Lung cancer: new risk prediction model includes CT scans


Takeaway

  • A new lung cancer risk prediction model (PLCO2012results) that combines past CT screening results with data from an existing, validated risk model (PLCOm2012) significantly improved predictions of future disease.
  • PLCO2012results may lead to fewer unnecessary screenings compared with PLCOm2012, which does not include screening results.

Why this matters

Study design

  • Secondary analysis of 22,229 people in a National Lung Screening Trial study who underwent 3 CT screenings.
  • Funding: None.

Key results

  • 1.3% developed lung cancer within 1-4 years of the third CT screen.
  • With PLCO2012, ORs compared with participants with 3 negative screens were:
    • 1 positive screen and last negative: OR, 1.93; 95% CI, 1.34-2.76.
    • 2 positive screens with last negative or 2 negative screens with last positive: OR, 2.66; 95% CI, 1.60-4.43.
    • ≥2 or more positive screens with last positive: OR, 8.97; 95% CI, 5.76-13.97.
  • Compared with PLCOm2012, PLCO2012results offered superior overall prediction (Brier score, 0.012 vs 0.013) and significantly greater discrimination (area under the curve, 0.761 vs 0.687; P<.001).
  • Having consecutive negative screens was associated with a lower risk in the PLCO2012results model.
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Liquid Biopsy Is Effective at Guiding Treatment of Lung Cancer, Study Finds


A tube of blood superimposed on a lung and a DNA helix

Summary

For people with lung cancer, a blood test known as a liquid biopsy can be a useful tool for guiding treatment decisions, according to a new study from researchers at Memorial Sloan Kettering, the University of Sydney, and a biotech company called Resolution Bioscience.

Doctors and patients alike have cheered the arrival of liquid biopsies to modern cancer medicine.

These high-tech tests measure infinitesimally small amounts of DNA that is shed from tumor cells and is circulating in the blood. The tests can provide doctors with information about which mutations are present in a person’s cancer, without needing to perform a surgical biopsy. Several are commercially available.

While much touted, liquid biopsies have yet to really prove their mettle when it comes to improving patient care.

“We still don’t have good evidence showing whether and how a liquid biopsy can help people who are struggling with cancer today,” says Bob Li, a medical oncologist at Memorial Sloan Kettering who specializes in the treatment of people with lung cancer. “There is an urgent need to demonstrate not only the scientific validity of the test but also its clinical utility — how it can help patients.”

That’s why, two years ago, Dr. Li and his colleagues began a prospective clinical study to evaluate whether a liquid biopsy test could help guide treatment decisions for people with lung cancer. The initial results of the ongoing study were published on November 28 in the Journal of the National Cancer Institute. The authors conclude that liquid biopsy–guided treatment is “feasible, rapid, and useful.”

Details of the Study

The paper covers the first 210 patients enrolled in the study. They all had advanced-stage non-small cell lung cancer that either had no known mutation that could be targeted with a drug or had stopped responding to a targeted therapy. Their cancers had spread beyond the primary location.

Each patient had the liquid biopsy test performed on a blood sample. About half of the patients (106) also had their tumor tissue genetically sequenced by MSK’s DNA-sequencing platform, called MSK-IMPACT™.

Among the most important benefits of the liquid biopsy was the quick turnaround time. It took a median of nine days from the time of the blood draw for doctors to get the results of the liquid biopsy. It takes a median of 20 days from the time a tissue specimen arrives in a lab to get results from tumor sequencing.

If I see that a patient has a liquid biopsy result that is positive … I’m confident that I can match the patient to a therapy and treat that patient immediately.
Bob T. Li
Bob T. Li medical oncologist

Given that people with late-stage lung cancer can be quite sick, that time difference can be significant.

“The overall health of a person suffering from advanced-stage lung cancer can deteriorate very rapidly in the space of a couple of weeks,” Dr. Li says. “Sometimes if you wait too long, you’ve missed the boat, so to speak, for effective treatment.”

But if a liquid biopsy turns up a targetable mutation, doctors can act on it right away.

In the study, just over 45% of the patients were found by liquid biopsy to have a mutation that could be targeted by an approved or investigational drug. About 22% of the patients (46 people) received one such drug, and nearly all of them experienced a benefit — namely, a decrease in the size of their tumors.

What the Liquid Biopsy Measures

The particular liquid biopsy test used in this study is made by Resolution Bioscience, a biotech company based in Redmond, Washington. It looks for mutations in 21 genes that are known to be involved in non-small cell lung cancer.

By comparing the results of the liquid biopsy to those of tumor tissue, the team determined that the overall concordance rate between the two approaches was 56.6%. This means that for a little more than half of the people, both tests identified at least one mutation in common.

What cheered the team more was that when they looked just at people who tested positive for a cancer mutation on the liquid biopsy, 89.6% had that same mutation also identified by the test of tumor tissue. Finally, when the investigators looked at only patients with driver mutations found on the liquid biopsy — those that matter most in terms of treatment — the rate of agreement between the two tests was 96.1%.

