Lung cancer poses the greatest threat to survival when it’s diagnosed in its later stages — and, unfortunately, that’s exactly when it’s typically found. But today, we have the opportunity to start turning the dial the other direction, toward earlier diagnosis and more lives saved. This is made possible by the recent move toward screening those at high risk for lung cancer with low-dose computed tomography (CT).

In the past, those suspected of having lung cancer were imaged via X-ray, and not as part of an organized nationwide screening program. The recent results of the National Lung Screening Trial demonstrated that screening a high-risk population via low-dose CT is an effective way to find early lung cancers, and that this strategy uncovers more of these cancers than X-ray can. The study found that CT screening, compared with X-ray, can prevent an extra three lung cancer deaths for every 1,000 people screened — a 20 percent improvement.

Based on those results, CT screening has been recommended by the U.S. Preventive Services Task Force for people aged 55 to 80 years who have a 30 pack-year smoking history and still smoke, or who have quit in the last 15 years.

Yet screening for cancer can be controversial, and its application in the search for lung cancer is no exception. Although most of the lesions found through screening with low-dose CT — or with X-ray, for that matter &mdash; turn out not to be cancer, these false positives can lead to a lot of worry by patients, and to further diagnostic testing, sometimes as invasive as surgery; these tests can, in turn, spark complications.

So why comply with these screening guidelines? Our article on screening for and diagnosing lung cancer shares the views of experts who have considered the balance between the costs and benefits of CT screening in this population.

, we focus on treatments for lung cancer across types and the spectrum of disease severity. Our article on stage 3 lung cancer examines the challenges of a disease that can look very different in different patients, and whose treatment must remain flexible as a result. And in a look at stage 4 lung cancer, we offer details about the latest targeted treatments and immunotherapies, as well as some strategies still on the horizon.

We hope these articles will leave you more informed about lung cancer, from its causes to its diagnosis and treatment options. If, after reading this 

, you are better able to make informed screening or treatment decisions, or help a loved one do so, then we will have succeeded in our mission to provide you with facts that help you throughout the cancer journey.

Articles

From the Chairman

Lung cancer poses the greatest threat to survival when it's diagnosed in its later stages.

Lives in the Balance

Imagine a therapy free of drugs and side effects, one that allows you to be surrounded by people facing similar diagnoses while promoting camaraderie, time to ask questions, a change in behavior to promote health and an enhancement of your quality of life. This treatment, known as pulmonary rehabilitation, is not a cure, but many people with chronic lung diseases are given the recommendation to participate with good reason.

Pulmonary rehabilitation (aka pulmonary rehab, or PR) is a medical program designed for people facing chronic lung disease. It was first implemented for patients with chronic obstructive pulmonary disease (COPD), and since has expanded to include patients with other diagnoses such as pulmonary fibrosis (lung scarring) and even lung cancer. The program is multidisciplinary, and includes the input of physicians, respiratory therapists, physical therapists, occupational therapists, psychologists, dieticians and/or nutritionists.

Patients start the program with a thorough medical assessment, followed by tailored, individualized sessions focused on exercise training, education, breathing techniques and behavioral change.

Supervised exercise training can increase upper and/or lower body strength using a combination of cyclers, treadmills and/or free weights. Educational sessions can help patients better understand their chronic lung disease; the reason for, and proper use of, any medications they may be taking for these conditions; the benefits of smoking cessation; and the relationship between disease and symptoms. Commonly taught breathing techniques are pursed-lips breathing and/or diaphragmatic breathing.

After completing the program, patients are encouraged to implement their learning and perform home exercises to help enhance long-term health. The program typically lasts four to 12 weeks, consisting of two to three sessions per week. In patients with chronic lung disease, PR has been shown to improve symptom burden (including shortness of breath) and exercise capacity, increase participation in everyday activities, promote autonomy, enhance quality of life and affect long-term behaviors that boost health.

Which patients with lung cancer may be eligible for PR?

Chronic lung diseases commonly considered for PR include COPD, interstitial lung disease (ILD)/pulmonary fibrosis, cystic fibrosis, bronchiectasis and pulmonary hypertension. Patients with lung cancer, partly due to their tendency to present at late (advanced) stages, are not traditionally considered to be good candidates for PR. However, there is emerging evidence that PR in lung cancer can lead to improved outcomes.

In addition, some chronic lung diseases, notably COPD and pulmonary fibrosis, are linked to lung cancer. Therefore, it is not uncommon for patients with lung cancer to have other co-existing chronic lung diseases that, in turn, benefit from PR. For instance, in one 2006 study that appeared in the journal Chest, COPD was found to be present in approximately 70 percent of men and 50 percent of women newly diagnosed with lung cancer.

Moreover, while lung cancer itself is highly challenging as both a chronic and frequently fatal illness, it is treatable and even curable in a subset of patients that are diagnosed at a relatively early stage. Yet, in some patients with early-stage lung cancer, where surgery and radiotherapy are commonly employed with curative intent, the chronic impact of lung resection or radiation can significantly impair functional status and lung function. PR may be appropriate in this subset of patients.

What are the benefits of PR in lung cancer?

The most common settings in which PR is used in lung cancer are before and/or after surgery. Before surgery, participation in PR can potentially lower the risk of having complications related to the procedure, a benefit that can lead to decreased time on life support, shorter duration of hospitalization and/or lower chances of acquiring hospital-associated infections. When used in this setting, the duration of PR is typically shortened so as to not delay the time to treatment (it’s abbreviated to between two and four weeks, instead of the typical eight to 10 weeks).

After lung cancer surgery, patients usually experience a decline in lung function, since portions of their lungs have been removed. As a result, some can develop exercise limitations and experience persistent symptoms (including shortness of breath and fatigue) and decreased quality of life. According to a 2009 German study, these effects are known to be most evident at three months after surgery, but can persist beyond one year. In such circumstances, PR can reduce some of the residual effects of lung cancer surgery, restore exercise capacity and improve symptoms, quality of life and long-term health.

In patients with advanced lung cancer (not typically surgical candidates), the effects of the disease itself, including shortness of breath, fatigue, deconditioning, muscle weakness, muscle wasting and anxiety, can be very limiting and disabling. Many patients with advanced lung cancer, therefore, are unable to participate in the traditional PR programs. Instead, home-based and less-intensive exercise programs have been designed to be better tolerated and feasible. In recent studies, these programs have been shown to potentially reduce symptoms and improve sleep quality and quality of life. In those undergoing chemotherapy and/or targeted therapy, the programs can also improve patients’ ability to tolerate those treatments.

In clinical practice, some clinicians have recommended limited activity in cancer patients to avoid making symptoms worse. Patients, sometimes at the encouragement of supporting family members, have also been known to limit their activities to prevent “getting worse.” Loved ones might ask: “Should you be exercising? After all, shouldn’t you rest and take it easy since your cancer is already limiting you so much?” Not according to medical evidence. For all but those with severe musculoskeletal and/or neurologic deficits that limit physical activity, exercise is encouraged.

