Chapter 11

Getting Personal with the Lungs

The lung is a wonder of cellular movement and cooperation. Lung cells participate in an elaborate system of communication in order to carry out their twofold mission: to keep air moving freely through the branching network of tubes while keeping noxious material out of that network. The lung’s complex defenses consists of goblet cells, which secrete mucus to trap invaders, and ciliated cells, topped with tiny hairs that beat in unison to drive the mucus-coated intruders out. Unwanted dust, bacteria, and viruses are removed from the lungs on a kind of conveyor belt, designed for the removal of debris, that carries unwanted material back into the atmosphere, where it is generally harmless.

This whole defense system, known as the mucociliary escalator, does an enormous amount of work, and all this work produces a lot of “cellular turnover,” that is, cell death and regeneration. Cellular turnover occurs in all organs, but the rate of turnover varies widely throughout the body. On one end are the organs with very high turnover rates, such as the bone marrow, breast, and gastrointestinal tract, while at the other end are the organs with very slow turnover rates, most notably the brain and heart. The lungs sit exactly in the middle of this scale, with a moderate rate of cellular death and regeneration.

Normally, higher rates of cellular turnover lead to greater potential for error, increasing the likelihood a cell will mutate. This is why tumors of the breast, colon, and bone marrow are quite common, while those of the heart and brain are less so. Historically, this pattern has not held for the lungs, which, prior to the twentieth century, were exceptionally resistant to developing cancers despite having a moderate rate of cellular turnover.

This, unfortunately, began to change at the beginning of the twentieth century, and one story drives this point home. In 1919, future thoracic surgeon Alton Ochsner was a medical student at Washington University in St. Louis. He had a love of the heart and lungs, and so when the entire class was invited to see the autopsy of a death from a rare lung disease, he jumped at the opportunity. The chief pathologist, Dr. George Dock, assured the class that it would be worth their time; this was a disease they would likely never see again. That day they would be doing an autopsy on somebody who had died from lung cancer.231

Sadly, as we know, this has changed. Today, lung cancer kills more people each year than the next three deadliest cancers combined. We know the cause well—with the advent of widespread cigarette smoking we have changed the lung from something almost immortal into something quite mortal. Some one hundred years into this malignant experiment, we must now put an end to it. Fortunately, there are signs we can, especially with our advancing knowledge of personalized medicine.

Late one afternoon in 2014, my team received a phone call from the primary medical team taking care of Glenda Abney: she was a middle-aged African American woman who presented to the hospital with pain in her chest, which proved to be caused by a large mass in her lung. I sat down at a computer with the fellow and looked at Glenda’s X-rays. What I saw was not pretty—a big, jagged mass of white in the middle of the lung. A jingle ran through my head—the rumor is tumor, the issue is tissue—meaning, we think it’s cancer, but we need a biopsy. A third verse completes the rhyme in most cases: And the answer is cancer.

Even though I’d done this exact same consult hundreds of times, I rehearsed what I was going to say in my mind before entering the room. I told Glenda she had a spot on her lung and she needed a biopsy. Her reaction, like all reactions, was unpredictable. For Glenda, it was not one of panic, or a million questions, or even a moment of regret. She just looked up at me, her eyes firm and resolute, and said, “Well, doc, we gotta do what we gotta do. So let’s get it done.”

I left the room and went to document our conversation in the chart. As I wrote, the frustration and anger that comes over all lung doctors faced with an almost certain cancer diagnosis came over me. We have failed these people on a very deep level. And almost always, because of the nature of lung cancer, there is no easy solution.

A day after I had the conversation with Glenda about the mass in her lung, I stood in the surgical suite watching my fellow numb-up Glenda’s nose and throat with lidocaine so we could stick a camera into her lungs and get our biopsies. Glenda’s demeanor hadn’t changed in the twenty-four hours since I had met her. She still answered my questions in succinct sentences, not revealing any emotion behind them. This was unusual to me. Most patients facing a cancer diagnosis exhibit some level of fear, or anger, or distrust. But not Glenda.

The thin camera went into her nose, back into her throat, and then hovered over her vocal cords. We sprayed some lidocaine over them, then dipped the camera through her trachea and deeper into her lungs. The camera cannot go very far, and what we could see in the large airways looked unremarkable. I had the fellow put the camera in the area where we thought the cancer was, based on the CT scan, then we turned on the X-ray machine to illuminate her lung. There, in an instant, the mass sprang into view, a sinister, white, jagged ghost within the dark lung. We got out our biopsy forceps and threaded them out into the deeper part of the lung, where the mass could be seen on the X-ray machine, and pulled some tissue out.

