FDA and Trans Fat in processed Food.

June 16, 2015
AMA Applauds U.S. Food and Drug Administration for Steps to Remove Trans Fat from Nation’s Food Supply

For immediate release:
June 16, 2015

FDA’s Action to Eliminate Trans Fat Will Help Prevent Cardiovascular Disease and Save American Lives

Statement attributable to: Steven J. Stack, M.D., President, American Medical Association

“The American Medical Association (AMA) commends the U.S. Food and Drug Administration (FDA) for its decision today to remove partially hydrogenated oils, the primary dietary source of artificial trans fat in processed foods, from all U.S. food products. Last year, we issued a letter in support of the FDA’s efforts to restrict trans fat and also urged the FDA to take additional steps to impose strict limits on the amount of trans fat in processed foods. Today, we support the FDA’s move to eliminate trans fat as an important component in a multipronged strategy needed to help improve public health.

“With ample scientific research linking the consumption of trans fat to dangerous health effects, including heart attack and stroke, the AMA believes that removing trans fat from our nation’s food supply will help reduce the risk of preventable diseases and ultimately save lives.

“The FDA’s action to remove trans fat aligns with the AMA’s ongoing efforts to prevent cardiovascular disease and type 2 diabetes and improve health outcomes. Last week, the AMA adopted policy at its 2015 Annual meeting supporting state and federal legislation banning the use of artificial trans fat in the U.S.

“The AMA is fully committed to improving the health of the nation and we will continue to support efforts and advocate for policies that help reduce the burden of preventable diseases—leading to a healthier nation and reducing health care costs.”

###

Media Contact:
Kelly Jakubek
AMA Media & Editorial
(312) 464-4443
Kelly.Jakubek@ama-assn.org

Follow AMA news on Facebook, Twitter and LinkedIn.

Prostate cancer: vessel-sparing radiation therapy and sexual function

Majority of prostate cancer patients surveyed five years after treatment with vessel-sparing radiation therapy report preserved sexual function

San Francisco, September 15, 2014



A comparison of five-year sexual function outcomes, as reported by patients treated with external beam radiotherapy (EBRT) versus combination EBRT plus brachytherapy, indicates that the utilization of vessel-sparing radiation therapy makes cure possible without compromising long-term sexual function, according to research presented today at the American Society for Radiation Oncology’s (ASTRO’s) 56th Annual Meeting.

The study examined the patient-reported outcomes of 91 men with prostate cancer who received MRI-guided, vessel-sparing radiation at University of Michigan Providence Cancer Institute. The vessel-sparing radiation technique limits the amount of radiation to critical erectile tissues using MRI scans to identify the blood vessels responsible for erections. When radiation dose is limited to these critical structures, the risk of erectile dysfunction is lowered.

Of the 91 patients studied, all patients received EBRT. Forty-two of the patients received only EBRT (>77.8Gy), and 49 patients received EBRT plus brachytherapy, the implantation of radioactive seeds near the prostate. The combination patients received brachytherapy in the form of an I-125 permanent prostate implant. None of the patients received androgen deprivation therapy (ADT).

Sexual function at baseline, two years and five years post-therapy was evaluated via patient reported outcomes using two scales— the International Index of Erectile Function (IIEF) scale and a simple, three-item questionnaire that asked patients to indicate which applied to them: 1) I am able to be sexually active without aids or medications; 2) I am able to be sexually active with aids or medications; or 3) I am not able to be sexually active.

The three-question scale was used in addition to the IIEF, which validates erection quality by sexual performance with a partner, because many men were not sexually active with a partner, despite their ability to be active with a partner. Patient-reported outcome on sexual performance according to the IIEF was lower than the outcome reported according to the three-question scale. The average two-year follow-up IIEF scores for EBRT patients and combination therapy patients were 16.5 and 20.8, respectively. The average five-year follow-up IIEF scores for EBRT patients and combination therapy patients were 15.4 and 16.9, respectively.

According to the three-question scale, erectile function was remarkably preserved using MRI-planned vessel-sparing treatment, even in patients who received combination therapy: 78.6 percent of patients who received EBRT (33 of 42) and 91.8 percent of patients who received combination therapy (45 of 49) reported the ability to be sexually active with or without aids at five years post-treatment.

“In the past, men with prostate cancer expected to pay a high toll in loss of quality of life to achieve cure and were willing to accept that as necessary,” said lead study author Patrick W. McLaughlin, MD, director of radiation oncology at University of Michigan Providence Cancer Institute in Novi, Mich. “This study makes it clear that even with combination radiation protocols, which are capable of curing the majority of prostate cancers more than 90 percent of the time, avoidance of critical adjacent tissues, such as vessel-sparing, makes cure and quality of life an achievable goal for many men.”

The abstract, “Comparison of External Beam and Combination Therapy for Prostate Cancer: Patient Reported Outcomes of Sexual Function with 5-Year Follow-up” will be presented in detail during a scientific session at ASTRO’s 56th Annual Meeting at 4:15 p.m. Pacific time on Monday, September 15, 2014. To speak with Dr. McLaughlin, please call Michelle Kirkwood on September 14 – 17, 2014, in the ASTRO Press Office at the Moscone Center in San Francisco at 415-978-3503 or 415-978-3504, or email Michelle Kirkwood.

Definitive and adjuvant radiation therapy for locally advanced non-small cell lung cancer

New ASTRO guideline on definitive and adjuvant radiation therapy for locally advanced non-small cell lung cancer, nearly one-quarter of all lung cancers, featured in May-June issue of PRO

Fairfax, Va., May 5, 2015


The American Society for Radiation Oncology (ASTRO) is issuing a new guideline, “Definitive and adjuvant radiotherapy in locally advanced non-small cell lung cancer: An American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline.” The guideline’s executive summary is published in the May-June issue of Practical Radiation Oncology (PRO), ASTRO’s clinical practice journal. The complete guideline, which cites 35 years of data to help guide current treatment and future research, is available online as an open-access article in PRO. The American Society of Clinical Oncology (ASCO) today issued an endorsement of ASTRO’s guideline.

ASTRO’s guideline panel included 14 leading lung cancer oncologists in the U.S. and Canada, reviewed 74 studies from English language publications within the PubMed database, published from January 1, 1966 to March 15, 2013. The panel developed five Key Questions on the role of definitive and adjuvant radiation therapy (RT) for locally advanced non-small cell lung cancer (LA NSCLC), which represents nearly one-quarter of all lung cancer patients. In addition to the 74 studies, 27 published clinical practice guideline documents that were relevant to one or more of the five Key Questions were reviewed to ensure the guideline panel obtained all appropriate clinical trial reports.

The first Key Question addresses the ideal external beam dose fractionation for curative-intent treatment of LA NSCLC with RT alone without chemotherapy. The evidence cited in the guideline suggests that RT alone was associated with improved overall survival when compared with observation strategies or chemotherapy alone; however, patients experienced treatment-related side effects such as esophagitis and pneumonitis. RT may be used alone as definitive radical treatment for patients with LA NSCLC who are not eligible for combined modality therapy. A minimum dose of 60 Gy is recommended to optimize clinical outcomes such as local control.

The second Key Question examines the ideal external beam dose fractionation for curative-intent treatment of LA NSCLC with chemotherapy. The standard thoracic RT dose fractionation for patients treated with concurrent chemotherapy is 60 Gy, administered as 2 Gy, once a day for six weeks. It has not been demonstrated that increasing the dose beyond 60 Gy with conventional fractionation is associated with any clinical benefits, including overall survival.

The third Key Question details the ideal timing of external beam RT in relation to systemic chemotherapy for curative-intent treatment of LA NSCLC. The guideline recommends that when RT and chemotherapy are used to treat LA NSCLC, RT should ideally begin at the same time chemotherapy begins (concurrent chemoradiation). For patients that cannot tolerate concurrent chemoradiation, the guideline recommends sequential chemotherapy followed by radical radiation treatment.

The fourth Key Question examines the indications for adjuvant post-operative RT for curative-intent treatment of LA NSCLC. The use of post-operative RT for completely resected LA NSCLC with N2 mediastinal disease is associated with improved local control but not improved overall survival. According to the guideline, post-operative RT is not commonly recommended for patients with N0 or N1 mediastinal disease. The guideline recommends that patients with microscopic or macroscopic residual primary and/or nodal disease should receive post-operative RT to improve local control.

The fifth Key Question addresses when neoadjuvant RT or chemoradiation prior to surgery is indicated for curative-intent treatment of LA NSCLC. According to the guideline, there is no Level I evidence recommending the routine use of pre-operative neoadjuvant RT or chemoradiation for the management of LA NSCLC. However, the guideline provides information on ideal patient selection, operation type and radiation dose for patients selected to receive RT prior to surgery.

“Radiation therapy is a central component of treatment protocols for patients with locally advanced non-small cell lung cancer, with five-year survival rates of approximately 26 percent” said George Rodrigues, MD, PhD, co-chair of the guideline panel and a radiation oncologist at London Health Sciences Centre in London, Ontario. “This guideline summarizes more than 35 years of clinical trial evidence to provide the best evidence-based guidance on RT to improve outcomes for this challenging patient population.”

The guideline was approved by ASTRO’s Board of Directors in June 2014 and has been endorsed by ASCO. ASCO’s endorsement, “Definitive and Adjuvant Radiotherapy in Locally Advanced Non-Small Cell Lung Cancer: ASTRO Clinical Practice Guideline: American Society of Clinical Oncology Endorsement,” was issued today in the Journal of Clinical Oncology and in the Journal of Oncology Practice and is available online at www.jco.org and http://jop.ascopubs.org. The guideline panel included radiation oncologists, a medical oncologist, a thoracic surgeon and a radiation oncology resident: Dr. Rodrigues (co-chair), Gregory Videtic, MD, CM (co-chair), Hak Choy, MD, Jeffrey Bradley, MD, Kenneth E. Rosenzweig, MD, FASTRO, Jeffrey Bogart, MD, Walter J. Curran Jr., MD, Elizabeth Gore, MD, Corey Langer, MD, Alexander Louie, MD, MS, MSc, Stephen Lutz, MD, FASTRO, Mitchell Machtay, MD, Varun Puri, MD, MSCI, and Maria Werner-Wasik, MD, FASTRO.