Inactivity can compound symptoms of lung cancer, resulting in a “downward spiral” of declining health, in which symptoms such as shortness of breath and fatigue lead to more inactivity, in turn accelerating the worsening of symptoms. Stopping such a downward spiral is a goal of PR and/or exercise programs. When symptoms are controlled through exercise, patients experience fewer symptoms on a day-to-day basis, improving their work capacity and endurance, and are thus able to do more. The result is better quality of life and improved overall health. Exercise and physical activity, especially through a guided (PR) protocol, are therefore safe, encouraged, and can provide clinical benefits in lung cancer.

How do I enroll in pulmonary rehabilitation?

To be considered for PR, you will need a referral from your health care provider (such as your local pulmonologist or primary care physician). Insurance coverage varies according to the specific disease and disease severity. Currently, PR is covered by Medicare for patients with COPD; other chronic lung diseases may also be covered, but this varies by regions of the country. Private insurance coverage also varies greatly. The coordinator of any pulmonary rehabilitation program you are considering joining can tell you if you qualify and what the cost will be.

PR programs are available at both teaching/academic and private institutions. To search for a program in your area, visit 

 previously published an article on the benefits of 

. In this article, recommendations were to start off with short periods of moderate activity several times a day, such as 10- to 15-minute walks three times a day, with the goal of exercising for at least 30 minutes a day, at least five times a week. However, these recommendations were meant to serve as a starting point. The key is to find what you’re able to do physically and build on it. Some exercise, at any duration or intensity, is likely to be better than no exercise at all.

Duc Ha, MD, Philippe Montgrain, MD, and Mark Fuster, MD, are from the University of California San Diego and VA San Diego Healthcare System

Side Note

Pulmonary rehabilitation is a medical program designed for people facing chronic lung disease. It was first implemented for patients with COPD, and since has expanded to include patients with other diagnoses such as pulmonary fibrosis and even lung cancer.

Breathing Easier: Pulmonary Rehabilitation Can Improve Function for Some With Lung Cancer

In lung cancer, prognoses are most dire when disease has reached stage 4, leaving patients, their doctors and the research community eager for improved treatment strategies. With recent advances in the molecular sequencing of non-small cell lung cancer has come a reason for hope — albeit for a small segment of affected patients.

A greater understanding of the genomics of nonsmall lung cancer — in particular, the identification of some genetic mutations that help drive the disease &mdash; has led to new medications that target these mutations. A glitch that causes tumors to overexpress or make a mutated version of the epidermal growth factor receptor, or EGFR, resulting in the rapid growth of cancer cells, can be treated with medications that disable that glitch, such as Tarceva (erlotinib) and Iressa (gefitinib). Antibodies to EGFR, including the recently approved Portrazza (necitumumab), can also be effective.

A different gene, ALK, can undergo several rearrangements that drive non-small cell lung cancer, but these mutations can now be targeted with the drugs Xalkori (crizotinib) or Zykadia (ceritinib). There’s even a molecular diagnostic test that can help identify some of the patients most likely to benefit from these drugs.

Unfortunately, these new medications work only for a minority of patients with non-small cell lung cancer, because not much more than 10 percent of them have the targeted mutations. Also, over time, resistance develops — we don’t know exactly how, but much effort is going into deciphering this process. Luckily, there are also other new tactics. Oncologists and scientists alike are excited about immunotherapies for the treatment of non-small cell lung cancer.

Particularly good news is that two recently approved immunotherapies, Opdivo (nivolumab) and Keytruda (pembrolizumab), may help a broader swath of patients than targeted drugs can. In general, immunotherapies tend to work best in smokers or former smokers, whose lung cancers seem to carry more mutations — and who comprise the majority of the population with non-small cell lung cancer. These drugs also may be less likely than targeted therapies to stimulate resistance from cancer. In a small group of patients, at least, immunotherapies seem to spark long-lasting responses. More work is needed to identify more precisely who is most likely to benefit.

While these new types of drugs can’t yet help everyone with advanced lung cancer, researchers are poised to build on their successes as they seek new molecular targets. At the same time, they’re testing additional immunotherapies, and combinations of those drugs, in the clinic.

These precision medicines represent an area of great promise that could vastly change the outlook for patients with this intransigent disease. In the pages of this 

, we share not only the strategies that are available now, but news about what’s waiting on the horizon.

Chair, Department of Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

Editor's Page

In lung cancer, prognoses are most dire when disease has reached stage 4, leaving patients, their doctors and the research community eager for improved treatment strategies.

Treating Lung Cancer With Precision

Andrea Stern Ferris is the president and chairman of LUNGevity Foundation.

You've just heard a devastating diagnosis: Your loved one has lung cancer. You freeze and try not to panic — but what now? There are so many questions to ask, so many things to do and so much still unknown. I know this feeling, because I have lived it.

My mother was diagnosed with lung cancer in 2006, and when that happened, my father and I found ourselves with new roles. I became more than my mother’s daughter. I became one of her caregivers and part of her support team. I was also a support to my father and my brothers. Being a caregiver means helping a loved one with everything from meal planning to getting to and from doctor’s appointments to ensuring that medical bills are paid on time.

Finding yourself in this position can be overwhelming, but if you do, you are not alone. In fact, 43.5 million people in the U.S. are caring for loved ones with cancer and other illnesses. This year, it is estimated that 221,200 new cases of lung cancer will be diagnosed, representing 13 percent of all cancer diagnoses. As caregivers, we play an important part in our loved ones’ fight against the disease. It’s not just the person with cancer who is affected — it’s all of us.

When my mother passed away in March 2008, my family and I founded Protect Your Lungs to help in the fight against lung cancer. In 2010, we joined forces with LUNGevity Foundation and have grown the organization into the nation’s largest nonprofit focused on funding research and providing support to the lung cancer community.

This year, LUNGevity has partnered with the biopharmaceutical company Celgene Corp. to create 

, a program providing tips, videos and information to help with some of the most pressing issues lung cancer caregivers face, including transitioning to the caregiver role, keeping family and friends informed and finding time to take care of yourself. Specially curated tip sheets and videos, which feature — and were designed with &mdash; input from caregivers, delve into how to ask for help from friends and family, ways to de-stress and stay healthy, what questions to ask your loved one’s health care team, tips for talking about and planning for the future, and many others.

As a caregiver, two things that I did not do, but in hindsight wish I had, were asking for help and taking care of myself. I wanted to do everything for my mother and to support my father, but I struggled while also being there for my husband and children and balancing the rest of my life. Being able to ask for help as a caregiver, so that you, too, can stay healthy, is very important. Support like this is the cornerstone of Your Journey Together.

