THERE ARE SEVERAL QUESTIONS surrounding how radiation therapy — especially combined with other agents &mdash; fits into the treatment of patients with oligometastatic lung cancer, according to Kevin Stephans, M.D.

Oligometastatic lung cancer is disease that has spread, but only to a limited number of sites in the body. As such, it can have a better prognosis than disease that has spread widely, and can possibly be treated differently.

“As we get more phase 3 data, we will have a better understanding of where (radiation) fits,” explains Stephans, who discussed oligometastases during the 2016 State of the Science Summit on Metastatic Non—Small Cell Lung Cancer offered by OncLive®, an online sister publication to CURE®. “Does it fit in up front, or does it fit in later? Do we treat patients up front when they have the biggest burden of disease to get rid of resistant clones [cells that can linger and cause a recurrence], or do we go with simple treatment up front and hold radiation for the time of progression?”

What is new in oligometastatic lung cancer?

In an interview with OncLive® during the meeting, Stephans, an associate staff member in radiation oncology at Cleveland Clinic, gave a recap of the latest research in oligometastases for patients with lung cancer.

Stephans: Most patients who have metastatic disease will present with multiple metastatic sites all over the body — though a small percentage will present with more isolated disease. Obviously, most of the therapies &mdash; such as the systemic chemotherapy or immunotherapy &mdash; are going to address disease anywhere. Stereotactic body radiation therapy is a particular technology that could address only localized disease. The advantage is that the side effects tend to be few because the treatment is localized, and the disadvantage is that it is only going to address disease at that site.

What do community oncologists not know about this type of disease?

There are different prognostic ways to pick patients who may be likely to progress at one or a few sites only. People who are younger with fewer sites are more likely to have a long response to chemotherapy. As long as those sites are not located somewhere that would be too toxic to deliver radiation, they could safely be treated. A very small set of patients may benefit from that therapy.

We do not have randomized trials that look at randomizing “yes or no” to radiation. We have trials that suggest that patients who are radiated do well, but we do not really know what the benefit of radiation is because they may just be people who were well-selected who were going to receive that treatment anyway. It is important to be very careful in choosing which patients receive which treatments. If they strictly meet the criteria, and they are expected to tolerate therapy, then that is a good way to go.

Another thing that has surprised people in the past is that, when radiation is combined with some different systemic agents, that regimen is also well tolerated, though occasionally there are expected side effects.

Are there any ongoing clinical trials for these patients taking place?

Using radiation together with a VEGF-targeted agent, such as Avastin (bevacizumab), has associated toxicities that are much higher than what was expected. That is one thing to be really careful of in these patients who are doing well; they are probably going to get more therapy down the line because they are still going to be a good fit. We have to be careful on how we select those therapies and be aware that they have had radiation in the past.

Most of the clinical trials have been phase 2 studies, so all of the patients receive the intervention. At the 2016 Annual Meeting of the American Society of Clinical Oncology, there were finally some phase 3 studies coming out in which people were randomized to consolidate a radiation, or consolidate a local therapy versus a more systemic therapy. It is too early to have data on survival, but the progression-free survival was pretty long. It was over one year for the radiated patients, and it was longer than it was for the patients on additional systemic therapy.

What are the biggest questions surrounding patients with oligometastases?

This was for those with one to three sites and stable disease on their prior chemotherapy regimen. It is a reasonable option for those patients; it allows the oncologist to hold back effective systemic therapy a little bit longer, and then have that agent available in the future.

Again, one of the biggest questions concerns where this type of therapy fits in, and people often discuss cost-effectiveness, as well. All of that may change as agents are out for longer periods of time. It is a moving target, and it is the same thing with radiation. However, one advantage is that radiation is a one-time therapy, or it does not have to be continued and repaid-for every month, so it may be very cost-effective in that model. Again, that is a moving target.

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For patients with lung cancer that is limited in its spread, radiation may help. But exactly who should try it, and when?

Which Lung Cancer Groups Should Get Radiation?

WE HAVE KNOWN THAT cancers evolve since we first started treating them with chemotherapy in the 1940s — and that, after responding, they could become resistant to treatment.

When we developed better tools to analyze the genes in tumors over time, we were then able to discern specific abnormalities, particularly mutations, that led to treatment resistance. However, obtaining biopsies, especially repeatedly, is expensive, and not entirely safe. This has changed with liquid biopsies, a new way to look for those mutations from DNA released by tumor cells — through a simple blood draw and a genomic analysis of that sample. In this special issue of 

, one of our articles highlights the importance of these new tests. Some are already approved to help make decisions about drugs that are specific for certain mutations. In the future, the ability to detect tumor DNA in the blood will allow researchers to study the evolution of tumors at the most detailed level. We are already aware of many genes that drive specific cancers during various stages of treatment, but we hope that ongoing analyses of mutational evolution over time will reveal more. Then, these could be targeted with a new generation of drugs that reverse resistance or could be given in combination with established drugs to make them work better and longer.

A study presented at the 2016 Annual Meeting of the American Society of Clinical Oncology looked at a genomic analysis of circulating tumor DNA in blood samples from more than 15,000 patients across multiple cancer types. According to researchers, a major finding of the study was that the patterns of mutation in circulating tumor DNA, found via liquid biopsy, matched up quite closely with those found through tissue analysis. This indicates the validity of liquid biopsy when compared with tissue biopsy. However, the matches were not perfect and some later evolutionary changes were missed.

The FDA has approved a couple of liquid biopsy tests to be used in diagnosing and characterizing lung cancer and melanoma, two cancer types with a number of known driver mutations. With these biopsies available in the clinic, we can now avoid the discomfort and the dangers of conducting tissue biopsies in difficult areas such as the lung or liver. Having knowledge of specific mutations is becoming increasingly more important in choosing the right treatments for individual patients, and this is starting to revolutionize clinical procedures. Liquid biopsies could contribute to our efficiency, turnaround time and decision-making processes as we pursue this important avenue.