“If I see that a patient has a liquid biopsy result that is positive, especially for a driver mutation, I’m confident that I can match the patient to a therapy and treat that patient immediately without waiting for the tissue results,” Dr. Li says.

One major caveat, he notes, is that a negative result on a liquid biopsy does not mean that a person has no targetable mutations. In that case, the person would need to have a tissue biopsy to look for a targetable mutation.

 

More than an Academic Pursuit

MSK, the University of Sydney, and Resolution Bioscience are academic collaborators on this study, and there is no exchange of money between them. Resolution Bioscience covers the costs associated with the test for all enrolled patients, and neither MSK nor the University of Sydney charges Resolution Bioscience for access to patients’ blood. Patients who consent to the study receive the liquid biopsy free of charge.

For Dr. Li, the results of the study are much more than a narrow academic concern. People’s lives depend on it.

He gives the example of a patient who was misdiagnosed at another hospital before coming to MSK. “This previously healthy young man was so sick with widespread metastases, he had lost 30 pounds,” Dr. Li recalls.

He ordered a liquid biopsy, and within days it showed that his patient had a targetable mutation. Dr. Li quickly started him on a matched drug.

“The patient immediately felt better,” he says. “This was about a year ago, and now he’s playing basketball and is back to work. He’s quite excited about the results of this study as well.”

Dr. Li suggests that patients talk to their doctor about whether a liquid biopsy might help direct or improve their treatment.

“We’re very pleased that our study showed the value of a liquid biopsy. We hope that such tests will eventually become an integral part of care to help many more patients,” he says.

Vaping and Lung Cancer: What You Should Know


Electronic cigarettes, or e-cigarettes, put nicotine into your lungs and bloodstream. And they do it without the smoke and tar of a regular cigarette. But other harmful things can get into your body when you vape. That’s especially true if you use flavored cigarettes.

E-cigarettes, sometimes called vapes, run on batteries and heat up nicotine, flavorings, and other chemicals. They turn them into a vapor you can breathe in. Many chemicals that cause cancer are in this vapor. That includes formaldehyde, heavy metals, and particles that can get stuck in the deepest parts of your lungs.

It’s hard to know how much of these chemicals you breathe in when you vape. The levels are usually lower in e-cigarettes than regular cigarettes. But some studies show that high-voltage e-cigarettes have more formaldehyde and other toxins than standard e-cigarettes.

Also, some chemicals in e-cigarettes can irritate the airways in your lungs. This can cause problems. Studies have found that flavorings like cinnamon can cause inflammation of lung cells. But more research is needed to understand the long-term health risks of vaping.

Popcorn Lung

One chemical in some e-cigarette flavorings is a buttery-flavored one called diacetyl. It’s been linked to a serious lung disease called bronchiolitis obliterans. It’s also known as popcorn lung.

The disease gets its name because people working in a microwave popcorn factory got sick with serious lung problems from breathing in diacetyl. It was being used to flavor popcorn, caramel, and dairy products. The way the chemical is breathed in with e-cigarettes is a lot like the way the workers at the microwave popcorn plants inhaled it.

The chemical can cause a dry cough that won’t go away. It also causes shortness of breath, wheezing, headache, fever, aches, and other health problems. The vapors also can irritate your eyes, skin, nose, and throat.

Diacetyl scars the tiny airs sacs in your lungs. That makes your airways thick and narrow.

After the link between diacetyl and lung disease was found, many popcorn companies took the chemical out of their products. But it’s still used in many e-cigarette flavors, including vanilla, maple, and coconut. It’s also been found in many alcohol-flavored, candy-flavored, and fruit-flavored e-cigarettes. These are choices that often appeal to kids, teenagers, and young adults.

There’s no cure for popcorn lung, but some medications can help keep it from getting worse. These include certain kinds of antibiotics, steroids to calm inflammation in your lungs, and drugs to slow down your immune system.

You know air pollution is dangerous, but what about the air INSIDE your home?


Image: You know air pollution is dangerous, but what about the air INSIDE your home?

You might want to get your homes checked to see if you’re harboring an invisible killer in the air. According to Dr. Aaron Goodarzi of the University of Calgary, houses may have well over the safe exposure limit of radon gas.

In an article in the Daily Mail, Dr. Goodarzi writes that at least one in 15 homes in the U.S. contain the invisible gas.

Radon, a radioactive, invisible, and colorless gas, is a major cause of lung cancer after cigarette smoke. In Canada, at least 4,000 new cases of lung cancer are attributed to radon exposure, while experts estimate 15,000 to 22,000 lung cancer deaths in the U.S. are linked to the gas.

He and his research team have been testing well over 2,300 homes in Canada for radon for years. According to the results of the testing, at least one in eight homes that were tested contained radon levels that are higher than acceptable levels. Interestingly enough, newer houses have the largest problem with radon levels.

However, the problem lies, according to Dr. Goodarzi, with people’s lack of awareness on the effects of radon gas.

Radon is a radioactive gas that’s invisible and contains no odor. While it naturally occurs from the breakdown of radium in the soil, the gas can seep into a building through cracks in the foundation as well as other openings.