The caregiver experience is different for each person, and not all needs are the same. Those differences helped to inform this program, and we hope that the resources available can help alleviate some of the burden on you and your loved ones during this difficult time.

For more information on Your Journey Together, including our tips and resources, visit 

Speaking Out

A nonprofit's new website section offers resources to caregivers of people with lung cancer.

Your Journey Together: New Resources for Caregivers of People With Lung Cancer

As smoking rates have dropped, so have the overall rates of lung cancer in the United States. Yet, lung cancer rates are increasing in people who have never smoked. In fact, today, nearly one in five people diagnosed with lung cancer are never-smokers.

This group includes a higher proportion of women, Asians and people with adenocarcinoma. Causes can include exposure to second-hand smoke, asbestos, radon, coal or certain cooking oils, and genetic susceptibility — most likely a combination of factors. Researchers are also studying whether the human papillomavirus can stimulate lung cancer in never-smokers, and whether the disease can be fueled by estrogen.

As scientists have learned more about lung cancer on the molecular level, they have discovered that lung cancer among never-smokers involves different changes or mutations in the DNA make-up of the tumor — so different, in fact, that some consider it a different disease altogether than that found in longtime smokers.

“We already know of some gene changes in the lung cancers of nonsmokers that are different from those in tumors from smokers. But we don’t know why these changes occur or how they interact with other environmental factors,” says David Carbone, director of the James Thoracic Center of The James Cancer Hospital and Solove Research Institute at the Ohio State University Comprehensive Cancer Center in Columbus, Ohio.

Tumors from smokers have a much higher total number of gene mutations, but mutations in a gene called EGFR are more frequently found in the lung cancers of never-smokers. Identifying this type of mutation is important, because patients who test positive for EGFR mutations or others, such as ALK alterations, can benefit from new lung cancer drugs that are specifically designed to “target” these characteristics. Unlike traditional chemotherapies, these targeted drugs are better at shrinking tumors with these specific mutations and come without most of the toxic side effects of chemotherapy.

Carbone says that never-smokers are far less likely to have their disease caught early, in part because “no one suspects it” and it “rarely presents symptoms” until it’s in the late stages. “You have a couple gallon milk jugs on each side worth of lung capacity, so a tumor can get to be pretty big before it causes any symptoms at all,” he says. Because symptoms of lung cancer like coughing, wheezing and shortness of breath are so similar to common illnesses, they are easily ignored by patients and misdiagnosed by physicians. “Most often people are diagnosed because of the symptoms from the disease having spread — a brain metastasis causing a seizure or bone metastasis causing pain &mdash; rather than symptoms from the tumor itself,” Carbone adds.

So, what can be done to catch these cancers early?

“Clearly, it does not make sense to do CT screening on an entire population of nonsmokers for lung cancer,” Wakelee points out. Instead, she says, “more research into additional screening tools, like molecular markers in the blood, sputum, urine — are needed.” These tests could help select people who are likely to benefit from low-dose CT screening or help identify those who’ve had positive low-dose CT screening tests who should undergo more evaluation.

Never-smokers are getting lung cancer more frequently, but detecting it at early stages is especially difficult.

Under the Radar: Detecting Lung Cancer Among Never-Smokers

As Karen Rak watched her sister die of lung cancer just three months after being diagnosed, she was scared that she, too, would suffer that fate. After all, the sisters had both been heavy smokers and, although Karen had long since quit the habit and was otherwise in good health, she knew her smoking history put her at high risk of developing the disease.

“I felt like a sitting duck,” says Rak, who is 75 years old.

Back then, about 10 years ago, there was no recommended screening for lung cancer. But there was a clinical trial a few hours from Rak’s home in Belfast, Maine, that was studying whether regular scans with low-dose computed tomography (CT) could detect lung cancer when tumors were still small enough to be curable. Rak didn’t hesitate to enroll.

“Anybody who has quit smoking just wants to make sure. In the back of their minds, they’re always wondering, if they have a cough or are sick, ‘Is this lung cancer?’ It was reassuring to be able to take a closer look,” she says.

As part of the trial, Rak had an annual CT scan beginning in 2006. All were normal until doctors noticed a suspicious nodule in 2012. A biopsy confirmed she had small cell lung cancer. At just 6 millimeters, Rak’s tumor was extremely small — something an X-ray could not have caught &mdash; and her cancer was treatable with surgery alone. Today, three years later, she remains cancer-free.

“I got the best outcome you could ask for. I’m a living, breathing example of why these screening programs work,” she says.

This year, an estimated 221,200 people will be diagnosed with lung cancer (either small cell or nonsmall cell) in the United States, more than with any other cancer except prostate and breast. Like Rak, most people diagnosed with lung cancer smoke or have formerly smoked, or had prolonged exposed to secondhand smoke. But few diagnosed with the disease will fare as well as Rak did.

Despite advances in treating the disease, lung cancer remains, by far, the most deadly of all cancers, surpassing the number of deaths among those with cancers of the colon, breast and prostate combined. Heather Wakelee, an oncologist and associate professor of medicine at the Stanford University Medical Center in California, says that’s because “the vast majority of lung cancers are diagnosed once the disease is in its advanced stages, when it’s hard to treat and a cure is very unlikely.”

Lung cancer, like some other cancers, often doesn’t produce symptoms until it has spread. Even when symptoms of lung cancer do appear — such as coughing or wheezing &mdash; they are so commonplace that many people may mistake them for other problems, such as allergies or a cold.

For instance, when non-small cell lung cancer is caught in its earliest stage, about half of all patients will survive for five years of more. But once the cancer has spread beyond the lungs to other parts of the body, reaching stage 4, those expected to survive five years plummets to just 1 percent.

“If we could diagnose a lot of these patients earlier, cure rates would improve tremendously,” Wakelee says.

There are colonoscopies to screen for colon cancer. There are mammograms to screen for breast cancer. Now, for patients who meet certain eligibility requirements, there is a screen for lung cancer. The hope associated with low-dose CT scans, says David M. Waterhouse, chair of the Department of Clinical Research at Oncology Hematology Care in Cincinnati, Ohio, is “to reduce the number of lung cancer deaths through the routine screening of those at highest risk of disease.”

As of April 2015, millions of Americans insured by Medicare have been eligible for free annual screening if they are between the ages of 55 to 77 years, have a 30 pack-year smoking history, and either currently smoke or have quit within the past 15 years. (A pack-year is calculated by multiplying the number of packs of cigarettes smoked per day by the number of years a person smoked. So, a 30 pack-year history means smoking a pack a day for 30 years, or two packs a day for 15 years, or three packs a day for 10 years, and so on). The U.S. Preventive Services Task Force recommends screening of this population, a move that has prompted most private insurers to also cover the cost of the scan.