I saw Glenda back in the office a few days later. Sitting in a chair, hands calmly folded in her lap, she patiently awaited my arrival. I wasted no time telling her what the pathologist had already told me—she had lung cancer. She took the news exactly the way I thought she would, the exact opposite of the way most patients do: “Well, I think I’ve got a few more years left, so let’s go ahead and do what we gotta do, doc.”

I told her she would need a PET scan to look for any other disease in her body. I told her I didn’t know if she was a surgical candidate, but we were going to explore every option.

“That’s about what I thought, doc,” she replied.

With those words she summarized what I believe most lung cancer patients are thinking when they get diagnosed. They have been smoking a long time, and the risk to their lungs is no secret. Glenda also clearly understood this. We got her the best care available, and she did well initially, but eventually, like most lung cancer patients, she passed from her disease, and way too young.

Dr. George Dock’s 1919 prophecy that Alton Ochsner wouldn’t see another case of lung cancer proved accurate until 1936, when then–Dr. Ochsner saw his next case. Shortly thereafter he saw another, and then another—nine cases in six months. Most of them were World War I veterans, products of the era during which the mass marketing of cigarettes to soldiers took hold. With the power to alleviate stress and boredom, cigarettes came to be seen as part of America’s arsenal during World War I, prompting American General John Pershing to state in 1917, “You ask me what we need to win this war. I answer tobacco, as much as bullets.”232

Dr. Ochsner quickly made the connection between smoking and lung cancer, writing presciently to a colleague in 1939: “In our opinion the increase in smoke with the universal custom of inhaling is probably a responsible factor [in the increase in pulmonary carcinoma], as the inhaled smoke, constantly repeated over a long period of time, undoubtedly is a source of chronic irritation to the bronchial mucosa.”233

Between 1930 and 1964, the voices on the side of science and medicine were loud and clear regarding the possible connection between smoking and lung cancer, but the voices on the side of the tobacco industry were just as loud in opposition. It was an ongoing debate in the minds of most Americans, which was finally resolved by two experts from London, physician Richard Doll and statistician Austin Hill. Dr. Doll was a smoker himself, and along with Austin Hill in the late 1940s, he was given the task of trying to understand the extraordinary increase in lung cancer cases seen in London’s hospitals during the preceding twenty years.

Some blamed tobacco smoke, others pollution from cars, dust from the new asphalt roads, and smoke from industrial plants. Previous studies had been published tying smoking to lung cancer, but none had had enough statistical rigor to hold up to scrutiny. In order to definitively settle this debate, Dr. Doll and Austin Hill employed a case-control study, a simple but powerful analysis that helps define risk. They were one of the first to use it, and its impact on our thinking about the effects of tobacco was profound.

They set up their study by asking twenty hospitals in London and the surrounding area to report any case of lung cancer admitted to the hospital. Their group would then interview the patients about prior occupations, exposures, and habits, including smoking. But then—and this is what set their study apart—they would put those same questions about exposure to age- and gender-matched control subjects admitted to the hospital at the same time for other reasons. With this study, Doll and Hill moved the analysis of lung cancer out of the realm of the observational and into the realm of rigorous epidemiology.

Between April 1948 and October 1949, their team interviewed 709 patients with lung cancer, and then 709 patients without lung cancer who served as controls. They then created a table comparing the gender ratio within the groups, along with comparisons of their age, place of residence, and socioeconomic status. All of this was an attempt to control for the elements of observation that can happen by chance.

The results Doll and Hill reported in their 1950 paper were conspicuous.234 A few of the patients were lost to incomplete follow-up, leaving 649 subjects in each group. In both men and women, the difference between those who had lung cancer and those who did not was the consumption of cigarettes. Everything else was similar—their age, their exposure to road dust, industrial plant smoke, and pollution from cars. The only thing that was divergent was the smoking, and using statistics, Doll and Hill proved this was not because of chance. They also showed an increased incidence based on the total number of cigarettes the patient had smoked in the past, again bolstering their hypothesis that exposure (smoking) leads to disease (lung cancer).

Word of Doll and Hill’s findings spread around the world, including to the tobacco industry. Interestingly, the tobacco companies did not attack the science themselves, understanding that science and physicians were held in high regard. Instead, they hired pro-tobacco physicians to put out statements refuting claims of a correlation, and they formed the Tobacco Industry Research Committee, in December 1953, to begin publishing (selective) studies of their own. A decades-long battle ensued between science, the government, and the tobacco industry, until the truth that Doll and Hill had uncovered would be completely accepted.

