Aimee Swartz

It’s not unusual these days to hear good news about various cancer types as novel treatments bring about significant reductions in the rates of new cases and deaths.

Liver cancer, though, has been heading in the other direction. In 2016, the world mourned the loss of legendary musician David Bowie, who reportedly died of the disease. And just a few years prior, it was a major factor in the death of Lou Reed, another influential musician.

But it’s not just rock stars who succumb to liver cancer. This year, about 40,710 people in the United States will be diagnosed with the disease, and it will be responsible 28,920 deaths. Among common cancers, its incidence is increasing at a rate second only to that of thyroid cancer, and liver cancer deaths are rising at the highest rate in this group.

This is particularly troubling to the medical community because it’s tough to catch liver cancer in its early stages, when potentially curative surgery is an option.

“Unfortunately, liver cancer does not commonly have early warning signs. Symptoms of liver cancer often do not appear until it is in its later stages, where it is harder to treat,” says Bassel El-Rayes, M.D., an oncologist at Emory Winship Cancer Institute, in Atlanta. These symptoms include pain in the upper right side of the belly, bloating, loss of appetite, feelings of fullness, weight loss, fatigue, nausea and vomiting, and yellow skin and eyes.

Avoiding risks such as hepatitis and obesity-related fatty liver may be the most effective and straightforward approach to lowering risk. But for those who have developed liver cancer, the good news is that researchers are working to improve existing treatments for the disease — and to develop new ones. In particular, experts say, targeted drugs and immunotherapies look promising.

While most treatments besides surgery are not considered curative, they may delay progression of cancer, and some remissions might be long-lasting.

“There have been many advances in understanding how to treat liver cancer,” says Ghassan K. Abou-Alfa, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, in New York. “I always tell my patients that this is a very hopeful time.”

Treatment options are available for people with all stages of liver cancer. Early-stage disease is often treatable with surgery, which offers the best chance of a cure, but advanced stages usually require alternative strategies.

Surgical tumor removal is an option for patients who have a single malignant liver tumor that has not grown into nearby blood vessels. Once the cancer is removed, a healthy liver has the capacity to grow back and, over time, can even regain some of the function it lost when part of it was taken out.

 Potential side effects of surgery include bleeding, infections, complications from anesthesia, blood clots and pneumonia. However, newer laparoscopic and roboticassisted surgical techniques typically cause fewer side effects and are associated with faster recovery times. These are options for patients whose liver tumors are not close to main vessels, or who have not had extensive liver surgery in the past.

Liver Transplantation may be an option for any patient whose cancer has not spread beyond the liver, or for many whose livers are cirrhotic. To be considered eligible, a patient must have either a) a single tumor that is 5 cm or smaller, or b) three or fewer tumors, none of which is larger than 3 cm. However, researchers are investigating the possibility of expanding the criteria for liver transplantation. Liver donors are rare and the wait lists can be long, so transplantation is not always an option, even for those who meet the eligibility criteria.

Possible side effects of this procedure include failure of the bile ducts, blood clots or bleeding, infection and the body’s rejection of the donated organ. High-energy radiation can kill cancer cells and shrink tumors. External beam radiation therapy uses a machine outside the body to deliver the radiation to liver tumor(s).

In internal radiation therapy, also known as brachytherapy, radioactive material is injected into or near the tumor(s). The radiation doesn’t travel far, so it’s less likely to damage nearby normal tissues.

Side effects associated with liver radiation can include skin irritation, stomach upset, low blood counts and fatigue.

Some cancer centers offer minimally invasive techniques that are particularly useful if surgery is not an option, and these may also be administered by a radiation oncologist. One is ablation, which kills small tumors by cutting, vaporizing, melting or using intense heat or cold; this may be done in combination with surgery, or without any surgery at all. Side effects can include infection and internal bleeding. Another minimally invasive technique is NanoKnife, which uses electrical currents to make holes in the cancer cells and destroy them.

 lessens or blocks the flow of blood to liver cancer cells, so that they cannot survive. There are two kinds of embolization:

 or chemoembolization is a procedure by which particles meant to cause an obstruction, or those particles plus a high dose of chemotherapy, are injected through a catheter directly into the hepatic artery, the blood vessel that feeds the liver cancer tumor. This strategy is commonly used to treat patients whose liver tumor(s) cannot be removed surgically. It is also increasingly used in many cancer centers, says El-Rayes, as a “bridge to transplant,” meaning it can often either shrink liver cancer tumors or keep them from growing until a liver is available for transplant.

 is a procedure by which small radioactive beads are injected through a catheter into the hepatic artery, through which they travel to reach the liver.