For a copy of the complete guideline, contact ASTRO’s Press Office. Learn more about PRO.

10 Molecular Types of Breast Cancer

Scientists Identify 10 Molecular Types of Breast Cancer -- How Long Until Progress Reaches the Clinic?
Posted: 05/03/2012 3:20 pm EDT Updated: 07/03/2012 5:12 am EDT
Dr. Elaine Schattner


Doctors have understood for decades that breast cancer is not one disease. Still, and with few exceptions, knowledge of breast cancer genetics -- information on cancer-causing mutations in the malignant cells -- has lagged. Here's the paradox: Because effective treatments exist for most patients with this disease, the pace of new drug development is slow; there's little impetus for people with early-stage tumors to try new forms of therapy. For women with metastatic breast cancer -- who've typically been through the mill with a combination of chemo and surgery, radiation or hormonal depletion -- most physicians still prescribe standard sorts of treatment.

A recent paper published in Nature could change this picture. The new analysis, based on patterns of DNA mutations and RNA expression in 2000 specimens, defines 10 molecular types of breast cancer. The enormously-detailed findings, augmented by virtual reams of open-access supportive data, should lead scientists and doctors to provide better, less toxic treatment options for women with all stages of the disease.

To keep this study in perspective -- it's about breast cancers in humans. No mice. The researchers examined nearly 2,000 specimens, with linked clinical records and follow-up through 15 years. First, they probed for inherited and acquired mutations in DNA from 997 tumors. They profiled gene expression by measuring tens of thousands of RNAs in each sample. They revealed mutation "hot spots," and correlated those findings with abnormal gene expression in the cancers. The list of implicated genes includes some old finds, like PTEN, MYC, CDK3 and -4, and others. They discovered that three genes, PPP2R2A, MTAP or MAP2K4 are deleted in some breast cancer cases. The paper is rich with details.

The scientists used cluster analyses to delineate 10 molecular subgroups. The new breast cancer categories, called "IntClust 1-10," defy old classifications of this disease. They turn out, also, to offer prognostic information. Finally -- in what's tantamount to a second report within the Nature paper -- the team probed a "validation set" of 995 more breast cancer specimens. Upon analyzing paired DNA mutations and profiles of RNA expression in these samples, the same 10 subtypes emerged. What's more, the prognostic (survival) information held up.

If confirmed, these observations could lead to smarter therapy for distinct breast cancer types. What's key -- and perhaps might deliver this work to the clinic -- is the investigators related the DNA abnormalities, including inherited and acquired variants in the copy numbers of particular genes, with altered RNA patterns. They observed turned-on gene sets, including enzymes that affect how cells grow and divide, and inflammatory regulators, among many examples. These "downstream" effects on gene expression -- apart from the DNA mutations -- might be vulnerable to innovative drugs. Through innovative trial strategies like I-SPY, it's possible that patients with particular molecular subgroups could be directed to small trials of new medications, including some agents already in the pipeline for this and other malignancies.

To be sure, these are preliminary findings. This is the first report on what's a proposed new molecular classification of breast cancer. That said, the paper reflects an enormous amount of cutting-edge work put together through an international consortium of investigators. It's an exquisite application of science in medicine. The results shouldn't be ignored, or sat upon for years, by researchers in the U.S. and elsewhere developing new drugs for breast cancer.

Until there's a way to prevent breast cancer, we need better ways to treat it. Oncologists see, now, that some cancers respond dramatically to drugs designed to hit specific genetic mutations. Recently-incurable malignancies, like advanced melanoma and GI stromal tumors, can be treated with pills, often with terrific responses. But for breast cancer, most treatments remain primitive -- like surgical carving, traditional chemotherapy and radiation. Herceptin and a few other monoclonal antibodies are used, but there's nothing approaching Gleevec-like pills for any form of this malignancy. Some doctors consider hormone therapy as targeted, and thereby "modern" and satisfactory. I don't.

This paper leads me to wonder if, in a few years, some breast cancers might be treated without surgery. Doctors could perform a small biopsy with a needle, check for the molecular type, and give the right breast cancer tablets. Perhaps patients would need a tad of chemo, later, to "mop up" any residual or resistant cells. But the mainstay of treatment would be a cocktail of drugs, by mouth, like patients take for hepatitis C, tuberculosis or AIDS. There'd be no lost breasts, no reconstruction, no lymphedema. Can you imagine?

Even if just a few of these newly-identified subtypes pan out and lead to this sort of radically-transformed breast cancer treatment, that would be a dream. This can't happen soon enough.

For more by Dr. Elaine Schattner, click here.

For more on breast cancer, click here.

Follow Dr. Elaine Schattner on Twitter: www.twitter.com/ElaineSchattner

Value in Drugs for cancer treatment

Medscape Medical News > Oncology
ASCO Wants Your Feedback on Plan to Define Value in Drugs

Megan Brooks June 22, 2015

The American Society of Clinical Oncology (ASCO) today unveiled an initial conceptual framework for assessing the value of new cancer treatment options in comparison with existing standards of care, and they are seeking public comment on it.

The treatments are limited to those that have been tested head to head in randomized clinical trials.

The ASCO Value Framework defines value as a measure of clinical benefit, toxicity, and cost. It was published online today in the Journal of Clinical Oncology and at www.asco.org/value and was developed by ASCO's Value in Cancer Care Task Force, with input from oncologists, patient advocates, representatives of the pharmaceutical and insurance industries, and others.

The framework is in response to a "very clear and urgent need" with regard to cancer patients and providers who care for them, ASCO President Julie M. Vose, MD, said during a media briefing.

The cost of new cancer drugs is having a "growing impact" on patients, and there are very few tools that clinicians and patients can use to objectively assess the costs and benefits of new drugs compared with older drugs, said Dr Vose.

"Cancer care costs are growing fast and are expected to increase from $125 billion in 2010 to $158 billion in 2020, and cancer drugs are the most rapidly growing component of these costs," added ASCO chief medical officer Richard Schilsky, MD.

On average, new cancer drugs now cost about $10,000 per month for a single drug, with some exceeding $30,000 per month. "Out-of-pocket costs, which matters most to our patients, are also rising, and total out-of-pocket burden for cancer patients is greater than for other patients with chronic diseases," Dr Schilsky noted. Studies have also shown that some cancer patients take less medication than prescribed or avoid filling prescriptions altogether because of concerns about cost, which in the long run could drive up costs of care, he said.

The ASCO Value Framework proposes a methodology to compare the relative clinical benefits, side effects, and costs of treatment regimens that have been tested head to head in randomized clinical trials, as noted above. Data on the clinical benefits and toxicity of a regimen are used to calculate a combined net health benefit score, or NHB.

"The NHB represents the added benefit that patients can expect to receive from the new therapy vs the current standard of care," ASCO explains in a news release. The NHB is presented alongside the patient's expected out-of-pocket costs for the regimens being compared, as well as the overall drug acquisition cost.

Definition of Value Highly Personal

"It's critical to distinguish between value and cost," Lowell E. Schnipper, MD, chair of ASCO's Value in Cancer Care Task Force, said in the release. "Sometimes the more valuable treatment will be the more expensive one, and sometimes it won't be. Ultimately, the definition of 'value' will be highly personalized for each patient, taking into account an individual's own preferences and circumstances. For example, in the setting of advanced cancer, is length of life the most important goal, or is quality of life? Is the proposed treatment affordable? That's why we're proposing to provide information on net health benefit and cost side by side," Dr Schnipper said.

To highlight the potential utility of the framework, the ASCO Task Force applied its methodology to metastatic lung cancer, advanced multiple myeloma, metastatic prostate cancer, and adjuvant therapy for HER2-positive breast cancer.

"The results were striking: in some clinical scenarios, a newer, more expensive regimen had a much larger NHB than the previous standard. In other scenarios, the newer, more expensive regimen showed little or no net health benefit. These are sample scenarios only, and NHBs for the same regimen may vary in different types of cancer or treatment settings," ASCO notes in the release.

The results were striking.


"We envision sometime in the future to have a software that is available to utilizing this value framework or one just like it that's curated with many comparative trials such that it would be very easy for a patient to see for a given clinical indication what the treatment options are," Dr Schnipper told reporters. "The patient then might literally adjust the preference if length of life is most important to them, or quality of life/absence of toxicity is more important to them, that individualization is of critical importance in clinical oncology, particularly in the advanced disease setting, and that's where we see this heading as it matures and evolves and goes through other iterations," he added.

Dr Vose said the goal in publishing this first version of the framework is to "drive discussion and debate on this critical issue, and we are soliciting feedback over the next 60 days from all stakeholders via our website. That feedback will form the evolution of the framework, which I'm sure will change over time," she added.

ASCO is accepting comments on the framework until August 21, 2015, at www.asco.org/value.

The European Society of Clinical Oncology also recently unveiled a tool to assess the value of cancer drugs, as reported by Medscape Medical News.

Oncologists at Memorial Sloan Kettering Cancer Center, in New York City, have come up with their own interactive drug value calculator for new cancer drugs, as described in a recent article in the Wall Street Journal.

