mazzone explained.

He says there are insufficient data about the benefits of smoking cessation counseling during regular office visits compared with counseling provided as part of LCS programs.

However, research is ongoing to identify unique features in patients recommended for LCS screening for whom the smoking cessation message may prove more beneficial if conveyed outside of the regular office visit.

“When programs are being developed, everyone recognizes that this may be a captive audience. They’ve come in to be screened, there is some concern and understanding about the consequences of smoking, and so it may be a great time to engage the patient in smoking cessation activities,” Mazzone added.

Thomson CC, McKee A, Borondy-Kitts A, et al. American Thoracic Society, American Lung Association. Lung cancer screening implementation guide. lung.org/assets/documents/lung-cancer/implementation-guide-for-lung. pdf. Accessed November 12, 2018.

National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. The Health Consequences of Smoking—50 Years of Progress. A Report of the Surgeon General. Atlanta, GA: US Centers for Disease Control and Prevention; 2014. ncbi.nlm.nih.gov/books/NBK179276/. Updated January 2014. Accessed November 5, 2018.

Townsend CO, Clark MM, Jett JR, et al. Relation between smoking cessation and receiving results from three annual spiral chest computed tomography scans for lung carcinoma screening. Cancer. 2005;103(10):2154-2162. doi: 10.1002/cncr.21045.

The Lung Cancer Screening Implementation Guide was a product of collaboration among 25 experts from 16 institutions. But it was also a product of both the successes and failures of lung cancer screening programs before it. 

Smoking Cessation Counseling in Lung Cancer Screening Programs

Setting up a lung cancer screening (LCS) program can be a challenge in a multitude of ways. Through detailing past programs and discussing how they've each addressed their own challenges, the American Thoracic Society and the American Lung Association's new LCS guide

 can help clinicians design, implement, conduct, and streamline lung cancer screening (LCS) programs, Peter J. Mazzone, MD, MPH, of Cleveland Clinic in Ohio, and author on the guidelines, said in an interview with MD Magazine

“If you’re trying to improve your program or if you’re starting up a program, you get to see and learn from others who’ve been there before,” Dr. Mazzone added.

The CMS and the US Preventive Services Task Force suggest yearly screenings for individuals who are at risk of lung cancer and provide the necessary eligibility recommendations, such as upper age bracket and smoking history. When determining whom to screen, program steering committees consider eligibility criteria and provide the following considerations:

Additional evaluation prior to denying screening to patients who are medically inoperable

A 5-year disease-free cutoff period before screening patients with prior malignancy

A 12-month waiting period before enrollment of an individual who had a recent diagnostic chest computed tomography (CT) scan

Delayed screening for patients presenting with respiratory symptoms prior to scheduled testing until their symptoms resolve

Determining clear eligibility criteria is crucial during the development of an LCS program. These criteria should balance the risks and benefits of screening and help primary care providers (PCPs) identify individuals who may qualify for LCS.

“You have to be sure you’re selecting the right group—a group that’s at enough risk of developing lung cancer to benefit but not so sick that they won’t be able to tolerate any evaluation or treatment for things that are found,” Dr. Mazzone explained.

To identify patients who meet the screening criteria, LCS programs must educate PCPs through in-person meetings, presentations that describe the characteristics of high-risk patients, and/or educational packets. Most LCS programs reach out to eligible patients identified by PCPs via letters, emails, or community programs.

Most LCS programs have systems in place to ensure compliance with the eligibility criteria before an exam is scheduled and a scan is performed. For patients who do not meet the eligibility criteria but still wish to undergo a CT scan and are willing to pay out of pocket, most hospitals have provisions. These patients may or may not be part of the LCS program.

Depending on the structure of the LCS program, patients who are deemed eligible for screening receive counseling about testing from either their PCP or a member of the LCS program.

“Many, many patients are bound to have lung nodules. Most of those aren’t cancer, but they might make your patient rather nervous,” Dr. Mazzone said.

This prescreening counseling, called shared decision making (SDM), is critical because it helps clinicians educate patients about the benefits and harms of the process and eases their anxiety about anticipated results.