There are some limitations, and for now most patients will still have to undergo tissue biopsies, but liquid biopsies hold a lot of promise when it comes to quickly, accurately and less invasively learning what drives a patient’s cancer.

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WE HAVE KNOWN THAT cancers evolve since we first started treating them with chemotherapy in the 1940s &mdash; and that, after responding, they could become resistant to treatment.

Liquid Biopsies are a Promising Method for Analyzing What Drives Cancers

AFTER DECADES OF TURNING first to chemotherapy when treating cancer, doctors and researchers are building a new path to the future, and immunotherapy is one of its most crucial components.

Immunotherapy is a term that continues to dominate oncology conference agendas and news headlines as studies push the field forward. This is especially true in the treatment of lung cancers, where immunotherapies are quickly becoming more and more important. In a feature story in this special issue of 

®, we look at the evolution of these drugs and other treatment strategies for the disease, including immunotherapy combinations and targeted therapies. In particular, we note that immunotherapies are considered appropriate first-line treatment for many who aren’t eligible for therapy with targeted drugs. In the past, these patients would have started with chemotherapy.

We point out that FDA-approved immunotherapies, such as Opdivo (nivolumab), Keytruda (pembrolizumab) and Tecentriq (atezolizumab), have demonstrated long-lasting benefits in lung cancer. Not only are they improving duration of survival, but they are allowing eligible patients to undergo treatment with fewer severe side effects. Mark Kris, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, explains that severe side effects are experienced by approximately half of patients who receive the chemotherapy docetaxel, but only by about 10 percent of patients who take immunotherapies.

It’s an exciting time for not only researchers who are committed to finding the best treatment options, but also for patients who are living longer as a result of these advancements.

Also in this issue, our cover story touches on the importance of smoking cessation. It’s crucial to note that it is never too late to quit. In fact, quitting today will cut your risk of dying from lung cancer in half in just 10 years. While it isn’t easy and there is no direct roadmap to your best way to stop smoking, 

® offers a variety of methods that you can consider.

We also take a closer look at six different groups that are strong advocates for people in the lung cancer community, with goals ranging from helping individual patients to raising awareness to raising money for research. Finally, we explore how earlier palliative care can improve outcomes in lung cancer, and we offer a special report on an investigational web app that helps improve overall survival in patients with the disease. As the science behind cancer care continues to evolve, so do patients’ treatment experiences and health outcomes. We hope you find this special issue helpful in your quest to understand what lies ahead when it comes to treatment for this disease.

Immunotherapy is Eclipsing Chemotherapy in First-Line Lung Cancer Treatment

It comes as no surprise that breathing clean air is better for a person than taking in polluted air, but new research proves the difference can be crucial for patients who have been diagnosed with lung cancer.

Researchers from the Keck School of Medicine at the University of Southern California (USC) found that the median survival of patients with early-stage lung cancers who lived in areas with high levels of pollution was approximately three years shorter.

The research is based on data from more than 350,000 patients in the California Cancer Registry who were diagnosed with lung cancer between 1988 and 2009. Researchers looked at patients with localized cancer and patients whose cancers had metastasized.

“There’s a growing number of articles out there that show air pollution is associated with lung cancer incidence and mortality,” says Sandrah Eckel, Ph.D., an assistant professor of preventive medicine at USC. “Due to the high case fatality rate, it’s actually been pretty hard to disentangle the relationship between air pollution and incidence or air pollution and mortality. We realized this lung cancer registry offered us an interesting opportunity to actually look at the effect of air pollution on survival after diagnosis.”

In those with localized lung cancer living in areas with higher levels of air pollution, the median survival was 2.4 years compared with 5.7 years in patients living in areas with lower levels. In cases in which lung cancer had metastasized, researchers observed shorter survival among patients overall, with little difference between high and low exposures of air pollution.

The pollutants studied in this analysis included nitrogen dioxide (NO2), ozone (O3) and particulate matter (PM10 and PM2.5). Eckel says strong associations were seen with N02, PM10 and PM2.5. Ozone pollution elicited the smallest change in median survival.

If patients diagnosed with early-stage lung cancer are concerned about air quality, Eckel explains that there are some common-sense precautions that all people — not just those with lung cancer &mdash; can take.

“If you’re planning to exercise, which is really important, maybe take into account what the air quality alert is for that day, and if it’s going to be a high pollution day, don’t exercise outside,” she says. “Exercise inside or rearrange your schedule to exercise at the time of day when air pollution is lower or in a park that’s not close to a busy roadway. If you’re at home and it’s a hot day out, rather than opening the windows, turn on the air conditioning to keep pollution out.”

Eckel adds that having an air filtration system in your home or using the recirculate setting on your car’s air conditioning system while sitting in heavy traffic is beneficial to one’s health, as well. She also notes that coastal regions tend to have cleaner air.

“One takeaway that I find interesting is that there’s been an emphasis on advance screening to detect early-stage lung cancer, so I think that we’re going to be seeing more of it. These are the people who we found air pollution had the biggest effect on,” Eckel says. “I think that the issue of air pollution for them is really important.”

While this study revealed important findings, Eckel says more studies need to be completed, such as possibly an intervention study to determine the effect of air filters in homes.

Air pollution may shorten the lives of those with early-stage lung cancer.

Living Under a Cloud: Examining Air Pollution's Effects on Lung Cancer

Keeping on top of treatment options, finances and emotions can become overwhelming when patients are faced with a lung cancer diagnosis.

However, thanks to a number of nonprofits and advocacy organizations, patients and caregivers can lessen their burden and take advantage of all the services, information and help that is provided.