J Clin Oncol. Published online June 22, 2015. Full text

The Optimal Blood Pressure Target

Medscape Cardiology > Black on Cardiology
Not Too High, Not Too Low: The Optimal Blood Pressure Target

Henry R. Black, MD Disclosures November 14, 2014


I am Dr Henry Black, adjunct professor of medicine at the Langone New York University School of Medicine. I want to talk about the J-shaped (or U-shaped) curve, an issue that has been bothering clinicians and epidemiologists who are interested in hypertension. The J- or U-shaped curve means that people at the top of the curve have the most risk. This concept is relevant to blood pressure and cholesterol. People at the lowest end of the curve are also at risk. We would like to find the optimal target for the treatment and epidemiologic study of high blood pressure, and the optimal cholesterol level as well, and data have now been provided in a very interesting study from the Southern California Kaiser Group.[1]

They looked at more than 3.4 million patients and identified approximately 500,000 who were being treated for hypertension, of whom approximately 460,000 had blood pressure measurements. They were trying to determine the optimal blood pressure in the treated group. Epidemiologic predictions are different, because rather than being based on treated people, they are based on untreated people, in whom the risk is linear: The lower you go, the better you are. But in treated patients, we are not sure what blood pressure is best. These investigators selected deciles of systolic blood pressure, from < 100 mm Hg to 110 mm Hg, and up to 170 mm Hg. They also analyzed diastolic blood pressures but focused primarily on systolic.

The optimal blood pressure turned out to be 137/71 mm Hg, and the optimal level to treat to was the lowest decile (130-139 mm Hg). They compared that decile with all of the others, and in every case, as the systolic blood pressure went up, so did the risk. As the blood pressure went down, the risk increased as well.

The so-called JNC 8 guidelines[2] recommend aiming for a systolic blood pressure < 150 mm Hg. That wasn't an evidence-based recommendation, although the title of the guidelines suggests that they are evidence-based. That recommendation was expert opinion–based. The finding that 130-139 mm Hg is the optimal target for treatment differs from what might be considered optimal epidemiologically, but those of us who are treating patients are more interested in the best treatment target. Our take-home message from this trial, published in the Journal of the American College of Cardiology, is that the optimal target for treatment is between 130 and 139 mm Hg systolic. Thank you very much.

GPs and cancer diagnoses

Medscape Medical News > Oncology
UK Reform Empowers PCPs to Improve Cancer Diagnoses

Liam Davenport June 25, 2015


A new cancer strategy for primary care practitioners that places an emphasis on early recognition and referral could save thousands of lives in the United Kingdom every year, says the UK's health watchdog.

The National Institute for Health and Care Excellence (NICE) issued new guidelines this week that focus on symptom-led cancer diagnosis in primary care, expand the tests available to general practitioners, and set out maximum referral times.

For example, the new guidelines mean that general practitioners (the British term for primary care physician) will now be able to order fasttrack endoscopies and MRI and CT scans, which were previously available only after specialist referral to a hospital.

Professor Mark Baker, clinical practice director at NICE, said in press release: "The best way to successfully treat cancer is to make an early diagnosis. The sooner the disease is identified, the more likely treatment is to be effective."

Britain has lagged behind "the best European countries" in terms of cancer outcome statistics, he said in a television interview. "The main reason for that is that people tend to present with a cancer at a more advanced stage."

People tend to present with a cancer at a more advanced stage. Prof Mark Baker


The new guidelines will save an estimated 5000 lives a year, according to Prof Baker.

The charity Cancer Research UK estimates that there more than 160,000 deaths due to cancer per year in the United Kingdom. Recent research suggests that up to 10,000 cancer deaths could be prevented each year in England alone with earlier diagnosis and more appropriate surgery.

Moreover, cancer survival rates in the United Kingdom and Ireland are low compared with the rest of Europe for a number of types of malignancies, including kidney, stomach, ovarian, colon, and lung cancers.

To bridge the gap, new recommendations shift the emphasis away from considering whether a patient has cancer and then crosschecking it against the symptoms and toward focusing on a patient's symptoms and then linking them to possible cancers and selecting the most appropriate tests.

NICE provided examples of their new proactive recommendations. For example, fatigue that is unexplained in an individual older than 40 years who has ever smoked would point to a chest X-ray for lung cancer and, in a woman, would merit a blood test for ovarian cancer.

public health community and e-cigarettes

Feature Tobacco
Why e-cigarettes are dividing the public health community
2015; 350 doi: http://dx.doi.org/10.1136/bmj.h3317 (Published 24 June 2015) Cite this as: 2015;350:h3317


Jonathan Gornall, journalist, Suffolk, UK

jgornall@mac.com

The tobacco industry used to be seen as the enemy of public health, but the move into e-cigarettes and harm reduction has seen some experts shift their views. Are they right or does industry have more cynical motives? Jonathan Gornall reports

Even the man from British American Tobacco (BAT) struggles to keep the sense of wonder out of his voice as he recounts the strange event that took place earlier this year in San Jose, California. The occasion was the 2015 annual meeting of the American Association for the Advancement of Science. Sharing the floor at the San Jose Convention Centre were two unlikely bedfellows: Deborah Arnott, chief executive of the UK charity Action on Smoking and Health, and Kevin Bridgman, chief medical officer of BAT’s electronic cigarette (e-cigarette) company, Nicoventures.

“Imagine that happening 10 years ago,” says Will Hill, public relations manager for BAT. “We’re now starting to share podiums with people like ASH at e-cigarette conferences.”

It’s a proposition that fills some in the public health community with dismay.

The subject of the symposium was “E-cigarettes: killing me softly or our greatest public health opportunity?” and Arnott and Bridgman—a former GP who is now working for Nicoventures offshoot Nicovations—were singing from the same hymn sheet.

Arnott’s talk highlighted her concern that “some groups” were calling for an outright ban on e-cigarettes, despite a lack of evidence of harm, “especially in comparison to smoking.” She wanted to focus on “counteracting moralistic dogma and separating fact from fiction.”1

Bridgman’s message was that “regulators should resist the urge to apply highly restrictive measures that would have the perverse effect of prolonging cigarette smoking.”2

For some, such an apparent convergence of views is a sign that the industry’s enthusiastic—and, critics maintain, cynical—embrace of the controversial concept of “harm reduction” in tobacco control is paying dividends.

“If the tobacco industry is busy arguing for deregulation and a number of our colleagues in public health find themselves arguing in the same direction as the industry then, with respect, we think that’s time to pause,” said Simon Capewell, professor of public health and policy at Liverpool university’s Institute of Psychology, Health and Society.

“It’s really regrettable,” says Capewell, who supports the Faculty of Public Health position that e-cigarettes should be “subject to the same controls as tobacco” and that the benefits of fewer people smoking must be weighed against “the risk of electronic cigarettes leading to more people starting to smoke, particularly children.”3

If the big tobacco companies were genuinely concerned about the disease and the harm they caused, says Capewell, “they would cease production—end of discussion. They would go into e-cigarette production 100%.”

Capewell and others argue that e-cigarettes help to glamorise and renormalise smoking. Worse, he says, they are being used by the industry “as a trojan horse to get inside ministries of health. They are saying ‘This is all about harm minimisation, we’re part of the solution, we’re no longer the problem.’”

Over at ASH, however, Arnott summarily dismisses such fears. “There are people in the public health community who are obsessed by e-cigarettes,” she says. “This idea that it renormalises smoking is absolute bullshit.” Furthermore, she insists, “There is no evidence so far that it is a gateway into smoking for young people.”

ASH’s concern, she says, “is quite the reverse—that because there is so much bad publicity about them, people’s understanding about the relative risk of smoking and e-cigarettes is being undermined. The risk is that smokers who could potentially use these as an alternative to smoking are being discouraged, and that’s not a good thing.”

For Arnott, the concept of harm reduction boils down to a simple proposition: “Do you want the tobacco industry to carry on making cigarettes which are highly addictive and kill when used as intended, or do you want them to move to a product which is much nearer licensed nicotine replacement therapy and is unlikely to kill anyone?”

Pragmatists versus idealists

Several experts on both sides of the harm reduction debate that I spoke to characterised the divide as being between pragmatists and idealists. The pragmatists are often practising clinicians with patients with progressive lung disease who still smoke, and they can see how they might be helped by switching even partly to e-cigarettes. The idealists are generally those working in public health who take a population view and suspect the industry’s motives.

In 2014 the tension boiled over into a pitched battle of words, fought in public in the run-up to the sixth conference of the parties to the World Health Organization’s Framework Convention on Tobacco Control.

The first salvo was fired in May 2014, when 56 “specialists in nicotine science and public health policy” wrote to Margaret Chan, director general of WHO, to complain that the “critical strategy” of harm reduction had been “overlooked or even purposefully marginalised” in preparations for the conference. Harm reduction, they insisted, was “part of the solution, not part of the problem.”4

There was a swift retaliation from the other side of the debate, signed by 129 public opposing experts organised by Stanton Glantz, director of the WHO Collaborating Centre on Tobacco Control and American Legacy Foundation distinguished professor of tobacco control at the University of California.

It was “fundamental,” they wrote, that WHO and other public health bodies did not “buy into the tobacco industry’s well-documented strategy of presenting itself as a partner.” If it were serious about reducing tobacco harm, it would stop manufacturing cigarettes, “rather than simply adding e-cigarettes to its product mix and rapidly taking over the e-cigarette market.” By moving into the market, the tobacco industry was “only maintaining its predatory practices and increasing profits.”

As the letter demonstrated, there were many in public health who had neither forgotten nor forgiven the industry’s cynical adoption of “low tar” cigarettes while knowing that they “did not actually reduce harm but were designed to promote cigarette sales by reassuring a concerned public that the new products were safer.”

The letter cited a US court ruling in 2006, which found that three tobacco companies— including Philip Morris, the world’s largest—had “deliberately deceived” consumers about “the lack of any significant health benefit from smoking ‘low tar,’ ‘light,’ ‘ultralight,’ ‘mild’ and ‘natural’ cigarettes.”5

The consequences of this, said the Glantz letter, could be seen today “in cancer and heart disease hospital wards throughout the world.”6

The original authors rapidly returned fire, accusing their critics of “an attempt to influence policy through misrepresentation of evidence.” The basic proposition of harm reduction, they stressed, was not that the alternative nicotine products are harmless but that they reduce the risk by at least 95% more compared with cigarettes and “provide a viable alternative to smokers who cannot or do not wish to quit.”

The challenge was “to find an appropriate framework for realising the significant public health opportunities this offers while managing residual risks.”7

Industry embrace

That BAT was following this spat with more than casual interest became apparent when it quickly incorporated a quote from the letter into its promotional material extolling the virtues of harm reduction.