In the nineteenth century, the famous German pathologist Rudolf Virchow articulated the Latin phrase omnis cellula e cellula, or “all cells from cells.” This dictum certainly holds true for cancers, which start out as a single cell that both lives longer and divides faster than the other cells in the body. The offspring of this cell also inherit these belligerent traits, and over time they crowd out the normally functioning cells of the organ they originated in, and then often jump into the bloodstream to seed another organ, in a process known as metastasis.

Lung cancer is one of the most lethal diseases because of how rapidly these cancer cells can grow and divide. Within the world of cancer, some are much more aggressive than others. In regards to lung cancer, the cells are on the biological equivalent of steroids, angrily dividing and growing in rapid fashion. Because of this, 80 percent of patients initially come to their physician with stage III or IV disease, both of which are very advanced.235 The average five-year survival rate for a new lung cancer diagnosis is about 18 percent, significantly lower than breast cancer at 90 percent and even colorectal cancer at 65 percent. Even for those with early-stage lung cancer, which is operable, the survival rate at five years is about 56 percent.236

In contrast to lung cancer, the cells of colon cancer grow slowly, and it can be effectively monitored. At first, it’s a premalignant lesion, then a small local cancer, then it moves to local lymph nodes. A colonic lesion takes a predictable amount of time to grow, and at each point there is an opportunity for surveillance and intervention. Get your colonoscopy every ten years—for those at high risk, every five years. Lung cancer is the opposite. Over half of lung cancer patients present with metastatic disease. One year one’s chest X-ray can be completely clear, and then twelve months later a doctor is explaining that the pain in one’s chest is from a mass in the lung and the cancer may have metastasized to one’s spine and brain.

This biology makes lung cancer by far the leading cause of cancer death for both men and women in the United States, with about 160,000 deaths per year, far outpacing the 40,000 breast cancer deaths every year and the 28,000 deaths from prostate cancer. Lung cancer causes more deaths per year than colon, breast, and prostate cancer combined.237

We are, as a species, influenced by emotion, so it’s understandable that the ratio of scientists to patients with pediatric leukemia is very high compared to the ratio for other diseases. Since lung cancer is the number one cancer cause of death, some correlation with the level of federal funding for research would be expected. In fact, however, lung cancer receives about one-half the funding of breast cancer, although it has a four-times higher death rate.238 Indeed, lung cancer is the stepchild of cancers, the least talked about and least recognized, with the most patients suffering.

Different ethnic groups also suffer more than others. A major study, published in the New England Journal of Medicine in 2006, compared lung cancer rates in African Americans, Native Hawaiians, Latinos, Caucasians, and Japanese Americans.239 Among those who smoked twenty or fewer cigarettes per day, which is about 80 percent of smokers, African Americans and Native Hawaiians were twice as likely to develop lung cancer as Caucasians, and three times as likely as Latinos or Japanese Americans. With higher levels of smoking, those differences started to disappear.

The reasons for these ethnic differences are not clear. They could not be explained by any obvious differences in the patients’ diets, occupations, or socioeconomic status, which leaves some potential genetic explanation, and/or some theories of different metabolism of carcinogens. Compared to other ethnicities, for example, African Americans appear to retain higher levels of nicotine in their bodies after smoking the same number of cigarettes, though no definitive conclusions have been drawn from this.

Happily, since the 1960s the rate of smoking has dropped at a very fast rate among African Americans. In 1960, about 60 percent of African American males smoked; today about 17 percent smoke. African American women have a lower rate of smoking today compared to either Caucasian men or women, at about 13 percent. The rate of smoking among African Americans aged twelve to seventeen is less than half the rate for Caucasians in that age group, at 3.2 percent.240

Overall cigarette smoking rates have declined in the United States from over 40 percent in the 1960s to an almost unprecedented 13.7 percent in 2018.241 Still, over 30 million Americans use cigarettes. An increase in e-cigarette usage, cigars, and hookah pipes is also slowing the overall decline in tobacco use, especially in teenagers, and cases of bad outcomes due to vaping are piling up. The battle is, unfortunately, far from over.

In his 1971 State of the Union address, President Richard Nixon declared war on cancer, and later that year he signed the National Cancer Act, which stated that the country needed to “attempt to find a cure, and to make a total national commitment to defeating this disease.”242 While aware of the many different kinds of cancers, Nixon talked about cancer as a single disease. Since then we have come to focus on organ-specific cancers, and even more recently on individual cancers, each having unique characteristics that can potentially be targeted for therapy. This was reflected in President Barack Obama’s 2015 State of the Union address, in which he specifically addressed the concept of personalized medicine, recognizing each person’s cancer as a unique disease.