No two advocacy organizations are the same, and it is important to research which can best provide the help that each patient needs. In addition to local organizations, there are many national and international lung cancer groups motivated to better the lives of patients. CURE® is thrilled to collaborate in an Advocacy Spotlight Partnership program with many well-respected lung cancer groups, including the ones listed below. As partners in this program, organizations supply CURE® with information about activities, trends, issues, educational opportunities and programs that are of interest to patients with cancer.

Patients with lung cancer and their caregivers can now call a toll-free number to receive emotional support and answers to some of their questions about life after diagnosis and maximizing quality of life. The hotline is run by Free to Breathe, a lung advocacy organization.

“With a five-year survival rate of only about 17 percent, it can be hard for patients to find other lung cancer survivors in their local community,” Cheryl Petersen, the program director, says. “In fact, many of the survivors and patients [Free to Breathe] talks to have never met another lung cancer survivor.”

To help ensure that the hotline is as helpful as possible for those affected by lung cancer, Free to Breathe conducted research and interviews using patient and caregiver perspectives to guide the program’s design.

Patients and caregivers alike stressed the importance of education about the condition. Many respondents explained that the level of distress they faced at the time of diagnosis precluded them from internalizing much of the information they were given.

The most requested information surrounded the following topics: lung cancer diagnosis and treatment; molecular testing; second opinions and centers of excellence; and clinical trials.

Another area of concern identified by Free to Breathe was the relatively weak support structure for caregivers. They specifically requested guidance on how to care for loved ones in the best way, concrete ideas for what they could do to help their loved ones, ways to discuss important topics about care when the disease progressed and reminders of the importance of self-care and a healthy lifestyle.

Each member of the Free to Breathe staff who answers phones undergoes training to ensure that callers receive a consistent level of support. The staff does not provide any medical or nursing advice, but rather encourages patients to consult with their health care providers in regard to any issues related to their health.

® that, ultimately, the patients and caregivers surveyed to help guide the hotline program “indicated their enjoyment of survivor stories, especially when the details were similar to their own circumstances.”

Patients and caregivers can call the support line at 1-844-835-4325. It is staffed Monday through Friday 8 a.m. to 4 p.m. CDT (9 a.m. to 5 p.m. EST).

The LUNGevity Foundation is literally getting active in its efforts to help people with lung cancer. Its latest work revolves around walk/run events designed to raise awareness, but the scope of its support services for patients and survivors is vast.

From educating patients and their families about the disease to supporting them through events and research, the LUNGevity Foundation has been focused on changing the outcome of lung cancer diagnoses since 2001.

“LUNGevity is committed to raising awareness that anyone can get lung cancer. We believe that the dialogue can move beyond the stigma of the past and focus on the incredible progress being made in lung cancer research over the last five years, resulting in new treatment options for patients,” says Linda Wenger, senior vice president of marketing and communications for the LUNGevity Foundation.

Wenger says LUNGevity utilizes “Breathe Deep” events, which are volunteer-run, throughout the country as one vehicle for awareness. These events, normally walk/run-type events, celebrate survivors and honor those lost to lung cancer. “These walks bring together patients and survivors, caretakers, advocates and health care providers to build community and support for those affected by lung cancer,” says Wenger.

LUNGevity also offers educational programs to patients with lung cancer and their families, such as Lung Cancer 101. This resource is a comprehensive, medically vetted online guide to understanding how lung cancer develops, how it can be found and how it can be treated.

Online survivor and caregiver resource centers are provided by LUNGevity to help patients live well despite their diagnosis, and even aid patients in formulating important questions to pose to their medical teams. The group also provides downloadable booklets on clinical trials, treatment options and types of lung cancers.

Beyond online resource centers and downloadable packets, LUNGevity also offers an entire spectrum of offline resources. “LUNGevity offers the largest network of online support and in-person survivorship programs for all people affected by lung cancer. Patients and caregivers can receive peer-to-peer support and information from our Lung Cancer Support Community (LCSC) message boards, and be matched with a LifeLine mentor who has had similar experiences,” says Wenger. “LUNGevity HOPE Summits are conferences designed specifically for patients, survivors and caregivers to hear from medical experts, inspirational speakers and each other. These unique meetings build communities of hope and support for people at all stages of a lung cancer diagnosis.”

For all the benefits patients reap through LUNGevity, the proverbial sowing is minimal.

“LUNGevity educational resources are free of charge to patients and their families, as are LCSC and Lifeline. HOPE Summits are free to attend; however, there is a $50 registration fee for the annual National HOPE Summit held in May in Washington, D.C., to cover two-and-a-half days of meals. First-time survivor participants may qualify for a full or partial travel grant,” says Wenger.

If Bonnie Addario has anything to say about it, researchers will soon understand why young never-smokers get lung cancer.

Unraveling genetic reasons for lung cancers that strike people under the age of 40 has become one of the research passions of the Bonnie J. Addario Lung Cancer Foundation. Addario, whose own battle with lung cancer started when she was in her 50s, turned her attention to the problems faced by younger patients about five years ago when she received a phone call from a distraught mother searching for help for her 21-year-old daughter.

Lung cancer is so prevalent that even a small percentage of young, healthy patients adds up to a large number of people, Addario notes. “If you look at 1.4 million people diagnosed around the world every year, 2 percent is a big number of patients,” she says.

The foundation started a group called Jill’s Legacy to help raise money for young patients with lung cancer. And, the Addario Lung Cancer Medical Institute (ALCMI), which the foundation formed to conduct a variety of research into the disease, set out to determine the characteristics of lung cancer in younger people.

Tapping into the best minds in the field, ALCMI designed an innovative clinical trial to find patients under age 40 and analyze their tumors to see whether they have gene mutations that are different from those found in older people with lung cancer. Barbara J. Gitlitz, M.D., from the University of Southern California, and Geoffrey R. Oxnard, M.D., from the Dana-Farber Cancer Institute, are leading the study.