The SDM visit helps the patient “make an informed decision, be prepared for the results, potentially participate in smoking cessation, and build a relationship with the team,” Mazzone said.

Perceived barriers to SDM from a patient’s perspective include fear of lung cancer death and stigma. For a physician, barriers include lack of organizational support, lack of decision aids, and lack of time.

If time is limited (eg, less than 5 minutes) for the SDM session, patients are provided SDM tools to review prior to the visit. Scheduling the exam and the SDM visit on the same day helps ensure that patients will adhere to the program.

Most LCS programs use an electronic health record (EHR) system to schedule exams. PCPs schedule exams for programs that use decentralized ordering, whereas coordinators and navigators schedule exams at institutions that follow a centralized program. In hybrid programs, both scheduling options are available.

Most EHR systems cannot make the distinction between an LCS follow-up CT and a diagnostic CT; therefore, programs must monitor this process, and different options for monitoring are used. Some programs rely on the radiologist to make the distinction, others use database check points to ensure the correct order is placed, and in some cases, an LCS program physician reviews reports to confirm that tests have been ordered appropriately.

“The benefit of screening is seen by a minority of everybody who is screened,” Mazzone explained. “By structuring the program around some key principles, whether centralized or decentralized, you can help to guarantee the highest-quality screening for your patients.”

Thomson CC, McKee A, Borondy-Kitts A, et al; American Thoracic Society, American Lung Association. Lung cancer screening implementation guide. lung.org/assets/documents/lung-cancer/implementation-guide-for-lung. pdf. Accessed November 5, 2018.

Through detailing past programs and discussing how they've each addressed their own challenges, the American Thoracic Society and the American Lung Association's new lung cancer screening guide can help clinicians design, implement, conduct, and streamline lung cancer screening programs.

Defining Eligibility and Providing Counseling Key for Lung Cancer Screening Programs

For clinicians who see patients at risk of developing lung cancer, a new guide on the implementation of lung cancer screening (LCS) programs has been developed by a panel of experts from the American Lung Association and the American Thoracic Society (ATS).

 In this pragmatic guide, experts from a variety of US institutions provide a toolkit for how to design, implement, and conduct LCS programs.

“The problem is that 75% of lung cancers are found at stage III or stage IV, where we can’t do surgery, and unless [patients] have some rare molecular mutation, they usually progress and die from lung cancer,” said Michael A. Pritchett, DO, MPH, of FirstHealth of the Carolinas and Pinehurst Medical Clinic in Pinehurst, North Carolina, in an interview with MD Magazine

“Several years ago, the National Lung Screening Trial found that we can [reduce] mortality [by 20%] by doing low-dose screening with CT [computed tomography] scans,” Dr. Pritchett said. “All the major societies have agreed that this is useful and can really create what’s called a stage shift. We want to shift that and flip those numbers, so at least 75% of patients are found at stage I or stage II [and] we can do surgery or just radiation therapy.”

The document was compiled using information from a survey designed to address real-world approaches to common problems encountered in LCS and program implementation for which guideline or consensus statements may not exist.

Annual LCS for individuals at risk of developing lung cancer is recommended by major medical organizations, including CMS and the US Preventive Services Task Force. According to Dr. Pritchett, patients have to be 55 to 77 years, with a 30-pack-per-year history of smoking. They also must be asymptomatic and cannot have had a CT scan in the last year.

“When we started this, we were getting everyone sent for LCS. [But] if they don’t meet the criteria, CMS won’t pay for it. The primary care physicians have to learn the criteria, know where patients can be scanned, and know we can take care of it [if they find something],” Dr. Pritchett said.

Core Domains of Lung Cancer Screening Programs

Policy statements from the American College of Chest Physicians and the ATS addressed who is screened, CT performance, reporting, lung nodule management, smoking cessation, patient and provider education, and data collection to ensure that the benefits of LCS outweigh potential harms as it is implemented.

LCS programs should collect data on lung cancer development risk for all enrolled subjects. The program must confirm an existing policy regarding individuals who will be offered screening, with the requirement that ≥90% of all screened subjects match this policy's criteria.