James “Rocky” Lagno stands as a testament to this new approach to cancer treatment. In November 2010, visiting family for Thanksgiving, he began to notice a cough that wouldn’t go away. He had rarely been sick before. His local primary care doctor diagnosed him with pneumonia and gave him an antibiotic. Nobody gave it another thought, because there was no reason to. Rocky didn’t smoke, he drank only socially, and he didn’t take any medications.

But the cough continued, and a few months after experiencing his initial symptoms he hacked up some bright-red blood. He drove himself immediately to a local urgent care center and got a chest X-ray. Since it showed a lung mass, he was then given a CT scan and a biopsy. A few days later, with his wife Geralynn at his side, Rocky was face to face with an oncologist, who acknowledged he had nonsurgical, advanced disease. The oncologist told Rocky that there was hope, and that this was treatable, but with the tyranny of the statistics weighing on him, he also told Rocky to make a “bucket list” of things he wanted to do, with the implication that he should start working on them sooner rather than later.

The oncologist then mentioned to Rocky and Geralynn some clinical trials of new medications that were showing dramatic results in patients with lung cancers that exhibited certain genetic changes. These genetic changes were more likely to occur in patients like Rocky, who never smoked. From her own research, Geralynn learned that tumors can look identical under the microscope but have formed through different genetic pathways.

Individual lung cancers have specific genetic mutations that drive cellular growth. With many cancers, if you shut off one switch, other circuits take over and the cancer continues to grow. Some cancers, though, have a main power switch, and once you discover what it is, you can shut it off with a targeted medicine, causing cells to stop dividing and effectively killing the cancer. If Rocky’s cancer had one of two particular mutations—the anaplastic lymphoma kinase (ALK) gene or endothelial growth factor receptor (EGFR) protein—that mutation could be exploited as a “kill switch.” However, only about 4 percent of lung cancers have these genetic changes.

Strangely, the oncologist they saw at their second consultation had little interest in taking another biopsy of Rocky’s cancer to see if it harbored one of the two genetic changes. Rocky soon commenced traditional radiation and chemotherapy, which kills cells en masse, some of them cancer cells, some of them not. The usual things happened to him, such as loss of energy and hair. With over thirty straight days of radiation to his chest, the skin on Rocky’s back bubbled up and bled, excruciatingly painful to the touch. Even worse, the radiation did not work. Geralynn asked again to get his tumor tested for specific mutations, and the doctor finally relented. And indeed, Rocky had one of the two mutations against which a targeted medicine could be used.

Rocky and Geralynn, not surprisingly, decided it was time to change physicians. They found their way to Dr. Alice Shaw, a rare oncologist who has chosen to specialize in lung cancer. She works at Massachusetts General Hospital, where she is a “translational researcher,” one who straddles the border between the two worlds of science and patient care. She quickly put Rocky on crizotinib, a medicine that specifically targets the ALK mutation that was present on his tumor. What happened next was nothing short of extraordinary. Rocky noticed an immediate improvement in his well-being and energy level, and the X-rays backed him up. His tumor was shrinking for the first time.

Over the next several years, Rocky would go through an almost continual roller coaster of treatments and complications. Fluid around his heart and lungs required tubes and drainage. A new focus of cancer appeared in his lung, followed by metastases in his brain. He went through radiation to his brain and began traditional chemotherapy again. An irregular heart rhythm increased his rate to 130 beats per minute, and blood clots required him to start a powerful blood thinner. Even worse, the crizotinib stopped working. Newer medicines that targeted the ALK mutation were in clinical development, but Rocky wasn’t eligible because of multiple complications. Undeterred, Dr. Shaw successfully lobbied the drug company for compassionate use. Rocky and Geralynn’s mantra was put to the test: “tough times don’t last, tough people do!”

Through all of the complications and advancing disease, Rocky and Geralynn spoke freely and openly about his cancer diagnosis, posting blog entries privately for friends and family to read. July 28, 2016, was a significant day for Rocky, and he wrote one of his longest blog posts ever: “We stand here today, exactly five years from a terrible prognosis with my health generally good, my spirits high and living a quality of life heretofore unthinkable for stage IV cancer patients. As with many cancer patients, I wanted to have it remain quiet but what a mistake that would have been. There were some very difficult times early on and also some tough after effects as time went on. Radiation burns, blood clots, fluid on the heart and lung with subsequent surgeries. Through it all I was able to stay positive and regain strength due to my wonderful wife’s support and care.”