“We use social media to find people around the world,” says Addario. “People can enter the study without ever leaving home.”

The ongoing study has attracted 120 participants from the United States and Europe thus far, according to findings presented at the World Conference on Lung Cancer in September. Preliminary results show that more than 75 percent of the participants have a mutation that can be treated with a targeted therapy.

Addario believes that shining a light on the nature of lung cancer among young people will help battle the stigma that accompanies the disease.

“I think they’re going to change the face of lung cancer,” she says of the young patients. “We’re starting to see people understanding that although smoking is a trigger for lung cancer — and many other cancers and heart disease &mdash; lung cancer was wrongly stigmatized for all these years and underfunded because of it.”

For more information about the Genomics of Young Lung Cancer study, visit its website at openmednet.org/ site/alcmi-goyl.

The stigma surrounding lung cancer is very real, and it has necessitated strong campaigning by the Lung Cancer Alliance to change people’s minds. Historically, lung cancer has been linked to smoking, and so people often believe that patients get lung cancer as a result of behavioral choices they have made.

In 2012, the alliance launched its first national lung cancer campaign with provocative images and a campaign that went viral and started people talking across the country. The “No One Deserves to Die” campaign used characters against whom the public might have an unconscious bias, such as a cat lover, a hipster or someone with a lot of tattoos.

Kay Bayne, director of marketing at the Lung Cancer Alliance, explains that the alliance ran ads that just said “Cat lovers deserve to die” and watched the reactions roll in. A week later, there was the reveal. The ads then said, “Cat lovers deserve to die if they have lung cancer.” That first campaign was the most successful, and really changed the way people spoke about the disease, Bayne says.

Changing the stigma around lung cancer can have a very important impact on individuals who are diagnosed with the disease. Although lung cancer claims more lives each year than colon, prostate and breast cancers combined, lung cancer research receives less funding than those other three cancers. According to Bayne, stigma is a large part of the puzzle when it comes to making progress combatting the disease.

In the second campaign, launched in 2013 and called “Moments,” the alliance focused on living more moments by getting screened, and noted that smoking is not the only risk factor for lung cancer.

“If we find lung cancer early, it can be surgically removed and you can live,” Bayne says. “Just like any other disease, to find it early and get it is better than to find it at a late stage when it has spread throughout your body.”

The campaign also discussed risk, informing former smokers that even if they have stopped smoking, they will always be at a higher risk than the nonsmoking population.

The alliance’s third campaign, in 2015, was titled “How It Feels,” and placed the focus on people diagnosed with lung cancer and their families, letting them know that there are others out there who understand what they are going through. Impact from that campaign has led to a growth in the organization.

“I think the importance of these campaigns, and how they can make people feel a part of the organization, cannot be overstated,” Bayne explains.

Lung cancer remains a silent epidemic among women, despite the number of patients who lose their battle to the disease each year.

The results of the American Lung Association’s (ALA’s) second annual Women’s Lung Health Barometer show that just 1 percent of women consider lung cancer to be a “top-of-mind” threat to their health, despite the fact that lung cancer kills nearly twice as many women as any other cancer each year.

With this knowledge gap in mind, the ALA launched LUNG FORCE — an initiative with the expressed mandate to “unite women to stand together against lung cancer and for lung health.”

In practice, LUNG FORCE seeks to make lung cancer a public health priority by bringing awareness to the issue and calling for policy changes and increased research funding for the disease.

American Lung Association National President and CEO Harold P. Wimmer, the architect behind the LUNG FORCE initiative, told CURE that, in general, the “strong, pervasive stigma associated with lung cancer” is the greatest challenge the initiative faces.

This stigma may be exacerbated for women, as lung cancer is sometimes perceived to be a “man’s disease.” Over the last 38 years, the lung cancer mortality rate for men fell significantly, while the mortality rate for women skyrocketed.

Stigma may also contribute to the fact that only 25 percent of women reported to the ALA Health Barometer that they’ve ever discussed lung cancer with their health providers. Just 17 percent of lung cancer cases among women are diagnosed early.

The ALA is calling for more investment in cancer research, and has committed to redoubling its efforts to make sure future federal austerity limits do no hamper this progress.

“The bottom line is that no one deserves cancer. Anyone can get lung cancer, and everyone deserves sympathy and support,” Wimmer concludes. LUNG FORCE is “a bold initiative to take lung cancer out of the shadows and address this disease head-on.”

The Global Lung Cancer Coalition (GLCC), like other organizations that advocate for patients with lung cancer, is focused on raising awareness — but on an international level.

For 15 years, and throughout 34 countries, the GLCC has been effectively raising awareness about the disease through its wide network of information, learning materials and organizations.

“The GLCC would like to see an increase in global public awareness of lung cancer. The GLCC is a loose coalition of over 30 organizations from over 20 countries,” says Jesme Fox, medical director for the GLCC. “Each organization has a focus on increasing awareness of this disease. The GLCC provides a network to share ideas and is a source of tools for member organizations to achieve this awareness-raising goal.”

The GLCC, which includes organizations from places including the United States, United Kingdom, Canada, Denmark, France and Germany, says it bases its information and efforts around four main goals. These goals are to place lung cancer on the global health agenda; to lessen the stigma of lung cancer among patients, families, health care providers, policy makers and the public; to empower lung cancer patients and their families to be active in their own care; and to effect change in legislative and regulatory policies in order to better the care of patients with lung cancer.