 Side effects of embolization for liver cancer can include fever, abdominal pain, nausea, an inflamed gallbladder, liver infection and blood clots.

Nexavar (sorafenib) is the only FDA-approved targeted drug for those with liver cancer; it’s indicated for patients with hepatocellular carcinoma for whom surgery is not an option. Nexavar works by blocking signals that tell cancer cells to grow, while also helping to prevent tumors from forming the new blood vessels that feed them.

Side effects can include, but are not limited to, skin problems, stomach upset, hair loss or thinning, dry mouth, diarrhea and fatigue.

For patients who are resistant to Nexavar, or for whom it is not an option, several targeted drugs are being explored in clinical trials.

“The clinical trials of today are testing the drugs that will become standards of care in 10 years, so it’s important for patients to consider clinical trials,” El-Rayes says.

Among the most promising targeted therapies in clinical trials, says Abou-Alfa, is cabozantinib, a drug that is already approved to treat thyroid and kidney cancers. Cabozantinib is under investigation in a phase 3 clinical trial, called CELESTIAL, for patients with advanced hepatocellular carcinoma who have already received Nexavar. A MET inhibitor, it works by blocking proteins that encourage the cancer to grow. Like Nexavar, it also stops tumors from growing blood vessels.

Abou-Alfa says he is also “very encouraged” by data on Stivarga (regorafenib), “a cousin to Nexavar,” and on the MET inhibitor tivantinib. In January, the U.S. Food and Drug Administration granted a priority review to Stivarga as a treatment for liver cancer, and expects to make a decision about whether to approve the drug by this summer.

While there is much enthusiasm about new targeted therapies, it is unclear how much these will extend remission times or improve survival until larger-scale trials are carried out. In addition, it is hoped that tissue or blood testing might personalize therapy and be able to match the right drug to the right situation.

Another area of “great interest,” says Abou-Alfa, is immunotherapy, which capitalizes on the body’s immune system — its natural defense system &mdash; to fight cancer.

However, he notes that immunotherapy’s full range of “side effects are unknown and should not be underestimated, especially given that liver cancer patients so often have hepatitis or cirrhosis.”

 The known side effects can include cough, fatigue, nausea and skin problems. In rare cases, the boosted immune system can attack healthy organs in the body, and that can lead to serious complications.

Mark Yarchoan, M.D., an oncologist at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, says a class of immunotherapeutic drugs called checkpoint inhibitors is “highly promising” for the treatment of liver cancer. These drugs, which inhibit proteins that would otherwise hold the immune system in check, are already approved for several cancers, including lung cancer, melanoma, kidney cancer and head and neck cancers.

Data from the CheckMate-040 study, a phase 3 clinical trial of the checkpoint inhibitor Opdivo (nivolumab) in patients with liver cancer, showed that “one in five patients had measurable tumor shrinkage with Opdivo, while many other patients got their disease to remain stable for sometimes a long time,” Yarchoan says. The results were “so positive,” he says, that “many in the field are hopeful that Opdivo will be better than any treatment that came before it for liver cancer.”

In addition, Abou-Alfa noted that Keytruda (pembrolizumab) and the experimental immunotherapies durvalumab and tremelimumab have “shown promise, but are being studied in clinical trials as well.”

In the future, Yarchoan says, there will likely be trials that combine targeted therapies and immunotherapies for the treatment of liver cancer, as there are for other cancers. “Different drugs destroy cancer cells in different ways,” Yarchoan says. “Using a combination of drugs can increase the chance more cancer cells will be destroyed. Many times, one drug will even help the other drug work better.”

Articles

Liver cancer diagnoses and mortality have been rising, but new treatments are designed to help reverse the trend.

Changing Direction on Liver Cancer Trends

The immunotherapy Keytruda (pembrolizumab), through a clinical trial, “gave me my life back.” — GARY TANKERSLEY, patient

Could the same drug that revolutionized melanoma and lung cancer treatment be used to help men with a deadly form of prostate cancer?