A low-dose CT for LCS should be performed based on American College of Radiology and Society of Thoracic Radiology specifications, and programs should collect data to verify that the average radiation dose complies with these recommendations.

A structured reporting system is recommended, and LCS programs should collect data related to compliance. Each program should confirm that at least 90% of CT screen reports are following the reporting system.

Regarding lung nodule management algorithms, programs should incorporate the following steps:

Clinicians who have expertise regarding lung nodule management and lung cancer treatmentA nodule-characterization method and management tracking

A communication approach between the ordering provider and the patient

Data collection on the use and outcomes from surveillance and diagnostic imaging and biopsies for management

LCS programs must be integrated with a smoking cessation program, and data should be collected regarding the interventions offered to active smokers.

Clinicians must be educated to discuss the risks and benefits of screening with patients. LCS programs must list educational strategies used to educate providers and demonstrate the availability of standardized educational material.

LCS programs are required to collect data related to each component, testing outcomes, and cancer diagnoses, and these data must be reported annually to an oversight body. The program must respond to concerns from this oversight body to maintain accreditation.

“The key takeaway is to know the parameters, and for every patient who meets those parameters, I want them to be sent for a LCS CT scan, and then we can take care of the rest,” Dr. Pritchett said. “We understand the primary care doctors are overwhelmed, and yes, we are asking for 1 more thing. But this 1 more thing can save somebody’s life.”

Thomson CC, McKee A, Borondy-Kitts A, et al; American Thoracic Society; American Lung Association. Lung Cancer Screening Implementation Guide lung.org/assets/documents/lung-cancer/implementation-guide-for-lung.pdf. Accessed October 31, 2018.

For clinicians who see patients at risk of developing lung cancer, a new guide on the implementation of lung cancer screening programs has been developed by a panel of experts from the American Lung Association and the American Thoracic Society.

Key Aspects for Implementing a Lung Cancer Screening Program

The gene encoding B-cell lymphoma-2 (BCL-2) was identified more than 30 years ago in a patient with follicular lymphoma (FL) who had a chromosomal translocation that led to dysregulated BCL-2 expression.

 gene product was reported to block cell death instead of enhancing cell proliferation, which was the expected action of oncogenes, the link among BCL-2, apoptosis, and cancer was established.

 This finding led to the idea that impaired apoptosis was an important feature required for tumorigenesis.

High BCL-2 expression levels discovered in hematologic malignancies have led to numerous clinical investigations, paving the way for the initial approval in chronic lymphocytic leukemia (CLL) for venetoclax (Venclexta), the first BCL-2 inhibitor indicated for cancer treatment, in 2016.

 Additional investigations of venetoclax are ongoing in hematologic malignances, and new drugs are in development. Meanwhile, investigators are hoping to develop BCL-2 as an actionable target in solid tumors, with recent findings in venetoclax studies providing potential support for these investigations.

 However, there are challenges for targeting BCL-2 in both hematologic and solid tumors. Resistance to BH3 mimetics that target BCL-2 and BCL-2/BCL-XL has been observed in vitro and in vivo.

 There are also altered cellular activities that have not been eliminated via BCL-2 protein targeting. In models of γ-irradiation—induced thymic lymphoma, overexpression of BCL-2, which is usually considered to be a procancer event, protects against the development of tumors.

 It is unclear at this time whether these concerns will remain in clinical trials; however, promising study results support the potential of BH3 mimetics to dramatically improve survival in patients with various cancer types.

The BCL-2 family proteins are important for regulation of cell death at both the mitochondria and the endoplasmic reticulum. The proteins function to regulate mitochondrial outer membrane permeabilization through a coordinated series of protein—protein and protein–membrane interactions that are associated with protein conformational changes that control pore formation in organelle membranes.

 When BCL-2 is overexpressed, it blocks BAX, an apoptotic protein, and prevents mitochondrial pore formation and inhibits the release of cytochrome C, which leads to inhibited or reduced cell death.

To maintain proliferation of cancer cells, tumors must prevent apoptosis and are reliant on BCL-2 proteins to block cell death under environmental pressure from the immune system or chemotherapeutic agents. In these conditions, tumors have been said to be “BCL-2 addicted” and more susceptible to BCL-2 inhibitors.