“The GLCC provides tools for member organizations to advocate on lung cancer issues. The GLCC facilitates an annual global lung cancer journalists’ award for excellence in lung cancer reporting, provides patient information on lung cancer signs and symptoms and in the area of new developments, such as immunotherapy, and has produced the global lung cancer e-atlas, available on the GLCC website (lungcancercoalition.org), which hosts lung cancer data for every WHO country,” says Fox. Fox adds that the GLCC also funds research and marketing efforts in order to better raise awareness about the disease and aid in the furthering of the treatment of patients with lung cancer.

“Though a common cancer, lung cancer is characterized by much negativity — overall poor prognosis, stigmatized by association with tobacco and relative lack of research investment. We are all committed to overcoming this,” Fox says.

Advocacy groups are making a difference in the lung cancer community. What can they do for you?

Lending a Hand: Lung Cancer Advocacy Groups Help Those in Need

You might say that smoking came naturally to Donna Fernandez. The 63-year-old Dallas resident grew up watching her dad smoke cigarettes and pipes. She was 16 when she took her first drag and 24 when she learned that her dad had lung cancer that had spread to his bones. “He stopped smoking cold-turkey that day,” she recalls. Despite her father’s death just six months later at age 49, and the knowledge that she could face a similar fate, Fernandez continued to smoke two packs a day for almost 40 years. “Nothing compares to the feeling you get from smoking a cigarette,” she says.

Occasionally, Fernandez would try to kick the habit using her dad’s method, relying on grit and determination. She was smoke-free for nine months while pregnant with her son, but started again soon after he was born. “I wanted to stop, for myself and for my family,” she says. “Giving up cigarettes is by far the hardest thing I’ve ever tried to do.”

Finally, in 2009, Fernandez decided that cigarettes were costing her too much — both in terms of money and her health. Although she took it for just three weeks instead of the full recommended course, the prescription smokingcessation medication Chantix was one thing that helped her quit. She’s been smoke-free for seven years.

But four years after Fernandez took her last drag off a cigarette, she noticed a knot on her collarbone. “I thought I might have thyroid cancer,” she recalls. Instead, a CT scan revealed that undetected lung cancer had spread to her lymph nodes.

The Centers for Disease Control and Prevention (CDC) rank cigarette smoking as the leading cause of preventable disease and death in the United States. It’s to blame for almost 90 percent of lung cancer diagnoses and one out of five deaths every year.

There are two main types of lung cancer: small cell and non-small cell. Non-small cell lung cancer accounts for up to 85 percent of diagnoses and is the most common one seen in nonsmokers. It tends to be slower to spread and easier to treat than small cell lung cancer, which is almost always linked to smoking.

Even though Americans today actually smoke less than they did in the 1960s, their odds of getting lung cancer are greater. This increase may be due to the use of more carcinogenic compounds. Today’s cigarettes contain about 600 ingredients and emit at least 69 known cancer- causing toxins, as well as other poisonous chemicals. In addition, the Surgeon General’s report in 2014 suggested that the introduction of cigarettes with ventilated filters, aimed at reducing the amount of toxins inhaled by smokers, actually result in smokers inhaling more often and more deeply, ultimately increasing the number of smoke particles left behind in the lungs. No definitive conclusions were made in the report about whether these filters have contributed to a rise in lung cancer, but the report deemed the association “likely.”

When inhaled, the chemicals in cigarettes can cause cells in the lungs to mutate or change. As these abnormal cells grow uncontrollably, they can form cancerous tumors that destroy healthy lung tissue. Particularly if left untreated, lung cancer can spread throughout the body, typically first to the chest wall or into an airway, and then, most often, to the lymph nodes, bones, brain, liver or adrenal glands. Smoking also increases the risk that someone will develop other kinds of cancer, as well as heart disease.

Because the lungs have few nerve endings, there’s little, if any, pain or discomfort during the early stages of cancer. Occasionally, respiratory problems, such as a persistent cough or frequent bouts of bronchitis or pneumonia, crop up. By the time more troubling symptoms start to appear — weight loss, headaches and bone pain or fractures &mdash; the disease is advanced and less treatable.

Of course, not everyone who gets lung cancer has a history of tobacco use. Up to 15 percent of people affected by the disease have never smoked. Some may have been affected by secondhand smoke in their homes while growing up. Others may have been exposed to asbestos or radon, a radioactive, odorless gas naturally produced by decaying uranium in the soil. Radon, the second-leading cause of lung cancer, seeps from the ground into homes and buildings. If a radon detection kit purchased online or at a home-improvement store indicates that your home has unsafe levels, a professionally installed radon mitigation system can make the air safe again.

In some cases, it is not known what has caused a person’s lung cancer. Researchers have found that a specific kind of gene mutation — which encourages cells to grow out of control, and which is treatable with targeted drugs &mdash; is much more common in never-smokers than in people who have smoked.

Still, smoking cigarettes remains the greatest risk factor for developing lung cancer. So why don’t smokers just quit? Many of them — nearly 70 percent, according to one recent CDC survey &mdash; want to. But kicking the habit is hard. Really, really hard.

Every time Chuck Schonter lights a cigarette, he wishes it was his last. The 64-year-old Madison, Virginia, resident was diagnosed with the early stages of lung cancer two years ago. Schonter, a pack-and-a-half-a-day smoker since age 14, quit cold-turkey the day he got his diagnosis. Unfortunately, his smoke-free days lasted only six months. “I’m down to fewer than 10 cigarettes a day now,” he says, “but I know that’s still too many.”

He’s right. Schonter has a better chance of beating the disease if he stops smoking for good. A British Medical Journal study found that people with early-stage lung cancer can double their five-year survival rate by giving up cigarettes. Those who don’t stop may develop another type of cancer or experience a relapse of treated lung cancer. Smoking also weakens the effectiveness of cancer treatments while making their side effects worse.