“That’s the hope,” says Julie Graff, M.D., prostate cancer oncologist and researcher with the OHSU Knight Cancer Institute and Portland VA Medical Center. She’s heading up a phase 2 clinical trial of a drug called Keytruda (pembrolizumab) in men with metastatic prostate cancer whose disease had progressed on hormone therapy. Keytruda is a form of immunotherapy known as a checkpoint inhibitor; it blocks a protein called PD-1, thus freeing up the immune system to attack the cancer.

Results to date from the trial of Keytruda plus the hormonal therapy Xtandi (enzalutamide), which is still ongoing, are “remarkable,” says Graff. Within months of treatment with Keytruda, prostate-specific antigen (PSA) levels in the blood, an early measure of treatment effect, plummeted in three out of 10 men enrolled in the trial (from 46, 71 and 2,503 ng/mL, respectively, to less than 0.1 ng/mL in all three cases); drugs currently available to treat metastatic, castration-resistant prostate cancer rarely result in PSA levels lower than 0.2 ng/mL after Xtandi or Zytiga (abiraterone) have stopped working. The three patients who responded to Keytruda had no disease progression for 30, 55 and 16 weeks, respectively, and two of the three gained such relief from cancer pain that they were able to stop taking opiate pain medication.

“It gave me my life back,” said 67-year-old Gary Tankersley, from North Plains, Oregon, who is part of the trial.

 Tankersley was diagnosed with prostate cancer in 2004. Over the years, he says he “tried everything, but nothing worked.” By the time he entered the trial, his PSA level had “skyrocketed,” he says, and he was homebound with cancer-related bone pain. “I got up, sat in a chair and looked out the window, then went to bed, then did it again the next day. And that was a good day,” he says.

Less than two months after starting on Keytruda, Tankersley’s PSA had “plummeted,” he says, and his pain is now manageable with Tylenol. He now walks several miles a day, tends to his farm in the foothills northwest of Portland, Oregon, and recently spent a week hustling through Disneyland with his wife and 7-year-old daughter and “loving every minute of it.”

Why did the treatment work so well for some patients? Men on the study took Xtandi along with Keytruda, and investigators are hypothesizing that treatment with this potent suppressor of androgen may enhance response to immunotherapy in some men. The researchers also found genomic characteristics in responders that can be studied to determine if they may help predict which future patients with prostate cancer will fare well on immunotherapy. These characteristics included microsatellite instability (a problem that interferes with DNA’s ability to repair itself) and the expression of PD-L1, a protein related to PD-1 that helps to hold the activity of the immune system in check.

Though Tankersley’s exceptional response is rare, it is illustrative of the progress being made in a disease that is expected to be diagnosed in 180,890 men this year alone, and in one of every seven men during his lifetime. Since 2010, half a dozen new treatments for prostate cancer have been approved by the U.S. Food and Drug Administration. Treatment innovations, in combination with earlier detection of the disease, have boosted the 10-year survival rate of prostate cancer to 98 percent, according to the American Cancer Society.

New agents are not emerging in just the immunotherapy realm. In the area of hormonal therapy, a staple of prostate cancer care, new drugs including apalutamide and ODM-201 are being explored. Further, anti-angiogenesis drugs, which kill the blood vessels that feed a tumor, are being explored by scientists as a potential new form of treatment for the disease.

 Novel ideas about the application of older therapies are being investigated, too. Among them is the addition of chemotherapy to radiation and hormonal therapy in newly diagnosed advanced cases of prostate cancer — something that looks promising, but isn’t yet employed routinely.

“Many treatments exist for men with prostate cancer, and we are supporting several others in clinical trials that appear to be beneficial, whether you’ve just been diagnosed with early-stage prostate cancer, your cancer has returned after treatment or you have more advanced disease,” said Jonathan Simons, M.D., president and CEO of the Prostate Cancer Foundation.

In the not-so-distant past, the use of active surveillance — an approach that involves closely monitoring a patient’s cancer over time and foregoing immediate treatment &mdash; was largely resisted by prostate cancer doctors. Today it is the standard of care for most patients with low-risk tumors, which grow slowly and rarely pose a health threat.

“The goal is to spare patients from treatment that they don’t need and that can cause lasting quality-of-life effects,” said Matthew Cooperberg, M.D., M.P.H., who specializes in treating patients with urologic cancers at the University of California, San Francisco.