It can be mostly found in the basement or cellars of homes, schools, and offices. There is no distinction with radon exposure: It can seep in any building, both old and new, in about all places where there is housing structure.

The correlation between radon gas and lung cancer was made in the 1970s after abnormally high cancer rates were detected in uranium miners in Elliot Lake in Ontario, Canada.

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Currently, studies have already established that long-term exposure to radon gas can cause irreparable harm to the DNA and lead to gene mutations that ultimately will lead to cancer. Next to smoking, radon exposure is the leading cause of cancer in non-smokers. (Related: Radon in Homes is the Second Leading Cause of Lung Cancer.)

Dr. Goodarzi writes that radon exposure is now a major public health concern in Canada. In his location in Alberta alone, he estimates that many patients in Alberta who have never smoked a day in their life, are faced with a high risk for lung cancer.

Still, radon-induced lung cancer can be avoided completely with testing and proper management. Health care costs will be saved by avoiding radon cancer, not to mention a decrease in human suffering.

However, a person who smokes and also lives in a home with radon gas puts him at a much greater hazard, with a one in four chance of developing lung cancer later on. Meanwhile, the percentage of smokers who may have avoided cancer if they were not also exposed to radon gas remains uncertain.

With the advancement of scientific studies regarding the dangers of radon gas, Dr. Goodarzi opines that this will translate to additional legislation to regulate the gas, especially since children have the greatest risk of radon exposure throughout their lives.

As the harmful effects of radon are now gaining ground, the team hopes that this will make radon testing for homes a normal requirement, especially in cases wherein the home was just purchased after a major home repair.

Sources include:

DailyMail.co.uk

Canada.ca

10 Habits to Quit in 2018 If You Want to Live a Long, Healthy, Happy Life


This year, do more good by doing less bad.

If you’re jonesing to give your life a major upgrade in 2018—and beyond—setting a few doable goals is the first step. That means nixing bad habits that may be sabotaging your progress in addition to promising to do more stuff that’s good for your health. Out with the old, in with the new, right? In that vein, experts discuss 10 of the most harmful habits you should leave behind in 2017.

1. Spending too much time on the couch.

While downtime is good for both your body and mind, too much of it can be damaging. “People living a sedentary lifestyle tend to be less healthy,” women’s health expert Jennifer Wider, M.D., tells SELF.

As a general rule, you should get at least 150 minutes of moderate aerobic activityor 75 minutes of vigorous aerobic activity per week, or some combination in between.

You should also be strength training, because it’s great for your bones, muscles, and health in general (it’s also an effective way to help increase your metabolism, if weight loss happens to be one of your goals). Aim for at least two days of strength training per week. To see exactly how to fit it all in, here’s what a perfect week of working out looks like.

2. Regularly drinking your way into a hangover.

Drinking a lot is a clear (if enjoyable) way to compromise your health. Moderate drinking is one drink a day for women, and heavy drinking is around eight or more per week, says the Centers for Disease Control and Prevention. Routinely blowing past these parameters can lead to issues such as weight gain, unintentional injuries like falls, and chronic diseases like liver cirrhosis, pancreatitis, and various cancers.

But! It’s not all bad news. Moderate drinking—while perhaps not the magical good-for-you habit that we’ve been led to believe—can be a perfectly fine thing to do, if you want to do it. Just understand that it’s probably not benefitting your health, and drinking too much can have detrimental effects.

3. Starting a strict diet, then falling off the wagon time and time again.

Yo-yo dieting is the result of routinely embarking upon diets that are too restrictive. When you inevitably dive into a pile of food, you’ll eventually gain back any weight you lost, and your baseline weight will inch up bit by bit, Wider explains. “It’s much better to adopt habits that will sustain a healthy weight—you don’t want to always be looking to lose weight,” she says. Plus, yo-yo dieting can have longterm effects on your health; studies have linked yo-yo dieting (repeatedly gaining and losing a significant amount of weight) to chronic issues like heart disease, stress, and high blood pressure.

But if you do want to lose weight and keep it off for good, it’s about building your life around eating patterns that aren’t rooted in deprivation, even though extreme cleanses and quick fixes might sound more appealing. They just don’t work—here’s what does.

4. Using electronics before bed.

You already know you should be getting between seven and nine hours of sleepper night. Putting a moratorium on before-bed Instagram scrolling will help you turn in for the night more quickly, sure. But it can also help you get better quality Zs, Wider says, by lowering your exposure to sleep-disturbing blue light, which can disrupt your circadian rhythm. Most sleep experts recommend finishing any screen time at least 20 minutes before you’re ready for bed.

5. Smoking.

Quitting smoking: Easier said than done? Yes. Completely, utterly worth it? Also yes, Wider (and every expert worth their salt) says. Smoking lowers life expectancy in many terrible ways, including boosting your risk of heart diseasestroke, lung cancer and cancers anywhere else in the body, and issues like emphysema and chronic bronchitis.