The fact that smokers like Schonter struggle to quit, even when faced with cancer, demonstrates the powerful hold cigarettes have. Nicotine, a drug naturally found in tobacco, may be as addictive as heroin and cocaine. “With each draw of a cigarette, the brain releases dopamine, a hormone that produces pleasurable feelings,” says certified tobacco treatment specialist and family nurse practitioner Melissa Stanley, who is also the lung cancer screening program coordinator at the University of Virginia Cancer Center, in Charlottesville. “As soon as that feeling fades, you need another cigarette.” Smokers also build up a tolerance to nicotine, meaning they need to smoke more to get the same feel-good effects.

This physical component is only one part of the addiction problem. “For many smokers, reaching for a cigarette during certain times of the day, or while doing an activity like driving, or when stressed, becomes an ingrained part of their routine. This is the mental part of addiction,” explains Bill Blatt, director of tobacco programs for the American Lung Association.

Then there’s the social aspect of smoking, such as taking smoke breaks with coworkers or lighting up while out to dinner or drinks with friends. “A smoker’s chances of quitting for good are greater when you address all three of these addiction links,” says Blatt.

Smokers rarely succeed in quitting the first time they try. “Almost everyone tries a few times before they quit for good,” says Blatt, who calls these attempts “practice quits.” “Every time you do a practice quit, you learn a little more about what works for you and what doesn’t. You get a little bit smarter about how to proceed the next time.”

For many smokers, figuring out how to quit is a challenge. “There is no right way to quit,” says Stanley. “What helped one former smoker might not work for another.” Going it alone (the infamous “cold turkey”) seems to be the worst approach. “The long-term success rate is approximately 3 percent,” says Stanley.

Of the seven FDA-approved smoking-cessation aids, five are nicotine replacement therapies (NRTs). These products deliver controlled, small amounts of nicotine via gum, lozenges, skin patches, inhalers or nasal sprays to help wean smokers from cigarettes. They work by easing nicotine withdrawal symptoms and reducing the urge to smoke. Even though NRTs contain nicotine, studies show that smokers who use them double their chances of quitting without increasing their cancer risk. Chantix, the prescription medication that worked for Fernandez, blocks dopamine’s feel-good effects. “Cigarettes become less pleasurable, so your desire to smoke decreases,” says Stanley. Other prescription drugs, Wellbutrin and Zyban (bupropion), are actually antidepressants. They work on brain chemistry, helping to blunt nicotine cravings.

Research shows that combining medications and/or NRTs with counseling offers the highest chance of success. “Counseling teaches techniques to avoid triggers,deal with cravings and manage the behavioral and mental aspects of smoking,” says Blatt.

Counseling doesn’t need to take place face-to-face in order to help. Toll-free telephone quit lines are available in every state and the District of Columbia (see “Getting Help”). Trained counselors help callers find the best quit plans based on their personal smoking histories. Studies indicate that smokers who use telephone counseling services have twice the success rate as those who don’t.

Support groups, either in person or online, also make a difference. “The phone and Internet are especially helpful for smokers who live in rural areas where smoking is more prevalent, yet access to smoking cessation programs is limited,” says Blatt. He noted that the American Lung Association offers a Quit Now: Freedom From Smoking online support group and discussion community, available at inspire.com/groups/freedom-from-smoking.

Some former smokers credit e-cigarettes with helping them cut back and eventually kick the habit. These mechanical cigarettes have a battery that heats up a cartridge of liquid nicotine solution. Users then inhale the nicotine vapor. The cartridges come in varying strengths of nicotine, giving smokers a bit more control over how much nicotine they take in.

“The problem is that there are hundreds of e-cigarettes on the market and the FDA isn’t yet regulating them,” says Blatt. “This means you could get more nicotine than what the package says.” You also may be inhaling other dangerous chemicals. One study found higher levels of nickel and silver in e-cigarette vapor than in cigarette smoke. “Because e-cigarettes are fairly new, we don’t have any comprehensive, long-term studies to show whether they are more or less harmful than actual cigarettes, or whether they help or hurt smoking-cessation efforts,” says Blatt.

While a 2016 Cochrane Review indicates that e-cigarettes may increase the chances of a successful quit effort, the researchers also noted a lack of studies about long-term effects. For this reason, most smoking-cessation experts recommend sticking with NRTs that are proven to be effective and safe.

Some smokers are interested in using complementary therapies, such as acupuncture, yoga, meditation or hypnotherapy to help them quit, sometimes in combination with FDA-approved tools, but there is little evidence, so far, showing that these methods increase success.

The good news is that Americans are winning the war against tobacco. More than 52 million smokers have successfully broken free from cigarettes, according to the American Lung Association. In fact, says Carly Ornstein, the organization’s national director of lung cancer education, former smokers now outnumber current smokers by an estimated 16 million. And, as the adage goes, it truly is never too late to stop. Quitting today reduces your risk of dying from lung cancer in half in just 10 years. Even if you already have lung cancer, there are still plenty of reasons to remain hopeful. “We’ve made a lot of progress with lung cancer treatments in the last 10 years,” Ornstein says.

Fernandez is living proof of that. Thanks to an immunotherapy clinical trial, she’s been enjoying time with her husband, son and grandchildren — all while living with lung cancer &mdash; for four years. “When my doctor told me my diagnosis, I wondered if I’d be gone in six months like my dad,” says Fernandez. “Fortunately, this new treatment gave me back my life. Some days, I forget I even have cancer.”

No matter how long you've been a smoker, quitting is still possible and the anti-cancer benefits are huge.

Quitting Smoking Is Possible and Reduces Cancer Risk

Being an oncologist treating non-small cell lung cancer these days is kind of like going on an amusement park ride: You need to hang on tightly.

David Gandara has experienced that firsthand.

“In lung cancer, things have never moved at such a fast pace,” Gandara, M.D., told a roomful of medical professionals when he discussed the changing landscape of treatment for the disease during the 2016 International Lung Cancer Congress held in August in Huntington Beach, California.