 Hematologic cancers generally are more dependent on BCL-2, whereas solid tumors have been reported to be more dependent on other antiapoptotic proteins, including BCL-XL or MCL-1.

 Therefore, selective antagonism of BCL-2 family proteins provides an opportunity to treat tumors.

Figure 2. BCL-2 Expression in Selected Cancer Types

The BCL-2 family proteins are classified based on structure and BCL-2 homology (BH) domains. There are 4 BH domains, BH1 to BH4, present in the antiapoptotic members (BCL-2, BCL-XL, BCL-W, MCL-1, and A1/BFL-1). These domains contain a hydrophobic groove that binds to the BH3 domain found in the proapoptotic proteins (BAX, BAK, and BOK) that contain BH1 to BH3.

 Another group of BCL-2 family proteins only contains the BH3 domain, including the proapoptotic activators BID and BIM and the proapoptotic sensitizers BAD, BIK, BMF, HRK, NOXA, and PUMA (

). BH3 mimetics have been developed to mimic the action of certain proteins that only contain the BH3 domain, resulting in inhibition of antiapoptotic BCL-2 family proteins and apoptosis promotion in cancer.

The majority of patients with CLL overexpress BCL-2.

 Increased BCL-2 expression is also found in most patients with acute lymphocytic leukemia and is frequently reported in acute myeloid leukemia (AML).

 Approximately 90% of patients with FL harbor a chromosomal translocation that is thought to cause BCL-2 overexpression.

 Relatively high BCL-2 expression also has been reported in over 40% of patients with diffuse large B-cell lymphoma (DLBCL).

 Altered BCL-2 expression has been reported in various solid tumor types, including prostate (30%-60% at diagnosis, nearly 100% of hormone-refractory cases), breast (75%), small cell lung cancer (SCLC; >90%), and non— small cell lung cancer (50%).

 Additionally, increased BCL-2 expression has been reported in ovarian, bladder, colorectal (60%), neuroblastoma, and some head and neck cancers (17%).25-29 (

Venetoclax, formerly known as ABT-199, is an orally available inhibitor that has 100-fold greater affinity for BCL-2 than BCL-XL.

 No thrombocytopenia has been reported with this inhibitor due to its high affinity for BCL-2 and low binding to BCL-XL. However, treatment led to tumor lysis syndrome in some patients because of its potent BCL-2 inhibition, requiring development of a dose-escalation strategy and close surveillance of patients.

 An 80% response rate and manageable adverse effects (AEs) were reported in patients with relapsed CLL or small lymphocytic leukemia (SLL).

Single-agent venetoclax was the first BH3 mimetic that the FDA approved for cancer treatment, with an indication for use after at least 1 prior therapy in patients with CLL and 17p chromosomal deletion (del17p), which is a biomarker for 

 The label subsequently was expanded to include CLL/SLL with or without del17p. Additionally, it is now indicated in combination with azacytidine, decitabine, or low-dose cytarabine for treating newly diagnosed AML in adults 75 years or older or those who have comorbidities that preclude the use of intensive induction chemotherapy.

Heterogeneous responses to venetoclax treatment were reported in patients with AML, multiple myeloma, and non-Hodgkin lymphoma (NHL).

 In an attempt to improve responses, several studies investigated venetoclax in combination with other therapies. The combination of venetoclax and hypomethylating agents (decitabine or azacytidine) led to a rate of complete remission, including with incomplete count recovery, in 67% of patients in a study of patients 65 years or older (median, 74 years) with AML.

 In vitro studies have also reported responses to venetoclax in certain breast and SCLC cell lines.

ABT-737 is a small molecule that was developed to match the binding pattern of BAD, which inhibited BCL-2, BCL-XL, and BCL-W, and demonstrated on-target activity and a requirement for BAK and BAX to induce apoptosis in preclinical studies.

Based on the crucial role of BCL-2 family proteins in apoptosis regulation, targeting these proteins using BCL-2 inhibitors offers a potentially new therapeutic option for patients with various types of hematologic malignancies and, more recently, patients with solid tumors.

Erin Burns, PhD