Patients undergoing active surveillance should be regularly monitored with PSA testing every three to six months, digital rectal examinations at least every year, and prostate biopsies. Treatment, such as surgery or radiation, is given if the cancer begins to grow, with the goal, Cooperberg says, “to cure the cancer.”

Not everyone is a candidate for active surveillance, though, and determining who is and who is not is not always clear-cut. “Men who appear to have low-risk disease, for example, but have imaging findings that show otherwise might be encouraged to begin treatment right away,” Cooperberg says.

Cooperberg hopes that, one day in the near future, new tools will not only allow doctors to better identify prostate cancer patients for whom active surveillance is the best way to manage low-risk disease, but also to tailor the level of surveillance according to an individual patient’s cancer. “Active surveillance is not a one-size-fits-all solution,” he says. “Nothing is, when it comes to cancer.”

The goal of surgery in men with prostate cancer is to try to eliminate a tumor before it spreads outside the prostate. During surgery, all or some of the prostate is removed, as well as a margin of healthy tissue that surrounds it. Two surgical approaches are commonly used:

 Radical prostatectomy, sometimes called an open prostatectomy, is a complex surgical procedure in which the surgeon makes a large incision in the lower abdomen and then removes the prostate. The seminal vesicles (the small glands that help produce semen), and a short segment of the urethra, which passes through the prostate, are also removed. The surgeon either uses the tools directly or uses a computer to precisely move robotic arms that hold the tools.

A laparoscopic prostatectomy is a less invasive surgery in which the surgeon makes several smaller incisions and uses long surgical tools to remove the prostate and surrounding tissues. As with radical prostatectomy, doctors may or may not perform robot-assisted surgery.

Although a laparoscopic prostatectomy usually causes less bleeding and pain, the sexual and urinary side effects are similar to those associated with a radical prostatectomy. Both procedures may cause temporary or permanent impotence (the inability to get an erection) and urinary incontinence (the inability to control the flow of urine.) Sometimes a nerve-sparing technique, which spares the erectile nerves that run alongside the prostate, can be used to increase the chance of maintaining sexual function. Even if the nerves cannot be spared, it is sometimes possible to surgically attach, or graft, nerves from other parts of the body to the ends of the cut erectile nerves. However, surgeons won’t know until the time of the procedure if nerve sparing is possible.

Radiation therapy often is used as the exclusive treatment for prostate cancer that is contained within the prostate or the tissues surrounding it, but the technique also can be used as part of a larger treatment regimen for more advanced prostate cancers. It involves the use of high-energy beams or radioactive seeds to eliminate tumors. The most common types are:

IMRT, or image-guided radiation therapy, is a kind of external radiation that projects radiation from a machine outside of the body. It tailors the radiation dose to the precise shape of the tumor to avoid or reduce exposure of healthy tissue and limit the side effects of treatment.

Brachytherapy, or internal radiation, involves placing tiny radioactive seeds inside of the prostate. It allows doctors to deliver higher doses of radiation to more specific areas of the body.

Proton therapy is a new kind of external radiation that targets even the most difficult to treat and reach tumors and is designed to allow higher doses of radiation to be delivered to the prostate with fewer side effects.

 The type of radiation therapy used varies based on the disease. Patients with early-stage disease often have a choice between surgery and radiation, with similar anticipated outcomes. For larger or more aggressive tumors, radiation therapy may be used in combination with hormone therapy. Radiation also may be used to treat prostate cancer tumors that are not completely removed or that come back after surgery.

Hormone therapy, also called androgen deprivation therapy, blocks testosterone production or blocks testosterone from interacting with the tumor cells. The majority of prostate cancers are hormone-sensitive, which means that male hormones (androgens), such as testosterone, fuel the growth of the cancer. These medications reduce the tumor size or make it grow more slowly. Hormone therapy may be given in different ways:

Hormone therapy alone: Hormone therapy is sometimes used alone in men with advanced, high-grade tumors or in patients with cancer that already has spread beyond the prostate to other parts of the body. It is also the standard treatment for men whose cancer has come back after being treated with radiation therapy or surgery.Adjuvant and neoadjuvant hormone therapy: Hormone therapy that is given after surgery or radiation to eliminate any remaining cancer or reduce the chance that cancer will return is called adjuvant hormone therapy. Men with early-stage prostate cancer who have an intermediate or high risk of recurrence often receive adjuvant hormone therapy after radiation therapy or surgery. Sometimes these men also have hormone therapy before surgery or radiation; this is called neoadjuvant hormone therapy. Studies have shown that men who have adjuvant hormone therapy after prostatectomy live longer without having a recurrence than men who have surgery alone, but they do not live longer overall. Men who have adjuvant hormone therapy after radiation therapy live longer overall and without having a recurrence than men treated with radiation therapy alone.