These policy changes were based largely on the results of the National Lung Screening Trial (NLST), the largest randomized study of lung cancer screening in a high-risk population to date and one of the largest cancer screening trials ever mounted. Launched in 2002, the NLST compared two ways of detecting lung cancer: low-dose helical CT — often referred to as spiral CT or low-dose CT &mdash; and standard chest X-ray. Helical CT provides a three-dimensional image of the entire chest, while a standard chest X-ray produces a single two-dimensional image in which anatomic structures overlie one another. The three-dimensional image of the lungs generated by the helical CT is more likely than an X-ray to reveal a tumor at its earliest stage.

 As part of the study, 53,454 current and former smokers were randomized to undergo screening annually for three years with either CT or chest X-rays. Findings showed that those who received low-dose helical CT scans had a 15 to 20 percent lower risk of dying from lung cancer than participants who received standard chest X-rays, and that annual screening with low-dose helical CT scans could prevent three lung cancer deaths for every 1,000 people screened.

The lung cancers detected in their earliest stages by CT scan were most frequently non-small cell lung cancers; small cell lung cancers, which tend to be more aggressive, were infrequently found in early stages this way, according to the National Cancer Institute.

Could the benefits of screening extend to those who do not qualify for screening? After all, screening is limited to certain ages and heavy smokers. What about those who are too young or too old? And what about those who were only light or “social” smokers, or who didn’t smoke at all?

“We don’t yet have the data to support routine screening for anyone outside the parameters of the study,” Waterhouse says.

Absent these data, he says it’s key to adhere to the guidelines. That’s because all screenings tests, including those for lung cancer, come with risks.

“It’s important that the benefit of a screening test outweigh the risk and, for now, that is only the case for some patients,” says Waterhouse.

A lung cancer screening test, for example, can suggest that a person has lung cancer when he or she does not. This is called a false positive. False-positive results can trigger unnecessary follow-up tests that are invasive and stressful and could potentially cause harm. Over the three rounds of screening, about one in four people in the NLST who were monitored by CT had positive test results, and about one of every 15 scanned by X-ray tested positive for lesions, but nearly all of those positive results turned out be false. In most cases, this was confirmed by further imaging, rather than via invasive procedures such as biopsy, bronchoscopy or surgery, according to the NCI.

“The CT scan is so powerful that it can pick up nodules that may not be cancerous, sometimes resulting in increased anxieties or complications as a result of further diagnostics,” Waterhouse says.

Specifically, of the nodules found via screening in the study, more than 90 percent were benign. Of the patients who had benign nodules, 1.2 percent underwent an invasive follow-up procedure such as bronchoscopy or needle biopsy, researchers reported in a 2014 paper in the journal Cancer Control. A smaller 0.7 percent of study enrollees who turned out not to have cancer underwent even more invasive follow-ups: thoracoscopy, mediastinoscopy or thoracotomy, reported the authors, Prema Nanavaty and colleagues.

They noted that, although rare, some complications and deaths occurred in the NLST after follow-up imaging or more invasive testing conducted in response to positive screening results. Among patients with lung nodules but no cancer, five of every 10,000 experienced a major complication and four of every 10,000 died — more than the number of people screened by X-ray who experienced the same results.

For any prevention or screening test, the benefit (lives saved) must be balanced against harms (side effects and lives lost) to make sure that the pluses outweigh the minuses. Evaluating bodies including the USPSTF and the American Cancer Society have agreed that CT screening can be beneficial for the identified at-risk population.

Another concern is that radiation from repeated screening tests could cause harm, even though the radiation exposure is relatively low compared to that emitted by a standard X-ray. Furthermore, some people who are screened may end up needing additional CT scans, and thus being exposed to more radiation.

Still, Waterhouse is quick to point out that, for those who do fit the screening profile, “the test can be lifesaving.” 

Features

Screening with low-dose CT creates opportunities to detect lung cancer at earlier stages, when treatment is more likely to cure the disease.

Containing a Threat: Screening Creates Opportunity to Cure Lung Cancer

By a sheer stroke of good luck, on the day Matt Hiznay was diagnosed with stage 4 non-small cell lung cancer in 2011, the FDA approved a new type of targeted treatment called Xalkori (crizotinib). The drug was designed for patients whose tumors have a specific abnormality in a gene called ALK. Less than 7 percent of lung cancer patients possess the wayward gene, but Hiznay, then just 24, was one of them.

Hiznay took the drug twice a day without any chemotherapy or other treatments, and his cancer went into remission for almost a year. His response was typical: More than half of patients in the clinical trials for Xalkori responded well to the drug, which produced a median duration of response of 42 to 48 weeks. Hiznay’s cancer eventually developed resistance to Xalkori, but then he was able to enter a trial for another ALK-targeted drug, Zykadia (ceritinib). That drug helped control his cancer for several more months, after which he had traditional chemotherapy and radiation to keep the disease at bay.

In March 2015, Hiznay entered yet another trial, this one of an experimental drug, PF-06463922, which targets not only ALK but also another tumor abnormality called ROS1 (C-ros oncogene 1). Hiznay, now 28, is in remission again and earning his Ph.D. in molecular medicine at Case Western Reserve University in Cleveland. The drug is now in midstage trials. Hiznay says he has no side effects and will be on the drug indefinitely.

“Targeted therapies are here and more are coming, and that’s good,” Hiznay says. “I’ve been fortunate. If I had gotten cancer four or five years earlier, I wouldn’t have access to all these drugs.”

The rise of targeted treatments has significantly improved the outlook for patients who are in the late stages of lung cancer. The past few years have witnessed the discovery of ALK and several other genetic mutations that can drive non-small cell lung cancer (NSCLC), the subtype that accounts for 85 to 90 percent of all lung cancer diagnoses, according to the American Cancer Society. Unlike chemotherapy, targeted drugs have relatively mild side effects — Xalkori, for example, commonly causes fatigue and stomach discomfort that can be easily managed &mdash; so they can be taken over long periods of time to control the disease. Unfortunately, the majority of patients with NSCLC don’t have genetic mutations that will respond to targeted therapies. Patients without the mutations are generally treated with chemotherapy drugs such as cisplatin or carboplatin, sometimes in combination. Radiation therapy is sometimes used after chemotherapy to help eliminate stray cancer cells, although this happens less commonly in stage 4 lung cancers than in earlier-stage disease.

At the same time, immunotherapy drugs, medicines that free up patients’ immune systems to fight cancer, are showing promise in lung cancer. All of these new developments have greatly expanded the toolbox for oncologists, says Guneet Walia, senior director of research and medical affairs at the Bonnie J. Addario Lung Cancer Foundation.

“For the longest time, it was about controlling the disease. Now we can start talking about trying to cure it,” Walia says.

About 221,000 cases of lung cancer were expected to be diagnosed in 2015, with more than 80 percent of those occurring in patients over age 60. In 40 percent of cases, the cancer is already in stage 4 — meaning it has spread to the other lung or beyond &mdash; when it is diagnosed, at which point the five-year survival rate for patients is just 4 percent. The disease is more common in men than women, and African Americans are more likely to get lung cancer than any other racial group.