In fact, Gandara, who directs the Thoracic Oncology Program at the UC Davis Comprehensive Cancer Center, said that treatment plans for advanced squamous and nonsquamous non-small cell lung cancer (NSCLC) drawn up by his staff in 2014 are already outdated. Specifically, chemotherapy has become less of a focus.

In 2014, Gandara’s team suggested that targeted drugs known as tyrosine kinase inhibitors (TKIs), which hone in on and disable mutations that drive cancer, should be given as the first line of defense to patients whose disease expressed EGFR and ALK mutations, with chemotherapy used only after that. But for lung cancers that didn’t express those mutations, the options were chemotherapy with Avastin (bevacizumab), a targeted drug that disables the blood vessels that feed tumors, followed by chemotherapy and the targeted drug Tarceva (erlotinib) as maintenance therapy.

While chemotherapy still has a role, doctors now much more frequently turn to immunotherapies to treat these patients. Chemotherapy is used first only in patients whose cancers don’t express mutations that indicate they are likely to benefit from TKIs or immunotherapies known as checkpoint inhibitors.

This illustrates how immunotherapies have established themselves in just a few years, Mark W. Kris, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, told 

“Last year, people received chemotherapy up front if they didn’t have an obvious (genetic) driver (of their cancer). If chemotherapy stopped working or had to be stopped, people immediately went to another chemotherapy,” said Kris. “In 2016, every single patient [in my practice] gets immunotherapy.”

But with the fast pace of evolution in the treatment and handling of advanced NSCLC over the past few years, some gray areas have become apparent. Doctors and scientists are working to fine-tune their understanding of how best to apply immunotherapies and targeted agents in lung cancer, and of how to incorporate testing for biomarkers that might predict how well, or whether, individual patients will respond to these drugs.

FDA-approved immunotherapies, such as Opdivo (nivolumab), Keytruda (pembrolizumab) and Tecentriq (atezolizumab), have demonstrated long-lasting benefits in lung cancer.

“People have tried to find a way to rev up the immune system to fight all cancers for more than 100 years,” Kris said. “Up until now, it has been a goal or a dream, and only recently are we able actually to deliver on that for patients with lung cancer.”

The immunotherapies generating such excitement in lung cancer are checkpoint inhibitors. These agents target the PD-1/PD-L1 or CTLA-4 signaling pathways, which are involved in keeping the immune system under control so that it doesn’t attack healthy tissue. Immunotherapies take the brakes off the immune system, helping it to recognize cancer and move into high gear to fight the disease. Opdivo and Keytruda are checkpoint inhibitors that target PD-L1 and PD-1, respectively. Tecentriq, approved in October for certain patients with metastatic NSCLC, targets PD-L1.

“What we have seen is that agents that target PD-1/PD-L1, and now agents that target CTLA-4, are very helpful in leading to dramatic benefits for patients with lung cancer,” Kris said. “There is very clear evidence that, particularly for Opdivo and Keytruda, they improve rates of shrinkage and improve duration of survival — which is an extremely impressive result &mdash; over standard chemotherapy (docetaxel).”

“Equally as important to those benefits in outcome are the benefits in terms of severe side effects, because approximately half of patients who receive docetaxel get some kind of a severe side effect,” Kris added. “Now, only about 10 percent of patients who receive immunotherapies get those side effects, so it has everything going for it.”

The path forward is clear, Kris said: Immunotherapies are going to be given first, and chemotherapy will follow if disease relapses or progresses.

In addition, immunotherapy combinations are on the horizon. Combining PD-1 or PD-L1 inhibitors with anti-CTLA-4 immunotherapies, such as Yervoy (ipilimumab), may bring better results, Kris said.

“At the 2016 Annual Meeting of ASCO (the American Society of Clinical Oncology), there was one presentation by Matthew Hellmann, M.D. (of Memorial Sloan Kettering Cancer Center) regarding the CheckMate 012 trial with Opdivo and Yervoy,” Kris said. “They were comparing it to patients in these same trials who received (only) Opdivo, (and those in the combination group had) higher rates of response, longer durations of response and better survival.”

Also, while Yervoy on its own tends to cause more and harsher side effects than PD-1/PD-L1 inhibitors, Kris noted that, “by adjusting the dosages and schedules of Yervoy and Opdivo, results showed very good tolerance, and truly almost the same degree of side effects with the combination as with Opdivo alone.”

The trial results were also compelling for other reasons, Kris said.

“What many people thought was the most amazing finding,” he said, “was that a number of people on that trial had no growth of their cancer after years of treatment. Some of them have come to surgery to remove what was left after years of treatment on those studies, and what they found is nothing — just scar tissue. Therefore, the benefits in the short term, in terms of response and fewer side effects and the chance for long survival, make these regimens very appealing.”

As immunotherapies evolve into their role in treating lung cancer, targeted agents, such as Avastin, Cyramza (ramucirumab) and Portrazza (necitumumab), among others, are also advancing the field.

Avastin works by stopping the growth of blood vessels that feed a tumor; Cyramza targets a VEGF gene mutation and stops it from driving the cancer; and Portrazza targets EGFR and slows or stops its contribution to lung cancer.

These kinds of drugs, and many immunotherapies, too, seem to work best in people with specific gene mutations, and multiple studies are being conducted to find out who, exactly, can benefit from them.

Linnea Olson became a pioneer in that effort after she was diagnosed with lung cancer in April 2005 at the age of 45, after two years of being misdiagnosed with asthma.

The 5 cm mass on her left lung was difficult to treat, and, in October 2008, she was told she’d reached the end of her therapy options. That was when she joined her first clinical trial.