In a public relations report, Harm Reduction: the Opportunity, BAT said an “increasing number of people in the scientific and public health community” were “now advocating harm reduction as the way forward for helping the 1.3 billion people worldwide who continue to smoke despite the known health risks.”

The only stumbling blocks to such progress, according to BAT, were that few governments currently supported harm reduction and that there were “some public health experts and organisations with concerns that not enough is known yet about the health risks of e-cigarettes and that they could undermine efforts to denormalise tobacco use.” Such doubters were “also suspicious of the tobacco industry’s involvement in tobacco harm reduction.”

While the company understood that this was “a contentious topic” it hoped that its actions would “demonstrate our continued commitment to harm reduction and that governments will carefully consider the potential benefits it can bring as part of a progressive approach to public health policy.”8

To those suspicious of the concept of harm reduction, this was breathtaking. The industry that had been killing so many people for so long was now planning to profit by offering a solution to the very problem it had created—if only all those obstructive scientists and governments would just get on board.

One of those who had was Gerry Stimson, former director of the department of social science and medicine at Imperial College London and one of the organisers of the first letter to WHO and the subsequent response to its critics. The letter was published on the website Nicotine Science and Policy, a forum run by Stimson’s company Knowledge-Action-Change. KAC is “committed to the development and promotion of evidence-based policies and interventions in the field of substance use and related areas of public health and public policy.”

Stimson has made no secret of his relations with the tobacco industry. From 2011 to 2013, he was a member of the NICE programme development group producing guidance on tobacco harm reduction. Minutes of the group’s first meeting, in October 2011, record he declared he had “received hospitality from British American staff and has reciprocated.”

In May 2012 he had “attended a Christmas drinks reception at British American Tobacco” and in February 2013 it was noted that he was “the director of a company, Knowledge-Action-Change, which has requested and received development funding from [the BAT offshoot] Nicoventures for a project to support smoking cessation in a closed setting.”9

The NICE guidelines on which Stimson worked were published in June 2013 and superseded an earlier document, published in 2008. The titles of the two documents tell their own story about the change of emphasis in the approach to smoking: document PH10, “Smoking cessation services,” had been replaced by PH45, “Tobacco: harm-reduction approaches to smoking.”

Stimson did not respond to requests for an interview. But in an earlier email he said he believed that “much of the work we need to do to reduce harm from legal psycho-active substances means that we will have to work with people who are producing and selling them.”

E-cigarettes and other nicotine delivery systems had “huge potential . . . to help shift people away from smoking,” he added. But “the quandary for many public health experts . . . is that the solution to smoking might well lie with the much reviled tobacco industry.”

Others clearly think so too. One is Karl Fagerström, a Swedish clinical psychologist who specialised in smoking cessation and nicotine dependence, was a founder of the Society for Research on Nicotine and Tobacco, and now runs his own consultancy.

Fagerström wrote an article for Nicotine Science and Policy, the website run by Stimson’s company KAC.10 He has also accepted money from BAT in the form of its flagship harm-reduction proxy, Nicoventures.

In March 2014 Fagerström was the coauthor of a paper published in Addictive Behaviours arguing that “the significant positive impact on public health that could be gained from encouraging people to switch from cigarettes to licensed medicinal nicotine products cannot be ignored.” The paper was funded by Nicoventures, and Fagerström’s coauthor was Bridgman, then the medical director of the company, which is now poised to market Voke, the first licensed medicinal nicotine product from a tobacco company.11

It isn’t the only time Fagerström has worked with the company. The BMJ has seen a copy of a lobbying letter sent by Nicoventures to members of the Australian parliament in July 2014, offering them a briefing from Fagerström, who is described as “a leading international smoking cessation/nicotine dependence expert.”

He would “be able to brief you on tobacco harm reduction—including the growing body of evidence around the benefits of significantly safer products including e-cigarettes in helping smokers transition away from harmful traditional cigarettes, and the approach many respected medical groups are taking towards them.”

Fagerström told The BMJ that he had now stopped doing consultancy work for Nicoventures. He had supported the development of Voke because it was regulated, but the company was now working on other products that would not be licensed as medicines.

Nevertheless, he considered that products such as e-cigarettes could have a role in reducing the harm caused by smoking and accused some in public health of losing sight of the true objective.

“When I started to become interested in [tobacco harm] in the mid-70s, we wanted to get rid of the diseases that followed tobacco,” he said. “But nowadays, there is a target conflict. For some, it’s more about getting rid of the tobacco industry rather than helping the poor smokers or to-be smokers.”

Evidence of this, he said, could be found in the way the attitude towards e-cigarettes altered among the public health community after the tobacco industry took over most of the small, independent pioneers in the field.

“When they first came on the market, five or six years ago, there was a positive openness and curiosity,” he said. But after the tobacco industry became involved the attitude changed, to one of suspicion and opposition.

Another of the signatories to the pro-harm reduction letter sent to Chan was John Britton, an epidemiologist who heads the UK Centre for Tobacco and Alcohol Studies, a network of 13 universities providing international research and policy development. He also sat as a member of the NICE programme development group, as had Stimson and Arnott of ASH, and is an ASH trustee.12

“I’m no apologist for or friend of the tobacco industry,” Britton told The BMJ. “But the fact is people smoke tobacco because they are addicted to nicotine, and tobacco companies are in the business of selling them nicotine. So if an alternative means of delivering nicotine to them comes along it’s inconceivable that tobacco companies will not get involved and seek to exploit it, and that’s a risk that has to be managed.”

He was, he said, concerned at the way the debate about harm reduction had evolved.

“Now it’s ‘The tobacco industry is getting into this, the tobacco industry is evil, therefore as a policy this is a bad idea, and anybody who argues otherwise is either an idiot or a tobacco industry poodle.’”

Public health experts who have grown up thinking of the industry as the evil opposition “find it very difficult when the tobacco industry, whether you trust it or believe it, starts to look as if it is coming up with a product that is actually a solution to some people’s dependence on smoking tobacco.”

For some, accepting this meant “softening a position that many have built careers on, and that’s quite difficult.”

But there’s another take on the tobacco industry’s rush into the e-cigarettes market, and it’s one that concerns Britton.

The industry, he says, “has been taken by surprise by e-cigarettes. It would rather they weren’t there, but now all the companies are buying them. The biggest threat is that they are buying them to have them fail.”

Profit motive

In September 2013, Bristol based Imperial, the world’s fourth largest tobacco company, bought Dragonite International, a Chinese company credited with inventing the e-cigarette. A year later, Imperial’s subsidiary Fontem Ventures launched Puritane, the company’s first e-cigarette market.13

But the true value to Imperial of the £48m (€67m; $76m) Dragonite purchase may lie in the multiple e-cigarette patents it now owns. It is too early to know conclusively how Imperial intends to wield this sword, but in March 2014 the company’s e-cigarettes division launched legal attacks against nine US makers of e-cigarettes, claiming they were in breach of its newly acquired patents.14

For Martin McKee, professor of European public health at the London School of Hygiene and Tropical Medicine there is no doubt that tobacco companies are entering the e-cigarette market “solely so they can say they are part of the solution.”

McKee freely admits he is “an e-cigarettes cynic.” He has also been an active supporter of ASH and says he has been “greatly dismayed” by its support for e-cigarettes. But there was, said McKee, still no evidence that e-cigarettes were effective in helping people to quit smoking, with recent studies indicating that smokers who used them might even be less likely to quit than those who did not.

Indeed, a recent meta-analysis of 11 published studies that compared smoking cessation rates among smokers who used e-cigarettes with those who did not, concluded that smokers who used e-cigarettes were “about 30% less likely to quit smoking than smokers who do not use e-cigarettes.”15

More recently, a draft report by the US Preventive Services Task Force concluded that current evidence was “insufficient to recommend electronic nicotine delivery systems for tobacco cessation” and that doctors should direct patients who smoked to “other cessation interventions with established effectiveness and safety.”16

Furthermore, reducing smoking—an ambition of 48% of the respondents to an ASH survey of e-cigarette use17—as opposed to stopping altogether, did not confer significant health gains, said McKee. A prospective 30 year Norwegian cohort study published in Tobacco Control in 2006 had looked at outcomes for a mix of more than 50 000 smokers, non-smokers, and former smokers and concluded there was “no evidence that heavy smokers who cut down their daily cigarette consumption by >50% reduce their risk of premature death significantly.”18

Personal attacks

McKee says the debate about harm reduction has been invaded and clouded by personal attacks on social media launched by “vapers” (as those who use e-cigarettes describe themselves) and others. After he wrote an article for The BMJ in 2013,19 “sceptical and raising a number of questions, I got attacked beyond belief.”

In a subsequent electronic response on thebmj.com he reported, “Within a few hours of it being posted on The BMJ website I was attracting hundreds of messages on Twitter, almost all personally abusive (‘Vile cretin’ was one of the kinder ones). I had no idea that the e-cigarette lobby was so well organised.”

In a letter to the Lancet in December 2014, McKee, Glantz, and two others noted that “anyone with the temerity to suggest that e-cigarettes are anything other than the game changing solution to the problem of tobacco will be subject to grossly offensive attacks, with growing evidence that these are being orchestrated.

“One recent example, a tweet directed at two of us, contained a picture of a noose with the caption ‘Your days are numbered.’”20

“It has been seriously unpleasant,” says McKee. “But when you’re getting that sort of treatment you realise you’re on to something.”

One of the problems, says Capewell, is that “the amount of time and effort that different public health folk are spending on fighting among themselves could be better used fighting the tobacco companies.”
Image makeover

And, as the debate rages on, the tobacco industry is quietly exploiting the schism in public health to gain the moral high ground.

In November 2014, after a letter from a member of the Electronic Cigarette Consumers Association and the New Nicotine Alliance appeared in the Lancet complaining that vapers were not being listened to in the public health debate,21 Imperial Tobacco was quick to pick up the ball.