The discovery of genetic mutations that drive NSCLC is rapidly improving the outlook for some patients in stage 4. One of the first breakthroughs was the discovery of the EGFR mutation, which is present in about 10 percent of Americans who are diagnosed with the disease. Tumors with this mutation produce too much EGFR (epidermal growth factor receptor), which signals cancer cells to grow at a fast pace. EGFR-targeting drugs — which include Tarceva (erlotinib) and Iressa (gefitinib) &mdash; halt that signal, thus slowing down the rate of tumor growth.

Most lung cancer patients with EGFR mutations who respond well to targeted treatments develop resistance to the drugs after a year or so, Walia says. “The cancer finds other ways to grow,” she says. “But now there are newer drugs that can be used as second-line treatments, so patients have a Plan B.”

Scientists are also discovering particular mutations that cause drug resistance in lung cancer and learning how to target them. For example, on Nov. 13, the FDA approved Tagrisso (osimertinib) for patients with a specific EGFR mutation called T790M. It was approved for patients who relapse after being treated with a different EGFR-targeted drug. A similar drug called rociletinib (CO-1686) is in late-stage trials in patients with the T790M resistance mutation.

Certain subtypes of NSCLC have genetic abnormalities that can now be detected with diagnostic tests. Some patients with the non-squamous form of the disease have the ROS1 mutation, which predicts a good response to drugs that were developed to target ALK mutations, seen in 2 to 7 percent of patients with NSCLC adenocarcinomas. The ROS1 mutation is rare — fewer than 1 percent of tumors test positive for it &mdash; but identifying those patients can be important for choosing the right therapy, says Gregory Masters, an oncologist at Christiana Care Health System’s Helen F. Graham Cancer Center in Newark, Delaware, and co-chair of an American Society of Clinical Oncology (ASCO) panel that recently revised the guidelines for treating NSCLC. “Many of us are now ordering this test even though it’s a very small group of patients,” Masters says.

Targeted treatments have proven so effective that it has now become standard practice for patients to have their tumors genetically sequenced as soon as they’re diagnosed. The 10 percent or so of patients with NSCLC who are eligible for targeted treatments are put straight on them. Chemotherapy only comes into play for patients who don’t test positive for targetable mutations or who stop responding to the new drugs. “Now that we have drugs that target certain mutations, we have a better chance of controlling the disease for a longer time,” Masters says.

Immunotherapy drugs promise to extend survival in stage 4 lung cancer even further. The idea behind these drugs is to block “checkpoints” that prevent the immune system from recognizing and destroying cancer cells. Checkpoints exist naturally to keep the immune system from being overactive and damaging normal tissue. In 2015, the FDA approved two checkpoint inhibitors for the treatment of lung cancer: Opdivo (nivolumab) and Keytruda (pembrolizumab). Both inhibit an immune checkpoint called PD-1 and are approved for patients with NSCLC who have stopped responding to chemotherapy.

People who never smoked are more likely to harbor EGFR mutations and ALK rearrangements that can be targeted. By contrast, smokers or ex-smokers are more likely to have many random mutations induced by tobacco carcinogens. There are more of these patients than those who have targetable mutations, and they seem to be responding particularly well to immunotherapy treatments, perhaps because smoking-related mutations make the tumor cells more recognizable by the immune system. “We’re still learning why that is, but it may be that the more mutated the tumor, the more likely the immune system is to recognize it as foreign,” Masters says.

In trials, patients on Opdivo had a 40 percent reduced risk of death compared with those on chemotherapy. With Keytruda, oncologists can use diagnostic testing to predict which patients will respond best to the drug. In trials, 41 percent of patients who tested high for PD-L1 — a protein that binds to PD-1 &mdash; responded well to the drug. Both drugs are useful in either squamous or non-squamous NSCLCs. 

 In September, Bristol-Myers Squibb, which makes Opdivo, presented more evidence that the drug works in non-squamous NSCLC when it released results from a trial showing that 39 percent of patients who took Opdivo were still alive after 18 months, versus 23 percent who took the commonly used chemotherapy drug docetaxel.

Some oncologists believe that the longer these immunotherapies are used, the longer the survival benefit will be for some patients. “It seems a small group of patients may have a very durable response,” says Giuseppe Giaccone, associate director for clinical research at Georgetown Lombardi Comprehensive Cancer Center. In melanoma, for which these drugs were first approved, some patients have responded to immunotherapy drugs for as long as five years, he says.

Drugs that inhibit the immune checkpoint PD-L1 are also under development for NSCLC, including atezolizumab (MPDL3280A), which was granted “breakthrough therapy” designation, a type of priority review, by the FDA in February 2015.

Stephan Silverman, 73, who was diagnosed with stage 4 lung cancer in November 2014, is in a trial of atezolizumab at Georgetown. His treatment consisted of 12 sessions of chemotherapy, followed by the immunotherapy every three weeks. Silverman, a retired school psychologist, says his primary tumor went from the size of a peach to the size of a cherry tomato, and his lymph nodes are now clear of cancer.

Silverman will stay on atezolizumab indefinitely, and says he’s not aware of any significant side effects. “I feel like I’m 80 percent,” he says. “I walk more than I did before, I gained weight. I’m grateful to the immunotherapy for saving my life.”

Now oncologists are testing combinations of immunotherapies in NSCLC in the hopes that activating the immune system from more than one angle will amplify the positive response. One idea currently being tested is to combine PD-1 inhibitors with drugs that block another immune checkpoint called CTLA-4. A late-stage trial of Opdivo plus Yervoy (ipilimumab), which inhibits CTLA-4, is currently underway in lung cancer, as is a combination of durvalumab (an anti-PD-L1 drug) with tremelimumab (an anti-CTLA-4 agent).

“Anti-CTLA-4 antibodies work to prime the T cells within lymph nodes, and anti-PD-1 or anti-PD-L1 antibodies work directly within the tumor, so combining these agents makes sense,” says Naiyer Rizvi, director of thoracic oncology and immunotherapeutics at Columbia University. “Combinations of CTLA-4 and PD-1 have clearly shown a benefit in melanoma. The question of whether you can use combinations to drive the immune system harder is now being studied in lung cancer.” Although more immune side effects can be expected with this more aggressive immunotherapy combination treatment, the preliminary studies with these combinations show a nearly doubling of response rate in NSCLC.

Rizvi adds that, because the side effects of these immunotherapies are relatively minimal and easily managed, they offer hope to many patients who might not have been able to be treated before. Similar to targeted drugs, immunotherapies typically produce side effects such as fatigue and stomach upset.

“About a quarter to a third of lung cancer patients who are newly diagnosed don’t even get to chemotherapy, because they are too sick and they can’t tolerate it,” Rizvi says. “But that paradigm doesn’t really apply to immunotherapy. These drugs are not that difficult to take, and we see activity in a broad range of patients.”