E-cigarettes aren’t exempt. According to the American Lung Association, “Initial studies show that e-cigarettes contain nicotine and also may add in other harmful chemicals, including carcinogens and lung irritants.” So make this the year you finally quit. Here are seven things that can make it easier to quit smoking cold turkey.

6. Comparing yourself to others on social media.

“Watching other people put forward manufactured lives on social media can leave you feeling bad about yourself, so you want to limit that,” Wider says. But social media can also give your happiness a lift by keeping you connected with people you love and admire.

It’s not about scrubbing your phone of all things social, but browsing mindfully. Know that no one’s life is really what it seems on social media, and remind yourself of that whenever you start to feel down (then go do something that helps you remember all the kickass parts of your own life). Also, maybe unfollow those accounts that always, without fail, leave you feeling like chewed gum stuck on the underside of a table.

7. Convincing yourself that everything you worry about will happen.

Worrying yourself into a mental tizzy is one of those common, sneaky bad habits most people indulge in without realizing it. But too much stress can have a negative effect on your health, leading to chronic conditions like heart disease, a suppressed immune system, or insomnia. “If you want to live a long, happy life, rein in the things that cause stress, like worrying,” Christine Carter, Ph.D., senior fellow at UC Berkeley’s Greater Good Science Center and author of The Sweet Spot: How To Find Your Groove At Home And Work, tells SELF.

“Anything you’re worrying about is usually just a thought, and here’s the funny thing: It’s not necessarily true,” Carter says. Take a moment to breathe, be present, and ask yourself if there’s any logical basis to your worry, Carter says. That should help you separate fact from unnecessary fiction. And if it still feels like your tendency to worry is unmanageable, reach out to a mental health professional for help.

8. Complaining non-stop.

Although it’s counterproductive, complaining actually feels great. “If things feel out of control, it tricks your brain into thinking you’re doing something about it,” Carter says. “But you’re not fixing anything when you complain.” You’re actually priming your brain to only look for the bad instead of the good: “Your braindoesn’t register everything in your environment; you train it to look for relevant patterns. When you complain, you train your brain to look for patterns in things you don’t like,” Carter explains.

When you catch yourself complaining, redirect your attention to something good about the situation, or start working on a plan to change what isn’t up to par. “It doesn’t necessarily mean accepting what you don’t like, but training your brain to look for things you appreciate,” Carter says.

9. Using distractions to numb your negative emotions.

“Every time you feel uncomfortable, the world offers you a host of ways to numb that discomfort. You can check Facebook endlessly, eat a pound of brownies, or have a couple of cocktails,” Carter says. Instead of actually cutting down anxietyor sadness, these tactics just bury those emotions so they can stew and eventually erupt.

You also can’t pick and choose what you’re numbing. To truly experience happiness, you have to let yourself experience the less shiny side of the coin sometimes and work on better coping habits for stress, like these. If you’ve tried these habits and nothing is helping calm your anxiety, you may want to try talking to a mental health professional for more effective ways to treat and cope with anxiety.

10. Making outsize goals that are hard to achieve.

This might sound incongruous after all of the above, but it actually meshes perfectly. “There’s a misconception that if you set a goal, you can achieve it through willpower. But humans change very slowly and incrementally, and people try to change too much too fast,” Carter says.

Instead of setting overly ambitious goals, take small steps and introduce change slowly so you can form the neural pathways that are essential in cementing habits, Carter says. Once you succeed at those, you can take on larger goals from there. If you’re setting a resolution this year, aim for something that is attainable, so you’re more apt to stick to the changes that will help you get there.

A new drug to treat lung cancer just got approved


The FDA just approved a new drug to treat lung cancer.

The drug, made by Japanese drug giant Takeda Pharmaceuticals, is called brigatinib. It’s a type of ALK-inhibitor that’s taken orally to treat a certain kind of lung cancer after a first round of drugs failed.

In the past two days, the FDA has approved a handful of drugs , including a treatment for a rare disease that has a list price of $702,000 a year .

 

Here’s what you need to know

  • There are two types of lung cancer: small cell lung cancer, and non-small cell lung cancer. Most people have the latter, and there are a number of types of non-small cell lung cancer .
  • Some of these cases have mutations that affect the ALK tyrosine kinase receptor. This makes these forms of lung cancer sensitive to a type of drug called ALK inhibitors. The first one, called Xalkori, was originally approved back in 2011. Since then, two more have come on the market that can be used when people become resistant to Xalkori. It’s at this point – when patients on Xalkori have become resistant – that brigatinib is approved to come in and treat the cancer.
  • The data used to approve brigatinib came from a phase 2 study that started back in 2014. In that study, progression-free survival – a clinical endpoint that basically means the cancer hasn’t grown – was 15.6 months.
  • Takeda picked up the drug when it acquired Ariad Pharmaceuticals, a deal which just closed in February .
  • Dr. David Kerstein, the global clinical lead for brigatinib, told Business Insider that the hope is to eventually have the drug be used as an alternative to Xalkori. A phase 3 trial that’s still ongoing is looking at Xalkori vs. brigatinib.