In the spring of 2019, Rocky was on his fourth ALK inhibitor, and able to stay just ahead of the cancer. He spoke then of a side effect of vivid dreams from the newest medication, which he described not with frustration or anger, but with a laugh, an acknowledgment that this was just another thing he would deal with. Sadly, he passed away in November 2019, but his survival for nine years after his initial diagnosis of stage IV lung cancer was an unheard-of outcome until recently.

The future of lung cancer treatment lies in continued genetic analysis of tumors, with the expectation that targeted therapy can be increased from the current level of 4 percent of patients. Other approaches are also being investigated, one of the most interesting of which harnesses our own immune system to attack the tumor. The medicine pembrolizumab was recently approved by the FDA for lung cancer. Its mechanism is unique, as it works by attaching to lymphocytes and activating them to attack cancer cells. A study showed that in people with very advanced disease, those who received pembrolizumab were 70 percent likely to be alive after one year versus 50 percent for those who received only standard chemotherapy.243

In addition to cutting down on smoking rates, we need to determine what else we are inhaling that is causing lung cancer. Lung cancer patients like Rocky, who never smoked, are becoming more common. The data on what these cancer-causing inhalants could be is scarce; the field is in its nascent stage. Radon gas appears to be a contributor. A naturally odorless gas, it occurs in harmless amounts outdoors but can build up inside homes constructed on soil contaminated by naturally occurring uranium deposits. Secondhand smoke is also a contributor, as is air pollution. Why some people do and others don’t develop cancers at similar exposures goes back to their genetics, of which there is much more to be understood. The lungs have traditionally had a robust system of cell death and replacement. We must try to understand what has changed in our environment that is altering this balance.

231. Alan Blum, “Alton Ochsner, MD, 1896–1981: Anti-Smoking Pioneer,” Ochsner Journal 1 (1999): 102–105.

232. Luca Paoletti, Bianca Jardin, Matthew Carpenter, et al., “Current Status of Tobacco Policy and Control,” Journal of Thoracic Imaging 27 (2012): 213–219.

233. Alton Ochsner and Michael DeBakey, “Primary Pulmonary Malignancy: Treatment by Total Pneumonectomy; Analysis of 79 Collected Cases and Presentation of 7 Personal Cases,” Surgery, Gynecology and Obstetrics 1, no. 3 (1939): 435–445.

234. Richard Doll and A. Bradford Hill, “Smoking and Carcinoma of the Lung,” British Medical Journal 2 (1950): 739–748.

235. S. S. Birring and M. D. Peake, “Symptoms and the Early Diagnosis of Lung Cancer,” Thorax 60 (2005): 268–269.

236. American Lung Association, “Lung Cancer Fact Sheet,” American Lung Association website, https://www.lung.org/lung-health-and-diseases/lung-disease-lookup/lung-cancer/resource-library/lung-cancer-fact-sheet.html.

237. National Institutes of Health, “Cancer Stat Facts: Common Cancer Sites,” National Cancer Institute, Surveillance, Epidemiology, and End Results website, accessed July 31, 2019, https://seer.cancer.gov/statfacts/html/common.html.

238. National Institutes of Health, “Estimates of Funding for Various Research, Condition, and Disease Categories,” Research Portfolio Online Reporting Tools website, accessed July 31, 2019, https://report.nih.gov/categorical_spending.aspx.

239. Christopher A. Haiman, Daniel O. Stram, Lynn R. Wilkens, et al., “Ethnic and Racial Differences in the Smoking-Related Risk of Lung Cancer,” New England Journal of Medicine 354 (January 26, 2006): 333–342.

240. American Lung Association, “Tobacco Use in Racial and Ethnic Populations,” ALA website, https://www.lung.org/stop-smoking/smoking-facts/tobacco-use-racial-and-ethnic.html.

241. Centers for Disease Control and Prevention, “Current Cigarette Smoking Among Adults in the United States,” CDC website, https://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm.

242. National Cancer Institute, “National Cancer Act of 1971,” National Cancer Institute website, https://dtp.cancer.gov/timeline/flash/milestones/M4_Nixon.htm.

243. Leena Gandhi, Delvys Rodriguez-Abreu, Shirish Gadgeel, et al., “Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer,” New England Journal of Medicine 378 (May 31, 2018): 2078–2092.