In a press release issued by Fontem Ventures, its e-cigarette subsidiary, it said that while it understood that e-cigarettes represented a regulatory challenge for the government, it was important to “look at the big picture and assess the overall impact on society.” The company would “welcome the opportunity to meet with regulators to ensure that consumers are given clear signals—in taxation, accessibility, and conditions of use.”22

BAT is already in the business of meeting with health regulators. An important waypoint on the industry’s journey to self rehabilitation was passed in September last year, when BAT became the first tobacco company to win marketing authority from the UK Medicines and Healthcare Products Regulatory Agency for a medical product, the nicotine inhaler Voke (box). Though it looks like an ordinary cigarette, it involves no heat, combustion, or smoke and, thanks to its medicinal licence, it will be sold in pharmacies.


Voke approval less than transparent

The Voke development provides further evidence that ASH has been highly influential in the harm reduction debate. Arnott, the charity’s chief executive, was also a member of the MHRA’s nicotine products working group that considered the Voke marketing application in 2013.23

Three more of the working group’s 18 members were signatories of the Chan letter urging WHO to support harm reduction: Britton, Martin Jarvis, professor of health psychology at University College London, and Marcus Munafò, professor of biological psychology at the University of Bristol. They also served with Arnott and Gerry Stimson on the NICE programme development group that produced guidance on tobacco harm reduction.

Under the Freedom of Information Act The BMJ asked the MHRA to provide all documents and communications relating to the granting of the marketing and manufacturing licences for Voke. Claiming that the exercise would cost more than the £600 ceiling set for dealing with these requests, the regulator provided only one document, an “excerpt” of the January 2013 meeting of the working group.

It was a less than transparent disclosure. Under sections 40 (personal information), 41 (information provided in confidence), and 43 (commercial interests) of the act, virtually the entire document was redacted. Consequently it is not clear which members of the working group attended this meeting. However, it did reveal that it had considered the Voke marketing authorisation application.

Asked for a copy of the minutes, Arnott referred The BMJ back to the MHRA and did not respond to a request to disclose the names of the other members of the working group. The names, however, were finally provided by the MHRA, which added that the minutes of the working group’s meeting, which had taken place 18 months earlier, “are yet to be published because some of the issues are still under discussion.”

After the MHRA granted the Voke medicines licence in September 2014, Arnott welcomed the decision in an ASH press release. Voke was a “new alternative to smoking, which . . . will allow smokers to choose a product which meets the high standards of medicines regulation and could be provided on prescription to help them stop smoking,” she said. ASH dismissed concerns that the device will be marketed by a tobacco company. Medicines regulation “will minimise the risk that tobacco companies market their products inappropriately.”24

But regardless of their true value in the battle against tobacco harm, and the ferocious row they have triggered in the public health community, are all such products anything other than a mere sideshow, designed to make the tobacco industry look good as cigarettes continue to kill up to half of the people who use them?25

While BAT says it is “committed to developing and promoting a range of next generation tobacco and nicotine products,” in its 2014 annual report it states clearly that tobacco remains “at the core of our business and will continue to provide us with opportunities for growth.”26

Indeed, despite economic downturns, tougher regulatory environments and higher taxes almost worldwide, the entire industry continues to enjoy vast profits and predicts future expansion of the global smoked tobacco market.27

BAT says “we want to reduce the public health impact of our products.” But anyone who thinks it would ever do so by heeding public health’s invitation to stop making them is fooling themselves, says Hill, its public relations manager.

“We have made meaningful steps in our journey to tobacco harm reduction,” he insists. “This is something we are committed to and that’s really happening.”

On the other hand, “BAT is a legal business [and] the lion’s share of our revenue and profits, certainly for the coming years, is going to come from the traditional cigarette side of our business.

“Simply to turn off that side of the business would not be acting in the best interests of our employees, our partners and suppliers or, of course, our shareholders.”

No mention, in that sentence, of the best interests of the six million killed each year by cigarettes.25
Notes

Cite this as: BMJ 2015;350:h3317

The 21st Century Cures Act

Perspective
The 21st Century Cures Act — Will It Take Us Back in Time?

Jerry Avorn, M.D., and Aaron S. Kesselheim, M.D., J.D., M.P.H.

N Engl J Med 2015; 372:2473-2475June 25, 2015DOI: 10.1056/NEJMp1506964



In May 2015, the 21st Century Cures Act was introduced in the U.S. House of Representatives, with the goal of promoting the development and speeding the approval of new drugs and devices.1 Championed by the pharmaceutical, biotechnology, and device industries, the bill was approved unanimously (51 to 0) in committee and continues to be debated. If enacted into law, some of its provisions could have a profound effect on what is known about the safety and efficacy of medical products, as well as which ones become available for use.

Some aspects of the bill could indeed enhance the development of and access to new drugs. The legislation calls for annual increases in the stagnating budget for the National Institutes of Health (NIH) amounting to about 3% per year for 3 years when adjusted for inflation. It would also provide an additional $2 billion per year for 5 years to create an “NIH Innovation Fund.” Together, this support would help counteract the effects of sequestration and budget cuts that have reduced the purchasing power of the NIH to its lowest level in years. Given the crucial role that NIH-funded research plays in generating the findings on which so many new drugs are based,2 this boost would be a welcome development. Another useful provision could make deidentified data from NIH-funded clinical trials more available to researchers.

Other proposed changes could lead to less salutary outcomes for patients and the health care system. An underlying premise of the bill is the need to accelerate approval for new products, but this process is already quite efficient. A third of new drugs are currently approved on the basis of a single pivotal trial; the median size for all pivotal trials is just 760 patients. More than two thirds of new drugs are approved on the basis of studies lasting 6 months or less3 — a potential problem for medications designed to be taken for a lifetime. Once the Food and Drug Administration (FDA) starts its review, it approves new medications about as quickly as any regulatory agency in the world, evaluating nearly all new drug applications within 6 to 10 months, an impressive turnaround for such complex assessments.

Nonetheless, as introduced, the 21st Century Cures Act instructs the FDA to consider nontraditional study designs and methods of data analysis to further speed approvals. Adaptive trial designs and the use of Bayesian methods hold promise in some kinds of evaluations, particularly in oncology. However, more problematic proposals include encouraging the use of “shorter or smaller clinical trials” for devices and the request that the FDA develop criteria for relying on “evidence from clinical experience,” including “observational studies, registries, and therapeutic use” instead of randomized, controlled trials for approving new uses for existing drugs. Although such data can provide important information about drug utilization and safety once a medication is in use, there is considerable evidence that these approaches are not as rigorous or valid as randomized trials in assessing efficacy.

The bill would also encourage the FDA to rely more on biomarkers and other surrogate measures rather than actual clinical end points in assessing the efficacy of both drugs and devices. The FDA already uses surrogate end points in about half of new drug approvals.3 Some biomarkers are accurate predictors of disease risk and can be useful measures of the efficacy of a new drug (such as low-density lipoprotein cholesterol for statins). But though a drug's effect on a biomarker can make approval quicker and less costly, especially if the comparator is placebo, it may not always predict the drug's capacity to improve patient outcomes. Bevacizumab (Avastin) delayed tumor progression in advanced breast cancer but was shown not to benefit patients. Similarly, rosiglitazone (Avandia) lowered glycated hemoglobin levels in patients with diabetes even as it increased their risk of myocardial infarction. In 2013, patients began to receive a new drug for tuberculosis approved on the basis of a randomized trial relying on a surrogate measure of bacterial counts in the sputum — even though patients given the drug in that trial had a death rate four times that in the comparison group, mostly from tuberculosis.4 These provisions in the legislation would not immediately change FDA approval standards, but they would give the agency greater discretion, backed by congressional support, to approve drugs on the basis of less rigorous data.

The proposed legislation would make immediate changes with respect to new antibiotics and antifungals by enabling their approval without conventional clinical trials, if needed to treat a “serious or life-threatening infection” in patients with an “unmet medical need.” In place of proof that the antimicrobial actually decreases morbidity or mortality, the FDA would be empowered to accept nontraditional efficacy measures drawn from small studies as well as “preclinical, pharmacologic, or pathophysiologic evidence; nonclinical susceptibility and pharmacokinetic data, data from phase 2 clinical trials; and such other confirmatory evidence as the secretary [of health and human services] determines appropriate to approve the drug.” Antimicrobials approved in this manner would carry disclaimers on their labeling, but there is no evidence that such a precaution would restrict prescribing to only the most appropriate patients. If passed in its current form, the bill would also provide hospitals with a financial bonus for administering costly new but unproven antibiotics, which could encourage their more widespread use. The bill gives the secretary of health and human services the authority to expand this nontraditional approval pathway to other drug categories as well, if “the public health would benefit from expansion.”

The 21st Century Cures Act goes still further in altering the requirements for approving medical devices — an area long criticized for lack of rigor as compared with drug evaluations,5 though regulatory oversight has improved in recent years. As proposed, the new law would redefine the evidence on which high-risk devices can be approved to include case studies, registries, and articles in the medical literature, rather than more rigorous clinical trials. Another section would allow device makers to pay a third-party organization to determine whether the manufacturer can be relied on to assess the safety and effectiveness of changes it makes to its devices, in place of submitting an application to the FDA. Thus certified by the external company, a device maker would be authorized to continue to assess its own products on an ongoing basis.

Informed consent by patients in drug trials has traditionally been sacrosanct, with exceptions made only when consent is impossible to obtain or contrary to a patient's best interests. But another clause in the proposed law adds a new kind of exception: studies in which “the proposed clinical testing poses no more than minimal risk” — a major departure from current human subject protections. It is not clear who gets to determine whether a given trial of a new drug poses “minimal risk.”

Embedded in the language of the 21st Century Cures Act are some good ideas that could streamline the development and evaluation of new drugs and devices; its call for increased NIH funding may prove to be its most useful component. But political forces have also introduced other provisions that could lead to the approval of drugs and devices that are less safe or effective than existing criteria would permit.