Molecular Imaging Tracks Lung Cancer Immunotherapy


Programmed death ligand (PD-L1) expression in tumors may predict response to checkpoint blockade therapy, but tissue samples are not always on hand to guide therapy. Imaging specialists have addressed this issue by developing and evaluating techniques for non-invasive imaging of PD-L1 expression in tumors.

“Non-invasive imaging of therapeutically effective PD-1 [programmed death 1] and PD-L1 antibodies is of high interest for preclinical and potentially also for the clinical development of these drugs, as it provides an elegant opportunity to obtain quantitative and kinetic information on the whole-body biodistribution of these antibodies, including parameters such as tumor accumulation and blood half-life,” explained Gabriele Niedermann, MD, PhD, of the German Cancer Research Center in Heidelburg, and colleagues, writing recently in Theranostics.

Niedermann’s group developed radiotracers, based on therapeutic checkpoint-blocking antibodies, that allowed for high-resolution PET imaging of both PD-1 and PD-L1 in immunocompetent mice. This “immunoPET” of naïve mice showed similar overall expression patterns for PD-1 and PD-L1 in secondary lymphoid organs (spleen and lymph nodes).

The research also found that PD-L1 tracer uptake was reduced in PD-L1 knockout tumors, and that monitoring the expression changes of PD-L1 in response to its main inducer, the effector T cell cytokine IFN-γ, revealed “robust upregulation in the lung.”

“This suggests that T cell responses in the lung, a vital organ continuously exposed to a variety of antigens, are strongly restrained by the PD-1 checkpoint. In turn, this could explain the association of PD-1 checkpoint inhibition with potentially fatal immune-mediated pneumonitis and partially also its efficacy in lung cancer,” Niedermann and colleagues wrote.

In another animal-model study, Samit Chatterjee, PhD, of Johns Hopkins University in Baltimore, and colleagues performed SPECT-CT imaging, biodistribution, and blocking studies in NSG (NOD scid gamma) mice bearing tumors with constitutive PD-L1 expression (CHO-PDL1) and in controls (CHO).

The preclinical evaluation of a humanized radiolabeled anti-PD-L1 antibody showed specific and increased uptake of radioligand in CHO tumors with stable PD-L1 expression compared with control CHO tumors. The results were confirmed in NSCLC xenografts with varying levels of PD-L1 expression, and in triple-negative breast cancer.

“Subcutaneous NSCLC xenografts showed specific uptake in H2444 tumors compared to H1155 tumors,” the researchers wrote.

They explained that the clinical utility of this antibody imaging agent and others would be to use the radiolabeled antibody accumulation in the tumors to guide therapeutic antibody dosing, and correlate that uptake with tumor response.

“This could be used to establish a relationship between tumor PD-L1 status and therapeutic response, which may have prognostic implications.”

Can these results be translated into humans? Yes, according to Jill Fredrickson, PhD, of Genentech in South San Francisco, and colleagues, who utilized FDG-PET-CT imaging to evaluate atezolizumab (Tecentriq) response among chemotherapy-naïve and previously treated stage IIIB/IV non-small cell lung cancer (NSCLC) patients.

Atezolizumab was developed by Roche, the owner of Genentech, and was grantedpriority review by the FDA in April 2016 for the treatment of locally advanced or metastatic NSCLC with PD-L1 expression.

Fredrickson’s group suggested that patients with NSCLC undergoing immunotherapy may benefit from FDG-PET imaging to assess their disease and predict treatment response, presenting the results of their multinational study at the 2016 Society of Nuclear Medicine and Molecular Imaging Annual Meeting.

Atezolizumab inhibits activity between the PD-1 receptor expressed on certain immune cells and PD-L1, leading to enhanced T-cell priming and re-invigoration of suppressed immune cells.

The primary endpoint of the phase II study was objective response rate on the basis of modified immune-related response criteria. Patients underwent single-time-point FDG-PET scanning — 60 minutes of radiotracer uptake prior to imaging — at baseline, at the time of first tumor assessment during week 6 of immunotherapy, and at disease progression.

Fredrickson and colleagues also wanted to determine if the PET modality and its FDG radiotracer could distinguish between radiographic pseudo progression — an increase in apparent tumor burden due to an anti-tumor T-cell response – from true disease progression.

The study enrolled 138 patients at 28 clinical sites in 5 countries, with 103 patients providing evaluable PET scans at baseline and a post-baseline time point. All patients received 1,200 mg of atezolizumab intravenously every 3 weeks. The scans were analyzed using European Organization for Research and Treatment of Cancer (EORTC) criteria.

Patients with metabolic response by EORTC criteria on scans at week 6 had a higher overall response rate (73.9%) than metabolic non-responders did (6.3%). A patient’s whole-body metabolic tumor volume at the FDG-PET baseline scan was found to be a significant negative prognostic maker for overall survival. A further increase of tumor volume at the 6-week scan was also a sign of decreased overall survival.

The researchers noted that response after apparent radiographic progression was seen in only two patients, so the utility of FDG-PET to distinguish pseudo from true progression could not be determined.