Immunotherapy is also proving useful in treating the squamous cell form of NSCLC, which affects about 25 percent of all patients and is most common in smokers. In two late-stage studies presented in 2015, Opdivo extended median overall survival (OS) rates for patients with this form of the disease by two to three months over docetaxel. In the larger of the two studies, the OS rate at an 18-month analysis was 28 percent with Opdivo versus 13 percent with docetaxel in previously treated patients with squamous NSCLC.

Another major development in lung cancer research has been an increased understanding of which chemotherapies and targeted treatments are most effective in subsets of patients at specific junctures in their treatment regimens. For example, the revised ASCO guidelines for treating NSCLC specify that, in second-line treatment settings, patients should be given docetaxel or, if they are EGFR-positive, Tarceva or Iressa.

The ASCO guidelines also specify that patients with non-squamous NSCLC are more likely to respond to treatment combinations that include the chemotherapy drug Alimta (pemetrexed), Masters says, while patients with squamous cancer are less likely to respond to that drug. “If you have non-squamous lung cancer but you don’t have a genetic mutation and you’re looking at chemotherapy, the combination of a platinum drug and pemetrexed is now the number-one choice,” Masters says.

Alimta is also now recommended as a standalone treatment for controlling non-squamous NSCLC after initial treatment, and though it has some of the side effects common in traditional chemotherapy, such as low blood counts, it has proven to be far less toxic than platinum-based chemotherapies. “It improves our ability to control those cancers,” Masters says. “It’s not curing the cancer, but we can treat those patients with maintenance chemotherapy and continue just the pemetrexed by itself and add to their quality of life.”

In small cell lung cancer (SCLC), which accounts for 15 percent of diagnoses and usually progresses very rapidly, there has been little progress in discovering and developing targeted treatments. The standard of care is chemotherapy and radiation, which is often used in a palliative setting. Although these treatments can be quite effective in the short term, most patients relapse within a few months.

That’s why oncologists are encouraged by early trials of immunotherapy treatments in small cell lung cancer. In one 2015 study, Keytruda was well tolerated in patients with PD-L1-positive SCLC and the response rate was 35 percent, though all the responses were partial. Another study testing a combination of Opdivo and Yervoy produced an overall response rate of 17 percent.

Some trials are now looking at the effectiveness of adding radiation to immunotherapy, in both small cell and non-small cell lung cancer. The idea is to use the radiation to release more tumor “antigens,” which are biological markers on tumor cells that trigger immune responses. “Radiation can also be a form of immunotherapy, so there has been a lot of interest in looking at combinations,” Rizvi says.

While oncology research is still a long way from a cure for late-stage lung cancer, the physicians treating the disease are optimistic that new treatments will help their patients to enjoy longer, more comfortable lives with the disease. “We have the potential to treat more people with lung cancer now,” Rizvi says, “and that’s really important.”

Targeted drugs, as well as immunotherapies, are beginning to change the treatment outlook for people with advanced non-small cell lung cancer.

Hitting a Target in Advanced Non-Small Cell Lung Cancer

Jenny White had doused the bathtub tiles at her home in Nashville, Tennessee, with an ammonia-based cleaner when she noticed a mold stain on the ceiling. She spritzed some bleach on the stain. As she waited for the bleach to soak in, she started coughing. So she opened a window. Then she coughed some more. She pulled her T-shirt up over her nose. But the coughing and wheezing had become unbearable. Still not quite right the next day, White went to see her family doctor. The doctor ordered a chest X-ray to rule out chemically induced pneumonia from the toxic cocktail of ammonia and bleach she had inhaled.

White didn’t have pneumonia, but the X-ray revealed a spot on her right lung that the doctor wanted to monitor through quarterly CT scans for the next two years.

“If, at the end of that two-year period, what you’re watching has not grown, then they call it a benign calcification,” White says. This was 2009. A September 2010 scan revealed that the spot on her lung had grown by 30 percent. It would have to be removed.

JENNY WHITE was treated with surgery and a targeted drug for her stage 1a lung cancer. [PHOTO BY SARAH BAILEY]

A minimally invasive surgery found that 49-year-old White had stage 1a non-small cell adenocarcinoma in the upper lobe of her right lung. When found at all, early-stage lung cancers like White’s are typically discovered by chance after a doctor orders a chest X-ray for some other reason. But low-dose spiral computed tomography (CT) now makes it possible to screen people at high risk for lung cancer before they ever show signs or symptoms, something that is recommended by the U.S. Preventive Services Task Force and is being widely taken up by the health care community. As cases are detected earlier, doctors have more opportunities to offer potentially life-saving treatments through improved surgery and radiation techniques and new drugs.

Until recently, detecting lung cancer at an early, more treatable stage was a rare or chance event. Symptoms of lung cancer — such as coughing or chest pain – that would prompt a doctor to order a chest X-ray are usually the signs of more advanced disease.

“Once the patient has symptoms from the cancer, their cure rates go way down, and we don’t really have a good marker to identify those folks earlier,” says Corey Langer, director of thoracic oncology at the Hospital of the University of Pennsylvania.

A chest X-ray can detect a tumor on the lung about the size of a dime. The newer screening technique of low-dose spiral CT can find tumors the size of a grain of rice. Using CT scans instead of X-rays could reduce lung cancer mortality rates by up to 20 percent in those screened.

In a study of 53,000 heavy smokers between the ages of 55 and 74, researchers compared the lung cancer mortality rates of those who underwent routine chest X-rays to those who had low-dose spiral CT scans. About one in four CT scans came back positive for abnormalities that could be lung cancer, while only about one in 15 X-rays raised such red flags. Over about seven years of observation, the CT group saw three fewer deaths per 1,000 screened than the X-ray group. 

 But the screening method is not perfect. With spiral CT, like chest X-ray, about 95 percent of positive results turn out to be false. Although some of these are resolved with additional and follow-up imaging, many undergo surgery for a benign lesion. According to the Mayo Clinic, 15 to 25 percent of surgeries done as follow-ups to positive CT scans reveal benign lesions. Also, for now, only heavy smokers on the order of a pack a day for 30 years or more are eligible for the screening.

“What about the 20 percent who get lung cancer who never smoked, or those who have less than 30 pack-years? We don’t have proof of a screening technique in those individuals,” Langer points out.

The scan also rarely detects small cell lung cancer, which accounts for about 15 percent of lung cancers, grows and spreads more quickly than non-small cell, and is more often caused by smoking.

Doctors seldom diagnose small cell lung cancer early enough that it can be removed through surgery. It is typically diagnosed at either limited or extensive stage. Limited-stage small cell lung cancer is found in only one lung and the nearby lymph nodes. Extensive stage has spread to other parts of the chest or other parts of the body.