Over the past 80 years, this country's regulatory approach has embraced steadily improving criteria for accurately assessing therapeutic efficacy and risk. Patients and physicians would not benefit from legislation that instead of catapulting us into the future, could actually bring back some of the problems we thought we had left behind in the 20th century.

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Original Article
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Dung T. Le, M.D., Jennifer N. Uram, Ph.D., Hao Wang, Ph.D., Bjarne R. Bartlett, B.S., Holly Kemberling, R.N., Aleksandra D. Eyring, M.Pharm., Andrew D. Skora, Ph.D., Brandon S. Luber, Sc.M., Nilofer S. Azad, M.D., Dan Laheru, M.D., Barbara Biedrzycki, Ph.D., C.N.R.P., Ross C. Donehower, M.D., Atif Zaheer, M.D., George A. Fisher, M.D., Ph.D., Todd S. Crocenzi, M.D., James J. Lee, M.D., Ph.D., Steven M. Duffy, M.D., Richard M. Goldberg, M.D., Albert de la Chapelle, M.D., Ph.D., Minori Koshiji, M.D., Ph.D., Feriyl Bhaijee, M.D., Thomas Huebner, M.D., Ralph H. Hruban, M.D., Laura D. Wood, M.D., Ph.D., Nathan Cuka, M.D., Drew M. Pardoll, M.D., Ph.D., Nickolas Papadopoulos, Ph.D., Kenneth W. Kinzler, Ph.D., Shibin Zhou, M.D., Ph.D., Toby C. Cornish, M.D., Ph.D., Janis M. Taube, M.D., Robert A. Anders, M.D., Ph.D., James R. Eshleman, M.D., Ph.D., Bert Vogelstein, M.D., and Luis A. Diaz, Jr., M.D.

N Engl J Med 2015; 372:2509-2520June 25, 2015DOI: 10.1056/NEJMoa1500596
Share:
Background

Somatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

Methods

We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.
Results

The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair–deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair–deficient tumors, as compared with 73 in mismatch repair–proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02).
Conclusions

This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.)

Unprovoked Venous Thromboembolism and Occult Cancer

Original Article
Screening for Occult Cancer in Unprovoked Venous Thromboembolism

Marc Carrier, M.D., Alejandro Lazo-Langner, M.D., Sudeep Shivakumar, M.D., Vicky Tagalakis, M.D., Ryan Zarychanski, M.D., Susan Solymoss, M.D., Nathalie Routhier, M.D., James Douketis, M.D., Kim Danovitch, C.C.R.P., Agnes Y. Lee, M.D., Gregoire Le Gal, M.D., Philip S. Wells, M.D., Daniel J. Corsi, Ph.D., Timothy Ramsay, Ph.D., Doug Coyle, Ph.D., Isabelle Chagnon, M.D., Zahra Kassam, M.D., Hardy Tao, M.D., and Marc A. Rodger, M.D. for the SOME Investigators

June 22, 2015DOI: 10.1056/NEJMoa1506623



Venous thromboembolism may be the earliest sign of cancer. Currently, there is a great diversity in practices regarding screening for occult cancer in a person who has an unprovoked venous thromboembolism. We sought to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed tomography (CT) of the abdomen and pelvis in patients who had a first unprovoked venous thromboembolism.

Methods

We conducted a multicenter, open-label, randomized, controlled trial in Canada. Patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period.

Results

Of the 854 patients who underwent randomization, 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up: 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P=0.28). In the primary outcome analysis, 4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P=1.0). There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P=0.88) or in cancer-related mortality (1.4% and 0.9%, P=0.75).

Conclusions

The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit. (Funded by the Heart and Stroke Foundation of Canada; SOME ClinicalTrials.gov number, NCT00773448.)

Oncologist's Attitude and Patient Outcomes

Medscape Oncology
Can the Oncologist's Attitude Affect Patient Outcomes?

Alice Goodman; William Pirl, MD, MPH Disclosures June 22, 2015

Editor's Note:
Over the past decade, much has been written about end-of-life care and about delivering bad news to cancer patients. Some of these articles and materials are written for patients and their families, while others are aimed at helping oncologists perform the difficult task of communicating with patients who have exhausted all treatment options and are facing death.

The interaction between oncologists' emotions and patients' emotions, however, is a neglected area of research, possibly because it is hard to quantify such interactions. Recently, some researchers have become interested in how oncologists and patients interact and how emotional cues influence that interaction.

At the recent 2015 annual meeting of the American Society of Clinical Oncology, investigators from Massachusetts reported on a study examining the association between oncologists' dispositional affect—their emotions and the manner in which they respond to a situation—and patients' symptoms of depression.[1] Medscape spoke with lead author William Pirl, MD, MPH, attending psychiatrist and director of psychiatric oncology at Massachusetts General Hospital, Boston, Massachusetts, about the study, what brought it about, and the dynamics of the oncologist-patient interaction.

Medscape: How did you become interested in the oncologist-patient interaction?
Oncologists and patients read each other's emotional cues in every encounter, and the emotions of one may impact the other.

Dr Pirl: One area of interest for me has been end-of-life conversations between oncologists, patients, and their families. There is scant literature about the emotional aspects of initiating discussions about stopping therapy as well as the interactions between doctors' and patients' emotions around that time.

I am interested in studying how oncologists' emotions affect the care they deliver to patients, the patient's experience of oncologist-patient encounters, and how these interactions affect medical decisions. Oncologists and patients read each other's emotional cues in every encounter, and the emotions of one may impact the other.

During a fellowship at the Radcliffe Institute, I had discussions with Jennifer Lerner, a leader in the field of how emotions affect decisions (mainly in economic areas). We identified a mutual interest in studying how oncologists' emotions affect patients and how patients' emotions affect oncologists.

One of our studies showed that increased psychological distress in patients at early-stage disease was associated with receiving more chemotherapy at the end of life.[2] This finding was the opposite of what we expected. I had assumed that patients who were distressed would receive less end-of-life care.

This study suggested that the interaction between the oncologist and the patient was more complicated than we had assumed. This led to our interest in the interaction between oncologists' mood and patients' mood. We hypothesized that in a high-emotion setting, such as metastatic cancer, oncologists' mood and patients' mood would affect medical decisions.

Medscape: Is there any published evidence about the oncologist-patient emotional interaction?
Dr Pirl: Very little has been published about this. Much of the emphasis has been on communication, not on the emotions behind the words.

A recent study tested an online intervention developed by a multidisciplinary team that is aimed at teaching patients strategies for expressing their emotional concerns to their providers and asking for support. This was a pilot study, and the intervention is now being evaluated in a randomized clinical trial.[3]

The goal of our study was to understand how the oncologist's dispositional affect—the range of feelings oncologists could experience in a given setting—might influence the care they deliver to patients, both at the end of life and early in the course of treatment. We wanted to determine whether there is a correlation between the oncologist's mood and the patient's mood.
Oncologist's Manner Affects the Patient, but to What Degree?

Medscape: Explain the study method and what you found.

Dr Pirl: Our study involved over 300 patients and 17 oncologists. As part of an ongoing trial of early palliative care, patients were assessed for depressive symptoms (using the Patient Health Questionnaire-9, PHQ9) within 8 weeks of diagnosis with metastatic cancers. Oncologists providing care for these patients completed the Positive and Negative Affect Scale (PANAS),[4] a validated measure of dispositional affect with positive and negative dimensions. Oncologists' negative affect was assessed by measuring feelings that included distressed, upset, guilty, scared, hostile, irritable, ashamed, nervous, jittery, and afraid.

Associations between patient depressive symptoms and positive and negative dispositional affect were tested with rank-sum tests and multivariate linear regressions. We found an association between the negative feelings that oncologists can have and depression in patients with newly diagnosed metastatic lung and gastrointestinal cancer. Although we found an association, we were not able to determine the directionality of this effect—that is, whether the oncologists' feelings led to the patients' depression or vice versa. We don't know from this study whether taking care of cancer patients makes oncologists depressed or whether patients' depressive mood affects oncologists.

An oncologist's affect may lead to a patient's depressive symptoms.


We found no association between oncologists' positive affect (as measured by feelings such as interested, excited, strong, enthusiastic, proud, alert, inspired, determined, attentive, active) and patients' depressive symptoms.

This study gives empiric evidence that oncologists' affect might influence patients on a clinical level. An oncologist's affect may lead to a patient's depressive symptoms.

Medscape: What is the next step in your research?

Dr Pirl: We want to explore whether oncologists' emotions are associated with patient outcomes and to demonstrate that oncologists' feelings can affect patient outcomes. If we can show this, it will bring more attention and awareness to the potential negative consequences for oncologists and patients.
Communication vs Disconnect

Medscape: Let's talk about the oncologist-patient interaction in a more general way. In your years of working with patients, what have you learned from them about the oncologist-patient interaction?

Dr Pirl: Patients are highly attuned to emotional cues related to the way the oncologist is acting: tone of voice, body language, facial expression. Patients interpret those cues as meaningful information about their own prognosis and treatment. In other words, if a doctor looks worried, that could mean the cancer is out of control. If the doctor comes into the room while the patient is waiting for test results and he is not smiling, the patient might interpret this as bad news.

Medscape: Is there ever a disconnect between the oncologist's and the patient's experience of an encounter?

Dr Pirl: Yes. This happens all the time. I have at times been surprised by the disconnect. I've seen both extremes: overinterpretation of what the oncologist said or not picking up on what the oncologist said.A patient may say, "The oncologist never told me my cancer was serious," while the oncologist has documented a discussion about the incurable nature of the cancer and the goal of therapy being to prolong life.

Or the oncologist may believe that a visit went well, but the patient views the oncologist as mean because he or she delivered bad news. A recent study showed that when bad news is delivered, patients view the oncologist as uncompassionate.[5] I've had patients say, "This doctor was so condescending. He told me I was going to die and walked out of the room." Yet, the oncologist reports a different scenario.

Medscape: Are there certain phases of treatment when emotions run high?