“The utility of FDG-PET in patients with NSCLC on immune blockade therapy appeared to be similar to what has been reported with conventional chemotherapeutic treatments, with early metabolic response predicting subsequent benefit,” the team concluded.

“This study is the first to prospectively evaluate FDG-PET imaging in a phase II trial of lung cancer patients receiving the novel immune checkpoint inhibitor atezolizumab,” Fredrickson said in a press statement. “These findings help define the potential role of FDG-PET as a prognostic and predictive biomarker in the treatment of lung cancer with such immunotherapeutics.”

Chemoradiotherapy-induced toxicity with high-dose three-dimensional conformal radiotherapy for lung cancer


  • Figure 1
  • SniderROC_figure01b
  • Figure 2
  • SniderROC_figure02b
  • SniderROC_figure02c
  • SniderROC_figure02d
  • Figure 3

CASE SUMMARY

A 58-year-old African-American woman presented with a slowly enlarging, inferior right upper lobe ground-glass opacity (2.8 cm) for which biopsy proved well-differentiated adenocarcinoma of lung origin. Seven years earlier, the patient had undergone concurrent chemoradiotherapy at an outside institution for a stage IIIA adenocarcinoma of the right middle lobe. She had received weekly carboplatin/paclitaxel with concurrent radiation prescribed to 74 Gy using a 3-dimensional conformal radiotherapy technique (3D-CRT). The arrangement employed 2 parallel-opposed, oblique fields (only a few degrees off laterals) for the entire course (Figure 1).

Upon re-presentation, she suffered from treatment-induced pulmonary fibrosis, chronic pericardial effusion, fractured ribs, chest wall fibrosis, and gastrostomy-tube dependent dysphagia (Figure 2). Because of the new lesion’s estimated abutment of the prior radiation’s superior field edge (Figure 2D) and her previous toxicity, the patient elected to undergo sublobar resection. Pulmonary function tests indicated only a mild restrictive pattern (FEV1-1.97L/73%;FVC-2.65L/82%;TLC-3.98L/79%). Surgery was relatively uncomplicated, but the patient suffered severe postoperative acute respiratory distress syndrome. This precipitated a complicated hospital course that ultimately led to death.

IMAGING FINDINGS

CT examination of the thorax at re-presentation demonstrated dramatic soft tissue changes corresponding to the previous radiation lateral field arrangement (Figures 1 and 2). Extraordinary bilateral rib fractures and chest wall fibrosis bracketed linear band-like pulmonary fibrosis traversing the patient’s chest as well as a moderate pericardial effusion.

DIAGNOSIS

Severe, late chemoradiotherapy-induced, lung, esophageal, heart, and chest wall toxicity, compounded by post-treatment surgical complications.

DISCUSSION

Radiation oncologists have a substantially increased workload in treatment planning and delivery when compared with the 2D and early 3D eras. Numerous treatment details and patient factors must be considered, and failure to do so can yield dramatic and unexpected toxicities. In particular, tumor and normal tissue delineation has become a labor of love, with contouring more akin to wielding the surgeon’s knife than the wax pencils of old. Physicians are then called upon to critically examine a variety of treatment criteria before selecting the “optimal” plan.

Rising concern focuses on chemoradiation-induced toxicities in treatment of locally advanced, nonsmall cell lung cancer (NSCLC). Publication of results from RTOG 0617 (randomized phase III comparison of standard-dose [60 Gy] vs high-dose [74 Gy] conformal radiotherapy with concurrent and consolidation carboplatin/paclitaxel ± cetuximab in patients with stage IIIA/IIIB NSCLC) has intensified uneasiness. Increased utilization of higher radiation doses, expansion of low-dose wash with intensity-modulated radiation therapy (IMRT), and potent radiosensitization with carboplatin/paclitaxel have each been implicated as contributors to treatment-induced morbidity/mortality.1-3

Recurrences and local failures in lung cancer remain common. Attempts to further intensify therapy have been met with mixed results. RTOG 0617 was initiated as a randomized, 2-by-2 factorial, phase III effort to investigate both the addition of cetuximab and dose escalation from 60 Gy to 74 Gy.1 Unfortunately, neither cetuximab nor dose escalation proved beneficial in this trial. Most disconcerting to radiation oncologists was the survival detriment in the 74 Gy arm, often attributed to treatment-related toxicity because no differences were noted in disease recurrence. On multivariate analysis, the prescription dose, maximal grade of esophagitis, planning target volume, heart V5, and heart V30 were each independent predictors of shorter overall survival.

When delivering such high doses of radiation therapy, IMRT is commonly employed to reduce dose to critical structures, such as the lung, heart, and esophagus. By using multiple computer-optimized and modulated fields, IMRT can achieve highly conformal dose distributions, with rapid fall-off toward nearby critical structures, that compare favorably with results from 3D-CRT.4 Quality of life (QoL) data from RTOG 0617 confirmed worse toxicity in the high-dose arm, but IMRT lessened clinically meaningful declines in QoL.5 It has been argued, however, that IMRT represents a double-edged sword, because it increases exposure of nearby normal tissue to a bath of lower doses (< 10 Gy). Healthy lung tissue may be particularly at risk.