“Unfortunately, the treatment options for small cell remain the same in 2015 as they were in 2005 and 1985,” Langer says.

People with limited-stage disease typically receive a combination of chemotherapy and radiation. The standard chemotherapy drugs in this case are etoposide and cisplatin. For extensive-stage disease, people usually receive the same chemotherapy regimen but without radiation. Because lung cancer often spreads to the brain, people who respond to chemotherapy may, after finishing that regimen, receive preventive radiation to the brain.

“Limited small cell is curable — at least for a quarter to a third of patients,” Langer explains. “Concurrent chemo and radiation can result in long-term and meaningful survival.”

While little has changed in the treatment landscape for this form of lung cancer, a targeted therapy may one day improve survival rates for some people. Targeted drugs can shut down a step in the process of cancer development. In an early trial, rovalpituzumab tesirine (Rova-T) has proven to destroy small cell lung tumor-initiating cells that are positive for the DLL3 protein, potentially creating a new treatment option for patients whose small cell lung cancer progresses or recurs after initial therapy.

Also being explored in the clinic are additional targeted drugs, such as the tyrosine kinase inhibitor Iclusig (ponatinib), which is approved for use in leukemia; drugs that stop blood vessel growth to tumors such as Avastin (bevacizumab); and immunotherapies, including vaccines and a drug already approved in non-small cell lung cancer that frees up the body’s own immune system to fight cancer, Opdivo (nivolumab).

Non-small cell lung cancer accounts for about 85 percent of lung cancers. The roughly 10 to 20 percent of lung cancers that develop in non-smokers, like Jenny White, are more often non-small cell.

Adenocarcinoma, the kind of non-small cell lung cancer White had, is the most common form of lung cancer. Though most people who get this and other lung cancers are smokers or former smokers, when non-smokers do get lung cancer, it’s usually adenocarcinoma. This form of the disease, which develops on the outer parts of the lungs, grows more slowly than other forms, so it’s more likely to be found before it spreads beyond the lung. Squamous cell — or epidermoid – carcinoma grows inside the bronchial tubes. Large cell carcinoma describes nonsmall cell lung cancers that are neither adenocarcinomas nor squamous cell carcinomas. They grow and spread more quickly than the other non-small cell lung cancers.

Doctors typically describe cancer stage by its TNM classification: T for the size of the tumor, N for the extent to which the lymph nodes are involved, and M for whether the cancer has metastasized, or spread, to other parts to of the body. Earlystage lung cancers are N0 or N1, because they may only include the nearby lymph nodes, and M0 (zero) because they have not metastasized.

Non-small cell lung cancers in stages 1a or 1b that have not spread to the lymph nodes (N0) and in which the tumor is no larger than 4 centimeters (T1-T2a) may be cured with surgery alone. Several minimally invasive options exist for these cancers.

White had video-assisted thoracoscopic surgery (VATS). In VATS, the surgeon inserts a tiny camera into the chest. The target area, either for biopsy or excision, is shown on a monitor so that the surgeon can remove the tissue through tiny incisions. Should surgeons need to remove any lymph nodes that the cancer has reached, they can do so through VATS as well.

Minimally invasive robotic surgery may also be an option. In this method, the surgeon sits at a console near the patient and operates the surgical instruments with controls. Studies have shown that this surgery is as effective as VATS.

“Although the incisions are small, it’s been difficult to show that the outcomes are actually better than in more conventional surgery,” says Jack Roth, chief of thoracic molecular oncology in the Department of Thoracic and Cardiovascular Surgery at MD Anderson Cancer Center in Houston, Texas.

That’s in part because even conventional open thoracic surgery is less invasive than it once was, Roth says. “It’s now done without cutting muscles and without cutting ribs,” he says. “Everything has moved in the direction of less invasion for the patient, less tissue destruction and better pain management.”

Not all lung tumors are operable. Traditionally, doctors have recommended radiation for tumors that cannot be removed due to their size or location or for patients who are not healthy enough for surgery. Over the last 10 years, a newer form of radiation therapy, called stereotactic ablative radiotherapy (SABR), has been shown to be a more efficient alternative to traditional radiation for people with inoperable tumors. It can deliver an extremely high dose of radiation directly to the tumor while applying very little radiation to the surrounding healthy tissue.

“Low-dose radiation beams come in from multiple directions and converge on the tumor, while the normal tissue is spared,” says Roth. 

 This year, Roth co-led a small clinical trial, including 58 patients, that showed that SABR was as effective as, and perhaps better than, surgery in treating small tumors in stage 1a lung cancer. Larger trials to test this concept are in the works.

Stage 2a and 2b lung cancers include tumors larger than 7 centimeters (T3) that have not spread to the lymph nodes (N0) or tumors up to 7 centimeters (T1a — T2b) where cancer may have spread to the nearest lymph nodes (N1).

For lung cancer at these stages, doctors may recommend four rounds of chemotherapy after surgery. This is called adjuvant chemotherapy, and it’s intended to help prevent recurrence. Doctors usually prescribe a platinum-based drug, such as cisplatin or carboplatin, and one other drug or “partner agent.”

“In early-stage, curative treatment, the data support cisplatin over carboplatin,” Langer says. “I will only use carbo if the patient is not up to cisplatin.” Of the two drugs, cisplatin is known for more severe side effects, including nausea, vomiting, nervous system damage, kidney damage, hearing loss, and reduced production of red blood cells, white blood cells and platelets.

Typical partner agents include paclitaxel, docetaxel, gemcitabine or vinorelbine. Some doctors recommend Alimta (pemetrexed) instead of other partner drugs for adenocarcinoma of the lung.

While later-stage lung cancers are often found because patients have symptoms, some stage 3 disease is found through screening. Treatment for stage 3 cancers involves a multi-modality approach, but can vary quite a bit depending on individual details. It can include surgery and a targeted drug, or various combinations of chemotherapy, radiation and/or surgery.

Doctors can analyze the genes in tumors removed through surgery to predict whether patients will benefit from particular drugs. In a group of ongoing trials, known together as ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials), researchers are exploring the benefits of targeted drugs already approved for later-stage lung cancers in people with earlier-stage disease. In two of the ALCHEMIST studies, researchers want to learn whether the targeted drugs can prevent or delay lung cancer recurrence in those who have undergone treatment for earlier stages of the disease.

The trials include patients whose tumors were completely removed at surgery and who have completed any post-surgery chemotherapy or radiation that their doctors prescribed. In one trial, participants’ tumors have a specific abnormality of the ALK gene, which experts believe plays a role in cancer growth. About 5 percent of people with certain types of non-small cell lung cancer have tumors with this particular gene defect. In this trial, participants receive either placebo or Xalkori (crizotinib) — a drug that blocks the cancer-promoting activity of the ALK abnormality.