Dr Pirl: Times of uncertainty are difficult emotionally. These include when changes in treatment are needed, when a patient wants more information (about treatment or recurrence), and when treatment is ending and the patient is fearful about what comes next. When a patient needs something from an oncologist, the oncologist's attitude may affect the patient. These times are highly stressful for oncologists too.
One of the best things you can do for patients is to listen to their concerns.

Medscape: What are some important lessons for oncologists?

Dr Pirl: It is important to give a patient the sense that you are listening and fully focused on the patient during the encounter, even if it is brief. Make the patient feel seen and heard. At the end of the discussion, be aware of your body language. Consider leaning back in your chair and appearing relaxed while you ask whether the patient has any questions, implying that you are receptive and not rushed. Looking at a computer while talking to a patient gives the opposite impression.

In the metastatic setting, emotions may be ratcheted up. One of the best things you can do for patients is to listen to their concerns.

Medscape: What about the effect of patients' emotions on the oncologist?

Dr Pirl: The patient-oncologist interaction is clearly not a one-way street. Doctors are human. They are not robots without emotion. If a patient is angry or irritable, that can affect the oncologist and the interaction.

I would emphasize to oncologists that they need to be attuned to their feelings. If their feelings are negative, they should take a step back and think about how those feelings affect patients and how the patients' emotions affect them. Attitudes such as anger, condescension, and irritability can compromise a positive interaction.

There is a whole literature on burnout among oncologists, in part from the emotional strain of caring for cancer patients.[6] It is not surprising that there is a high rate of burnout among oncologists, but as yet, this has not been shown to affect patient outcomes. We need to determine whether burnout affects patient care and whether the effect is bi-directional. It would be valuable to develop strategies to help oncologists overcome burnout and distress.

www.cancer.net/blog

Inform Your Patients About Common Cancer Myths

By ASCO
June 10, 2015, Volume 6, Issue 10



Misinformation is everywhere. Direct your patients to visit www.cancer.net/blog to learn what is science fact and what is science fiction in this blog post on nine common cancer myths. Also, order ASCO Answers Fact Sheet—Myths and Facts About Cancer for your practice at www.cancer.net/estore.■

Intraperitoneal Treatment in Advanced Ovarian Cancer

What Is the Future of Intraperitoneal Treatment in Advanced Ovarian Cancer?

By Robert L. Coleman, MD
June 10, 2015, Volume 6, Issue 10


Continuous interrogation into the biology of ovarian cancer and its microenvironment may hold new avenues of clinical investigation for intraperitoneal treatment.
—Robert L. Coleman, MD

An analysis of Gynecologic Oncology Group (GOG) studies recently reported in the Journal of Clinical Oncology by Tewari and colleagues and reviewed in this issue of The ASCO Post showed a survival benefit of intraperitoneal chemotherapy vs intravenous chemotherapy over long-term follow-up in women with advanced ovarian cancer.1 The findings add to the ongoing conversation on the fate of intraperitoneal treatment in this setting.

A ‘Trifecta’ of Sorts

The publication of GOG-172 in 2006 completed an intraperitoneal chemotherapy “trifecta” of sorts in demonstrating its utility as primary adjuvant therapy in women with advanced-stage ovarian cancer.2-4 Although at the time of its publication, there had been eight prospective clinical trials of intraperitoneal therapy, the three from GOG/Southwest Oncology Group (SWOG) represented the largest, with the strongest treatment effects.5 Concomitant with this latter trial’s publication came a National Cancer Institute (NCI) clinical announcement on January 4, 2006, stating that intraperitoneal therapy was “encouraged…after surgery, for women with advanced ovarian cancer.”

However, long before this landmark publication and rare NCI media release, presentations and debates at national and international conferences discussing the implications of each of these three studies (GOG-104/SWOG-8501, GOG-114, and GOG-172) had already tainted the touted benefit as bittersweet, citing excessive toxicity of the regimen, poorer patient-reported outcomes, catheter complications, and physician and patient inconvenience among the oncology community.6,7

It was noteworthy, and in some respects affirming, that the NCI announcement did not endorse a specific intraperitoneal regimen, despite heralding the results of GOG-172. This is likely due to the unique designs, endpoints, and findings of the three trials, not the least of which was that each evaluated a different intraperitoneal experimental arm. Since GOG-114 and GOG-172 compared intraperitoneal therapy with a common intravenous regimen (24-hour paclitaxel on day 1 followed by cisplatin on day 2) in a relatively contemporary ovarian cancer population, Tewari and colleagues combined the data sets and performed a long-term follow-up analysis.

As expected in this setting, the combined analysis (now with 10-year follow-up) of two individually “positive” trials was a “positive” evaluation—notably, there was an impressive 23% adjusted reduced risk of death for patients treated with intraperitoneal vs intravenous therapy. This amounted to an approximate 10.4-month survival advantage at the median between the two modalities of delivery. Few trials before or since have documented this kind of impact among this patient cohort. Progression-free survival was similarly and consistently “positive” in this analysis.

However, one of the acknowledged difficulties with intraperitoneal therapy is inconsistent delivery success throughout the intent-to-treat interval after surgery. In GOG-104, GOG-114, and GOG-172, only 58%, 71%, and 42% of intraperitoneal patients, respectively, received all six cycles of intended therapy via that route.

Although these data were/are alarming for any modality in front-line therapy, they grossly underestimated the difficulty of extrapolation to a broader medical community, particularly those outside the experienced investigators, nurses, and support staff of the cooperative group sites. Thus, it is not surprising that many clinicians considering intraperitoneal therapy as a practice standard never embraced the data and that some brave enough to try experienced significant challenges—particularly in adoption of GOG-172’s multiday/weekly strategy.

Criticisms Temper Clinical Adoption

One of the many criticisms of the “trifecta” was choice of the control arm in each of the studies. GOG-104, published the same year as GOG-111, which introduced paclitaxel in the front-line setting to poorer-prognosis patients, lacked this new agent. GOG-114 and GOG-172 used 24-hour infusion of paclitaxel and cisplatin (day 2). However, data from GOG-158, featuring paclitaxel (3-hour infusion) with carboplatin (area under the curve = 7.5) compared with the same intravenous control arm used in GOG-172, were already known and a community standard.

In addition, cross-trial evaluation (albeit statistically invalid) of the control arm in GOG-172 vs the experimental arm in GOG-158 implied “underperformance” of GOG-172’s control arm. Furthermore, at the time of GOG-172’s publication, intense interest was focused on bevacizumab (Avastin), which was serving in experimental arms of new GOG and international front-line phase III trials.8,9 This, along with an extremely provocative dose-dense, dose-intense intravenous paclitaxel phase III study by the Japanese GOG demonstrating similar efficacy results on overall survival, tempered clinical adoption of intraperitoneal therapy.10

New Light on Its Potential

Nevertheless, a series of reports like the current article by Tewari et al have cast new light on the potential for intraperitoneal therapy. First is the significant improvement in surgical standards for primary cytoreduction. At the time of initial reports on intraperitoneal therapy, the rate of complete surgical cytoreduction (R0) was 10% to 25%; R0 rates have now doubled, largely due to more aggressive surgery and advanced surgical training, globally, of gynecologic oncologists.11 Several reports, including the Tewari et al analysis, have suggested that the R0 cohort represents the subgroup most likely to benefit from intraperitoneal therapy.

Second, improvements in supportive care and alterations in the dosing/infusion schedules of the agents have dramatically improved the proportion of patients completing all six cycles of intended intraperitoneal chemotherapy.12 Although it remains a risk that alterations in dosing/schedule could impact survival efficacy, this may be countered by the ability to complete all therapy via intraperitoneal administration.

Third, understanding genomic alterations in the tumor may further clarify who should be given intraperitoneal therapy. Recently, an analysis of somatic loss of BRCA1 in patients participating in GOG-172 demonstrated a profound effect on overall survival.13 In this analysis of 393 patients (94% of GOG-172 participants), somatic loss of BRCA1 was observed in 48%. Among this cohort, the median overall survival for intraperitoneal vs intravenous therapy was 84 vs 47 months (P = .0002), amounting to a 33% reduction in the hazard for death. There was no difference between intraperitoneal and intravenous therapy among patients with normal expression of BRCA1.

Finally, histology may be important, as patients with serous cancer, the most prevalent subtype, appeared to benefit from intraperitoneal therapy, but only if six cycles could be administered.

Looking Ahead

The future of intraperitoneal therapy will likely undergo another transition, as the results of the GOG-252 (clinicaltrials.gov, NCT00951496), iPocc (NCT01506856), and NCIC-OV21 (NCT00993655) trials become available. In GOG-252, two different intraperitoneal infusion strategies are being evaluated in combination with bevacizumab against a contemporary control arm (paclitaxel, carboplatin, bevacizumab followed by bevacizumab maintenance).

The Japanese iPocc trial is comparing the same dose-dense, dose-intense paclitaxel intravenous arm as in its previous trial vs intraperitoneal carboplatin (same intravenous and intraperitoneal doses) but is allowing both optimal and suboptimal surgical cytoreduction patients to participate.

NCIC-OV21 is focusing exclusively on the neoadjuvant chemotherapy population, administering intravenous or one of two intraperitoneal regimens following interval debulking surgery planned after three to four induction cycles of intravenous platinum-based therapy.

Although each of these trials has the potential to solidify and/or broaden the potential audience for intraperitoneal therapy, they may also define it as a relic of early ovarian cancer clinical therapy. Nevertheless, continuous interrogation into the biology of ovarian cancer and its microenvironment may hold new avenues of clinical investigation for intraperitoneal treatment. ■

Trabectedin in Advanced Soft-Tissue Sarcoma

Priority Review Granted for Trabectedin in Advanced Soft-Tissue Sarcoma

By The ASCO Post
March 25, 2015, Volume 6, Issue 5



The U.S. Food and Drug Administration (FDA) has granted Priority Review for the New Drug Application (NDA) for trabectedin to treat patients with advanced soft-tissue sarcoma, including liposarcoma and leiomyosarcoma subtypes, who have received prior chemotherapy including an anthracycline. The NDA for trabectedin was submitted to the FDA on November 24, 2014.