The lung V20 first emerged as the most predictive marker for pneumonitis in early 3D-CRT approaches (APPA followed by parallel opposed obliques off-cord).6 With modern 3D-CRT/IMRT techniques, the entire dose–volume curve has increased in significance. Retrospective data from MD Anderson Cancer Center have posited that the V5, V25, V35, V45, and absolute volumes may each predict for radiation pneumonitis.7,8 Ultimately, balancing low- and high-dose conformality seems to produce optimal plans.9 Additional recently presented findings from RTOG 0617 suggest that IMRT reduces rates of clinically significant pneumonitis despite increased integral dose.10Multiple published IMRT clinical experiences, reporting reasonable rates of toxicity, are reassuring,7,8 In the patient presented, a comparative IMRT plan was generated but rejected in favor of 3D-CRT.

In this case, 3D-CRT was nominally utilized, although the resultant plan is relatively non-“conformal.” The dose-volume histogram (DVH) in Figure 3 accompanied the treatment fields. The delivered plan possessed a lower V5 and V20 than the comparison IMRT plan (unavailable). However, the lateral fields resulted in large hotspots in normal lung, chest wall, heart, and esophagus, with a maximum point dose of 84.76 Gy (~115%) (Figure 1). The IMRT plan had a similar V5 and V20, raising concern that the number of fields employed may have been similarly few and not thoughtfully oriented. Despite the superficial appearance of 3D-CRT dosimetric superiority in this case, selection of this plan was misguided.

In addition, the heart, esophagus, and bilateral chest walls in this relatively young patient demonstrated life-altering toxicity: feeding-tube dependence for 7 years; multiple rib fractures/chest wall fibrosis; and chronic pericardial effusions. Only one of these structures (heart) was contoured. With either forward or inverse planning techniques, the ideal radiation therapy plan can be achieved only with thorough and thoughtful contour delineation. Optimal technique selection in modern planning is built on a foundation of accurate, reproducible volumes.

CONCLUSION

This case serves as a potent reminder that radiation oncologists must be diligent in contouring and plan evaluation. Beam arrangement, radiotherapy dose, conformality, modulation complexity, homogeneity, patient-specific features, and chemotherapeutic regimen (among others) must be examined. IMRT remains a viable and useful approach in the appropriate clinical setting. It should be noted that, despite initial stage IIIA disease, the patient had a durable response to initial chemoradiotherapy—but this came at a terrible cost.

‘Liquid biopsy’ blood test accurately detects key genetic mutations in most common form of lung cancer, study finds


A simple blood test can rapidly and accurately detect mutations in two key genes in non-small cell lung tumors, researchers at Dana-Farber Cancer Institute and other institutions report in a new study – demonstrating the test’s potential as a clinical tool for identifying patients who can benefit from drugs targeting those mutations.

The test, known as a liquid biopsy, proved so reliable in the study that Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) expects to offer it soon to all patients with non-small cell lung cancer (NSCLC), either at the time of first diagnosis or of relapse following previous treatment.

NSCLC is the most common form of lung cancer, diagnosed in more than 200,000 people in the United States each year, according to the American Cancer Society. An estimated 30 percent of NSCLC patients have mutations in either of the genes included in the study, and can often be treated with targeted therapies. The study is being published online today by the journal JAMA Oncology.

The liquid biopsy tested in the study – technically known as rapid plasma genotyping – involves taking a test tube-full of blood, which contains free-floating DNA from cancer cells, and analyzing that DNA for mutations or other abnormalities. (When tumor cells die, their DNA spills into the bloodstream, where it’s known as cell-free DNA.) The technique, which provides a “snapshot” of key genetic irregularities in a tumor, is a common tool in research for probing the molecular make-up of different kinds of cancers.

“We see plasma genotyping as having enormous potential as a clinical test, or assay – a rapid, noninvasive way of screening a cancer for common genetic fingerprints, while avoiding the challenges of traditional invasive biopsies,” said the senior author of the study, Geoffrey Oxnard, MD, thoracic oncologist and lung cancer researcher at Dana-Farber and Brigham and Women’s Hospital. “Our study was the first to demonstrate prospectively that a liquid biopsy technique can be a practical tool for making treatment decisions in cancer patients. The trial was such a success that we are transitioning the assay into a clinical test for lung cancer patients at DF/BWCC.”

The study involved 180 patients with NSCLC, 120 of whom were newly diagnosed, and 60 of whom had become resistant to a previous treatment, allowing the disease to recur. Participants’ cell-free DNA was tested for mutations in the EGFR and KRAS genes, and for a separate mutation in EGFR that allows tumor cells to become resistant to front-line targeted drugs. The test was performed with a technique known as droplet digital polymerase chain reaction (ddPCR), which counts the individual letters of the genetic code in cell-free DNA to determine if specific mutations are present. Each participant also underwent a conventional tissue biopsy to test for the same mutations. The results of the liquid biopsies were then compared to those of the tissue biopsies.