“This opportunity arose after it was discovered that I had an ALK mutation, and on Oct. 1, 2008, I became the fourth person in the world with NSCLC to take crizotinib, now marketed as Xalkori,” Olson said. “This was a phase 1 clinical trial, and my expectations were low — the only other participant at my hospital had died within weeks of starting trial, in part because of side effects from the experimental therapy.”

But given only months to live, Olson decided it was worth the leap of faith, which paid off when she saw a 70 percent reduction in tumor burden. “I went from preparing for my death to living again. However, I knew that this did not represent a cure.”

Olson went on to be enrolled in two more phase 1 clinical trials — a trial for the ALK inhibitor Zykadia (ceritinib) and another for lorlatinib, a still-investigational drug that targets both ALK and ROS1 mutations.

“I consider clinical trials my lifeline,” she said. “I would definitely encourage other patients to explore this option. Sometimes it is the best course of action and, in my own case, offered me an avenue just as it seemed I’d come to the end of my journey.”

In the search for meaningful biomarkers, Portrazza was at the heart of one defining trial in 2015. The SQUIRE trial tested the effectiveness of chemotherapy with or without Portrazza in advanced squamous NSCLC, and its results, which Gandara called “deceptively modest,” showed that overall survival (OS) was 11.5 months in the Portrazza arm versus 9.9 months with chemotherapy only.

One thing that set this trial apart was that many previous trials had failed to show any OS advantage from targeted agents, Gandara said. Just as important, he said, was that the SQUIRE results helped to clarify the potential of biomarker strategies in squamous NSCLC. For EGFR-positive patients, OS widened to 12.6 months in the combination arm of the trial, versus 9.2 months for the standard gemcitabine-cisplatin chemotherapy group.

Gandara said that this evaluation showed “that we could potentially identify a biomarker strategy for this class of agents which would make them more robust in the treatment of squamous cell lung cancer, so I hope that we will be able to pursue this and find out which patients are most likely to benefit.”

Two phase 3 CheckMate trials (017 and 057) involving Opdivo versus docetaxel showed an advantage with the PD-L1 inhibitor for both squamous and non-squamous NSCLC patients; however, at the 12-month point, the OS rate was significantly better for non-squamous tumors (51 percent) than for squamous (42 percent) — “telling us once again that squamous cell lung cancer and non-squamous cell lung cancer are very different diseases,” Gandara noted.

Further analysis of these two trials found that, in squamous NSCLC, the survival benefit from Opdivo was independent of PD-L1 expression, whereas among non-squamous patients, OS directly correlated with PD-L1 status. In the KEYNOTE 010 trial, Keytruda improved OS versus docetaxel in patients with advanced NSCLC who had previously been treated with platinum-based chemotherapy. Moreover, in the strongly PD-L1-positive subgroup, progression-free survival also improved with Keytruda versus chemotherapy, once again strengthening the evidence supporting the potential for biomarker guidance in NSCLC, Gandara said.

Finally, the KEYNOTE-024 trial evaluating Keytruda versus chemotherapy as first-line treatment for advanced NSCLC removed all doubt about the value of high-expression PD-L1 as a “smoking-gun” biomarker, Gandara said.

Reported in June, the results of the trial showed that frontline Keytruda improved OS versus chemotherapy in patients with NSCLC who had high levels of PD-L1 expression. Keytruda was also shown to extend progression- free survival (PFS) in the first-line NSCLC setting. Gandara predicted that “this trial will alter the standard of care in first-line therapy of the great majority of patients with advanced NSCLC.”

He said that a question now demanding attention is whether it’s wise to continue the use of checkpoint inhibitors after first-line treatment and disease progression. “In other words,” he asked, “is there something there that will continue to benefit patients even though they look like they’ve progressed?”

Gandara pointed to a joint ECOG-SWOG proposal for an advanced non-squamous NSCLC trial that hopes to shed light on this issue. Patients would be randomized to first-line Keytruda, followed by carboplatin-pemetrexed chemotherapy with or without Keytruda as a second-line treatment.

Backed by new evidence, updated guidelines have added actionable biomarkers and more drugs to the list of acceptable treatment paths. In lung adenocarcinoma, targeted drugs like Cabometyx (cabozantinib) for those with RET mutations and Xalkori for those with ROS1 mutations are producing impressive response rates, although these mutations are rare, so there’s a limited population of patients who can benefit from these, he said.

Figuring out how best to use new drugs like Tagrisso (osimertinib), which targets a specific EGFR mutation that causes resistance to EGFR inhibitors like Tarceva, also should become a priority, he advised.

“Can we do combinations to make this drug more effective?” he asked. “We need to think this way.”

He added that it is no longer necessary to test for a huge number of genes in order to make it worthwhile to use multiplexing and next-generation genome sequencing. “I think we have to convince (private insurers), CMS (Medicare/ Medicaid) — everybody &mdash; that we are at that point where it is cost-effective to use next-generation sequencing,” he said. To aid in that kind of testing, new tools have materialized virtually overnight, Gandara noted, including “liquid biopsies” that analyze blood instead of tissue for gene mutations and other tumor markers.

Gandara would like to see more attention paid to the merits of repeat biopsies to guide treatment processes more accurately. This is because tumor biology has a tendency to evolve, he explained.

“You find an oncogene, you treat, and you re-biopsy on progression. You determine a new therapy, you retreat, and when there is progressive disease, you re-biopsy again. I have some patients now who are on their third or fourth re-biopsy with an oncogene-positive cancer,” he said.

“Now there are strategies in place where we can do what would be called ‘biomarker switch therapy,’ where you monitor for a mechanism of resistance, and you switch [patients] to an alternative drug — not when the CT scan turns bad, but based on a plasma biomarker.”

He cautioned, however: “These concepts have to be proven in randomized trials.”

The role of immunotherapies and targeted treatments in lung cancer is evolving at breakneck speed.

Lung Special Issue | CURE