Chemotherapy is the use of drugs to destroy cancer cells. Several kinds of chemotherapy are used to treat prostate cancer, and others are in various phases of clinical trials.

“Both surgery and radiation really only treat the pelvis and the prostate itself. When you add on hormone therapy or chemotherapy, then you begin to get the cells that might have escaped and caused the disease to spread,” says Graff.

Until recently, chemotherapy was used only to relieve symptoms associated with advanced or metastatic disease. Today, it is used to prolong the lives of men with prostate cancer that no longer responds to hormone therapy. The standard chemotherapy for prostate cancer is Taxotere (docetaxel) combined with a steroid called prednisone. If Taxotere does not work (or stops working), Jevtana (cabazitaxel) is often the next chemotherapy used.

 Chemotherapy may also benefit some patients when given in addition to standard therapies. One 2015 clinical trial, for example, showed that Taxotere improved survival when given alongside standard hormone therapy in patients with newly diagnosed advanced prostate cancer not previously treated with hormone therapy; men who received the addition of Taxotere plus standard therapy lived on average 10 months longer than those who did not. In another clinical trial, the addition to Taxotere was shown to improve four-year survival when given alongside hormone therapy and radiation to patients with high-risk localized prostate cancer; in the study, also reported in 2015, the four-year survival rate was 93 percent for men treated with the standard treatment of hormone therapy and radiation plus Taxotere compared to 89 percent when treated with the standard treatment alone.

Graff stresses that more evidence is needed before recommending the addition of Taxotere to standard therapies. “It does indeed delay the time to the cancer returning and keep the cancer from returning, but we don’t know yet if it saves lives in the long run,” she says. In the meantime, it’s up to the patient and provider to decide. “It’s not really a clear decision right now.”

Xofigo (radium-223) is a first-in-class alpha-emitting radiopharmaceutical that was approved in 2013 to treat metastatic castration-resistant prostate cancer with bone metastases, on the grounds that it improved overall survival and progression-free survival in a clinical trial.

Now, trials are investigating the success of the drug when used in combination with hormonal therapies such as Zytiga or Xtandi.

These treatments empower the immune system, the body’s natural defense system, to fight cancer. Several immune-based therapies are being used to help men who have prostate cancer, including those with advanced or recurrent disease.

 Vaccines: Unlike preventive vaccines, which protect people from developing particular diseases, an FDAapproved vaccine called Provenge (sipuleucel-T) is given to people who have already developed prostate cancer. Provenge is for men with advanced, metastatic prostate cancer that does not get better with hormone therapy and with minimal or no symptoms. It’s made from a man’s own immune cells, mixed with a protein that helps the medication specifically reach prostate cancer cells. Other vaccines are being studied in clinical trials.

Checkpoint inhibitors, approved in several cancers but not yet in prostate cancer, prevent cancer cells from turning off some types of immune cells, called T cells. This allows T cells to infiltrate a tumor and kill cancer cells. Keytruda, the drug that Tankersley is receiving, is an example of this type of checkpoint inhibitor. It targets the immune checkpoint protein PD-1, which is on the surface of some immune system cells. Another checkpoint inhibitor called Yervoy (ipilimumab) targets the immune checkpoint protein CTLA-4 on certain immune cells. Yervoy is already used to treat melanoma, and is now being tested in men with advanced prostate cancer.

After a host of recent advances in the treatment of prostate cancer, the forward push continues as immunotherapy and combinations of older agents are tested in patients.

Forward March: Push Continues for Immunotherapy in Prostate 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.” 

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

Aimee Swartz

Changing Direction on Liver Cancer Trends

Forward March: Push Continues for Immunotherapy in Prostate Cancer

Under the Radar: Detecting Lung Cancer Among Never-Smokers

Containing a Threat: Screening Creates Opportunity to Cure Lung Cancer

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