The data showed that liquid biopsies returned results much more quickly. The median turnaround time for liquid biopsies was three days, compared to 12 days for tissue biopsies in newly diagnosed patients and 27 days in drug-resistant patients.

Liquid biopsy was also found to be highly accurate. In newly diagnosed patients, the “predictive value” of plasma ddPCR was 100 percent for the primary EGFR mutation and the KRAS mutation – meaning that a patient who tested positive for either mutation was certain to have that mutation in his or her tumor. For patients with the EGFR resistance mutation, the predictive value of the ddPCR test was 79 percent, suggesting the blood test was able to find additional cases with the mutation that were missed using standard biopsies.

“In some patients with the EGFR resistance mutation, ddPCR detected mutations missed by standard tissue biopsy,” Oxnard remarked. “A resistant tumor is inherently made up of multiple subsets of cells, some of which carry different patterns of genetic mutations. A single biopsy is only analyzing a single part of the tumor, and may miss a mutation present elsewhere in the body. A liquid biopsy, in contrast, may better reflect the distribution of mutations in the tumor as a whole.”

When ddPCR failed to detect these mutations, the cause was less clear-cut, Oxnard says. It could indicate that the tumor cells don’t carry the mutations or, alternatively, that the tumor isn’t shedding its DNA into the bloodstream. This discrepancy between the test results and the presence of mutations was less common in patients whose cancer had metastasized to multiple sites in the body, researchers found.

The ddPCR-based test, or assay, was piloted and optimized for patients at the Translational Resarch lab of the Belfer Center for Applied Cancer Science at Dana-Farber. It was then validated for clinical use at Dana-Farber’s Lowe Center for Thoracic Oncology.

An advantage of this form of liquid biopsy is that it can help doctors quickly determine whether a patient is responding to therapy. Fifty participants in the study had repeat testing done after starting treatment for their cancer. “Those whose blood tests showed a disappearance of the mutations within two weeks were more likely to stay on the treatment than patients who didn’t see such a reduction,” said the study’s lead author, Adrian Sacher, MD, of Dana-Farber and Brigham and Women’s Hospital.

And because tumors are constantly evolving and acquiring additional mutations, repeated liquid biopsies can provide early detection of a new mutation – such as the EGFR resistance mutation – that can potentially be treated with targeted agents.

“The study data are compelling,” said DF/BWCC pathologist Lynette Sholl, MD, explaining the center’s decision to begin offering ddPCR-based liquid biopsy to all lung cancer patients. “We validated the authors’ findings by cross-comparing results from liquid and tissue biopsies in 34 NSCLC patients. To work as a real-world clinical test, liquid biopsy needs to provide reliable, accurate data and be logistically practical. That’s what we’ve seen with the ddPCR-based blood test.

“The test has great utility both for patients newly diagnosed with NSCLC and for those with a recurrence of the disease,” she continued. “It’s fast, it’s quantitative (it indicates the amount of mutant DNA in a sample), and it can be readily employed at a cancer treatment center.”

New triple-therapy treatment may help in fighting lung cancer


Representational Image. (Picture Courtesy: File photo)

Representational Image. (Picture Courtesy: File photo)

Washington: A triple therapy treatment consisting of two experimental drugs and radiation therapy may help fight lung cancers that are resistant to current treatments, a new study has claimed. Although the most common type of lung cancer – non-small cell lung cancer (NSCLC) – has recently seen major treatment advances in some genetic subtypes, other subtypes continue to evade effective treatment, researchers said.

Roughly 85 per cent of all lung cancers belong to the NSCLC type. Although there have been some advances in treating this disease, only two per cent of survivors live five years beyond treatment. Drugs have been developed to target the ALK- and EGFR-mutated subtypes, and are to some degree effective,
however, one genetic subset, NSCLCs with mutations in the gene KRAS have been resistant to conventional and targeted therapies.

The new study in mice has shown that cancers with KRAS-related gene mutations might benefit from a triple therapy with two experimental drugs plus radiation therapy. “Currently there is a clinical trial underway to evaluate the combination of two cancer drugs, trametinib and palbociclib, made by two pharma companies for patients with solid tumours and melanoma,” said Bo Lu, Professor of Radiation Oncology at Thomas Jefferson University in US. “Although further research in human subjects is needed to confirm the finding, our study suggests that we may be able to identify non-small cell lung cancer patients who are likely to benefit most from this combination of therapies,” Lu said.

The researchers studied the KRAS-mutant subset in NSCLC cells and found that there was variation within this subset; some were more resistant to a drug that targeted the KRAS gene pathway than others. An additional mutation in a protein called p16 appeared to be responsible for this difference.
After scanning a database of lung-cancer patient genotypes, the researchers saw that patients with the p16 mutation had a lower overall survival rate than those without the mutation.

In order to help make these resistant KRAS mutants more susceptible to therapy, the researchers combined the KRAS-targeting drug with another drug that would undo the effects of the p16 mutation. They showed that the combination of the two drugs make these resistant cancer cells susceptible to radiation treatment.

The research could help identify the patients who could potentially benefit from a triple-therapy treatment. The study was published in the journal Clinical Cancer Research.

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