Another component of the trial includes people whose tumors have a known mutation of the EGFR gene, which may also play a role in cancer growth. Participants in this trial receive placebo or Tarceva (erlotinib), which blocks EGFR activity.

White’s tumor had the relevant EGFR mutation, and her doctor prescribed a regimen similar to that in the ALCHEMIST trial, although it is not considered standard. White took Tarceva for six months after her surgery to eliminate any microscopic cancer cells that may have been left behind after her surgery, she says. While the drug itself didn’t bring White any serious side effects, she was not allowed to take her acid reflux medication while she was taking the targeted therapy.

Immunotherapy for Early-Stage Non-Small Cell Lung Cancer

“I was pretty miserable from GI upset during that time,” she recalls. Today, White remains cancer-free.

Soon ALCHEMIST will be amended to offer immunotherapy drugs to those who did not have one of the genetic abnormalities necessary to receive Xalkori or Tarceva. Study participants will be randomly assigned to receive Opdivo (nivolumab), a drug already approved for advanced non-small cell lung cancer, versus observation, says Langer, who is an investigator on the trial.

Opdivo blocks PD-1, a protein found on immune cells that serves as the brakes for the immune system. The immune system attacks foreign cells that pose a threat. PD-1 prevents the system from flaring up and attacking every innocuous unknown cell it encounters. Many cancer cells take advantage of this brake system and carry a corresponding protein, PD-L1, that signals immune cells to put on the brakes and let the cancer cells slip by. Opdivo takes the foot off these PD-1 brakes, unleashing the immune system on cancer cells.

Studies suggest that every lung tumor should be genotyped after removal, and some cancer centers are following suit. “We try to use genomic testing on all the patients where we have tumor available. Certain types of treatment are dictated by genomic results,” says Roth.

New detection techniques help diagnose lung cancer when it’s at a far more curable stage, but surgery and radiation alone do not cure everyone. Targeted and immune therapies at these stages may lead to more cures.

“In early-stage lung cancer, the majority of patients are cured, but there’s still about 30 percent of patients whose tumors recur and who, as a result, ultimately die of their disease,” Roth says. “We still have room for improvement in treating early-stage lung cancer, with systemic agents, not just surgery and radiation therapy.” 

Until recently, detecting lung cancer at an early, more treatable stage was a rare or chance event.

Better Detection, Surgery, Systemic Therapies Improving Cure Rates in Early-Stage Lung Cancer

Curt Hammock, 67, found out he had stage 3b lung cancer on his birthday, Jan. 10, in 2011. “I just wanted some socks, but I got cancer instead,” he quips.

Hammock had tumors in his neck and one lung. But because treatment for stage 3 lung cancer is the least straightforward of all stages, it was a month or so before he began treatment.

“There were huge discussions about what to do, because I had two tumors at the same time,” remembers Hammock, a retired auto parts distributor.

Hammock’s experience is typical of stage 3 patients, doctors say. Stage 3 lung cancer: It’s complicated.

Most lung cancer patients are diagnosed at advanced stages, about 30 percent of them at stage 3, which can also be described as “locally advanced disease.” Another 40 percent get diagnosed at stage 4, when the cancer has metastasized to other organs.

After his diagnosis with stage 3 lung cancer, CURT HAMMOCK waited a month as doctors considered his many possible treatment options. [PHOTO COURTESY OF CURT HAMMOCK]

Lung cancer, including both small cell and non-small cell, is the second most common type of cancer in both men and women. The average age at diagnosis is about 70. The disease accounts for 27 percent of all cancer deaths, more than all breast, prostate and colon cancer deaths combined.

Yet while oncologists are generally united about how to treat early-stage lung cancer (aggressive treatment in hope of a cure) and late-stage lung cancer (palliative care to keep the patient comfortable, but with no hope of cure), there’s less agreement about how to handle stage 3 cases.

Doctors wrestle with questions such as: How aggressive should the treatment be? Should these patients be encouraged to try clinical trials, one possibility recommended by the National Cancer Institute, because a relatively small percentage will survive with conventional treatments? If new techniques make surgery an option for stage 3 patients, will that surgery make a difference? In what order should treatments be administered? Which doses of chemotherapy and radiation are most effective? What balance should there be between quality of life and the effectiveness of treatment? 

 “Stage 3 is the most controversial disease we have in lung cancer,” explains Jyoti Patel, a thoracic oncologist at Northwestern University’s Feinberg School of Medicine. “There is wide variation in these patients. Some may only have microscopic lymph involvement. Others may have large nodes that are causing symptoms like shortness of breath. And yet we lump all these patients together. One size definitely does not fit all. Treatment has to be personalized for your stage and your body.”

It’s more common than not for stage 3 patients to receive two or more kinds of treatment, what doctors call “multimodality therapy.” However, since stage 3 patients can vary so widely when it comes to their disease characteristics, it’s been difficult to devise studies that would make general recommendations possible, according to a 2013 review in the journal Chest. The paramount goal in treating stage 3 patients, the review says, is to eradicate the visible disease in the chest and reduce the incidence of metastases elsewhere in the body.

Patel advises patients that the most important thing is to get a biopsy to make absolutely sure that their disease is stage 3, cancer that has spread from the lungs to lymph nodes in the chest. If only lymph nodes on the same side of the chest as the primary cancer are involved, that’s considered stage 3a. If disease has spread to the neck or to lymph nodes on the opposite side, that’s considered stage 3b.

Stage 3 refers to non-small cell lung cancer (NSCLC) cases. Small cell lung cancer, which accounts for 15 percent of cases, is divided into “limited stage” (all within the chest area) and “extensive stage” (spread beyond the chest). Treatments for the two types are similar, involving chemotherapy, sometimes radiation therapy and rarely surgery, but are distinct from treatment strategies for NSCLCs.

Of those diagnosed at stage 3a, about 27 percent will be alive five years later. Of stage 3b patients, 10 percent will survive to the five-year mark. It’s important to remember, though, that many, many factors play into survival rates: overall health, other health conditions, gender, race, age and how well treatment is tolerated.

Surgery is often part of a stage 3 treatment plan. In the past, surgery was only possible for stage 3 patients if their disease had not spread very far. The chest is complex, and tumors are often close to vital organs such as the superior vena cava (the large vein that carries oxygen-depleted blood to the heart), the trachea (windpipe) and the esophagus. The location of stage 3 disease makes it difficult to remove cancers without damaging other organs, and difficult to get disease-free margins in the tissue removed.

Today, advances in imaging (PET scans) and minimally invasive techniques (doing an operation through small incisions rather than opening up the chest) have made it possible to remove some tumors that might have been inoperable a decade ago.

Nevertheless, the effectiveness of surgery for stage 3 patients remains largely unclear.

The characteristics of stage 3 lung cancer can vary widely, leaving patients and their doctors to wrestle with questions about how best to treat the disease.

Lung Cancer Special Issue | CURE