Trabectedin is a novel, multimodal, synthetically produced antitumor agent—originally derived from the sea squirt Ecteinascidia ­turbinata—that prevents tumor cells from ­multiplying.

The filing is based on the phase III randomized, open-label study ET743-SAR-3007. This trial is evaluating the safety and efficacy of trabectedin vs dacarbazine for the treatment of patients with advanced liposarcoma and leiomyosarcoma. Results will be presented at a later date. ■

Role of Ramucirumab in Colorectal Cancer

Addition of Ramucirumab to Second-Line FOLFIRI Improves Overall Survival in Metastatic Colorectal Cancer

By Matthew Stenger
June 10, 2015, Volume 6, Issue 10

Josep Tabernero, MD, PhD

Role of Ramucirumab in Colorectal Cancer

Predictive biomarkers to identify patients with tumors most sensitive to antiangiogenic agents would probably further improve the efficacy outcomes of trials of these drugs. Such improvements might be a necessity owing to increasing scrutiny of cost-to-benefit ratios for treatments.
—Josep Tabernero, MD, PhD

In the phase III RAISE trial reported in The Lancet Oncology, Josep Tabernero, MD, PhD, Head of Medical Oncology at Vall d’Hebron Institute of Oncology, Barcelona, and colleagues found that the addition of the antiangiogenic anti–vascular endothelial growth factor receptor 2 (VEGFR2) antibody ramucirumab (Cyramza) to second-line FOLFIRI (leucovorin, fluorouracil, irinotecan) improved overall survival in patients with metastatic colorectal cancer that had progressed on first-line bevacizumab, oxaliplatin, and fluoropyrimidine treatment.1

Study Details

In this double-blind trial, 1,072 patients from 24 countries were randomly assigned between December 2010 and August 2013 to receive ramucirumab at 8 mg/kg plus FOLFIRI (n = 536) or FOLFIRI plus placebo (n = 536) every 2 weeks until disease progression or unacceptable toxicity after progression on first-line therapy. Randomization was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population.

The ramucirumab and control groups were generally balanced for age (mean, 62 years in both, 40% ≥ 65 years in both), sex (54% and 61% male), ethnicity (76% and 77% white, 21% and 19% Asian), region (Europe for 44% in both, North America for 27% in both), Eastern Cooperative Oncology Group performance status (0 for 49% and 48%, 1 for 50% and 51%), time to progression after start of first-line treatment (≥ 6 months for 77% and 76%), KRAS mutation status (mutant in 50% and 49%), carcinoembryonic antigen level (< 200/µg/L in 73% in both), number of metastatic sites (1 in 32% and 29%, 2 in 33% and 36%, ≥ 3 in 29% and 34%), and site of primary tumor (colon in 67% in both, rectum in 33% and 32%).
Improved Overall Survival

After study medication, subsequent systemic anticancer therapy was received by 54% of the ramucirumab group and 56% of the control group. Median follow-up was 21.7 months.

Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4–14.5 months) in the ramucirumab group vs 11.7 months (95% CI = 10.8–12.7 months) in the control group (hazard ratio [HR] = 0.844, P = .0219). Hazard ratios favored the ramucirumab group in all evaluated subgroups, including KRAS status, time to disease progression, and region subgroups.

Median progression-free survival was 5.7 months (95% CI = 5.5–6.2 months) vs 4.5 months (95% CI = 4.2–5.4 months; HR = 0.793, P < .0005), with hazard ratios favoring ramucirumab in all evaluated subgroups. Objective response rates were 13.4% vs 12.5%, (P = .63). Adverse Events

Grade ≥ 3 adverse events occurred in 79% of the ramucirumab group (grade 4 in 17%) vs 62% of the control group (grade 4 in 14%). The most common were neutropenia (38% vs 23%), hypertension (11% vs 3%), diarrhea (11% vs 10%), and fatigue (12% vs 8%). Febrile neutropenia occurred in 3% vs 2%.

Grade 5 adverse events consisted of bleeding/hemorrhagic events in three patients in the ramucirumab group and one in the control group, gastrointestinal (GI) hemorrhage in three and one, liver injury/failure in one and one, GI perforation in four and zero , arterial thromboembolic event in one and five, and congestive heart failure in one and two.

Serious adverse events occurred in 36% vs 31% of patients. Adverse events led to dose modification in 83% vs 75% and discontinuation in 11% vs 4%. Ramucirumab dose omission, dose reduction, and discontinuation occurred in 8%, 6%, and 4%, respectively.

The investigators concluded:

In view of our results, the combination of ramucirumab with FOLFIRI is an effective second-line treatment for patients with metastatic colorectal carcinoma. Predictive biomarkers to identify patients with tumors most sensitive to antiangiogenic agents would probably further improve the efficacy outcomes of trials of these drugs. Such improvements might be a necessity owing to increasing scrutiny of cost-to-benefit ratios for treatments. We have begun translational research of prespecified potential biomarkers to assist in selection of patients. ■

Disclosure: The study was funded by Eli Lilly. For full disclosures of the study authors, visit www.thelancet.com.

Physical Activity Protects Motor Function in Older Adults

From Medscape Education Clinical Briefs
Physical Activity Protects Motor Function in Older Adults CME/CE

News Author: Pauline Anderson
CME Author: Laurie Barclay, MD



Motor impairment in the elderly population is common and linked to morbidity. Public health strategies have therefore emphasized the need for older adults to increase their physical activity level.

White matter hyperintensities (WMHs) seen on brain imaging are common in elderly adults and are associated with level of motor function. The goal of this cross-sectional study by Fleischman and colleagues was to test the hypothesis that physical activity modifies the association between WMH burden and motor function in healthy older persons without dementia.

Study Synopsis and Perspective

Just as higher education and social connections seem to provide a cognitive reserve as people age, physical activity may build a motor reserve that protects against the harmful effects of WMHs in the brain on motor function, new research suggests.

The results point to a potential biological mechanism that may at least partly explain the well-established association between physical activity and motor function in healthy older adults, said lead author Debra A. Fleischman, PhD, professor, neurological sciences and behavioral sciences, Rush University Medical Center and Rush Alzheimer's Disease Center, Chicago, Illinois.

"The data suggest that physical activity may protect motor function from the untoward effects of small vessel disease," seen on magnetic resonance imaging (MRI) as WMHs.

The new findings emphasize the importance of an active lifestyle in protecting motor function from the adverse neurobiological effects of aging, Dr Fleischman said.

The study was published online March 11 and in the March 31 issue of Neurology.

Brain Volume

The study used data from 167 community-dwelling adults without dementia who were participants in the Rush Memory and Aging Project, an ongoing longitudinal clinical pathologic study of aging and dementia. Their mean age was 80 years, and approximately 21% were men.

Researchers used a composite measure of global cognition from 19 individual computer-scored cognitive tests. To assess motor function, they created a composite measure from 11 individual motor tests that included both upper- and lower-extremity motor performance.

Using actigraphs, the investigators measured total daily activity, including all exercise and nonexercise physical activity. Participants wore a watch-like monitor on the nondominant wrist for 24 hours per day for up to 11 days. The data were then downloaded to a computer for analysis. Researchers also calculated intensity of activity.

To assess WMH burden, they used a well-established, automated computer program that measures the total volume of brain tissue affected by WMHs as shown on fluid-attenuated inversion recovery MRI. Dr Fleischman noted that although studies suggest that WMHs on MRI reflect small-vessel disease, more studies are needed to characterize the pathologic bases of WMH.

After adjustment for age, gender, and education, total daily activity was not associated with WMH burden (P = .169).

As did previous research, this study showed that a higher level of WMH burden was associated with poorer motor function, but it also found that the harmful effects of WMHs disappeared in active people.

Comparing participants in different percentiles of total daily activity, they showed that in those with the highest activity (90th percentile) WMH burden did not affect motor function. In contrast, those at the 50th percentile of physical activity showed a negative effect of WMH burden on motor function, and this effect was even stronger for those in the 10th percentile of activity.

The difference between the 90th and 50th percentiles is roughly an additional 1.5 hours of walking per day at 2.5 miles per hour, Dr Fleischman noted. And the difference between the 50th and 10th percentiles translates to just less than 1 hour of additional walking per day.

This interaction persisted after controlling for various potential confounding variables, including depressive symptoms, body mass index, vascular diseases, functional status, and interactions with WMH burden.

"Together these findings suggest that higher levels of physical activity may provide reserve against the effects of brain pathology on motor function in older age," the authors conclude.

Dr Fleischman stressed that the association was significant when 2 different actigraphic measures were used: total daily activity and intensity of daily activity. There was no association when physical activity was measured by self-report.

Neural Reserve

That physical activity was not associated with WMH burden suggests that the benefit on motor function is through a neural reserve mechanism rather than through a direct association with WMH. Dr Fleischman suggested possible candidate mechanisms, including increases in various trophic factors that promote tissue survivability and genesis. However, she said, more work needs to be done to examine the potential mechanisms underlying motor reserve.

The concept of reserve has been frequently used in relationship to cognition. Studies show that older patients with higher levels of education, social networks, and purpose in life have better cognitive function despite significant Alzheimer disease pathology burden.

The same concept may be at play here: physically active people may have the same amount of brain damage as physically inactive people, but this damage does not seem to affect their motor function. Unlike education, however, physical activity is a modifiable behavior at any age.

The motor reserve provided by physical activity may have an influence at multiple sites along motor pathways. Although in the current study, the brain proxy measure was limited to WMH burden, further studies that examine a wider array of central nervous system abnormalities and other components of the motor pathways "will be crucial for defining the neurobiological basis of reserve provided by physical activity," said the authors.

The new findings underscore the importance of facilitating a more active lifestyle to prevent late-life motor impairment, improve survivability, and maintain independence and well-being, said the authors.

For people older than 65 years, the US Centers for Disease Control and Prevention recommends that older adults get at least:

2 hours and 30 minutes of moderate-intensity aerobic activity (eg, brisk walking) every week plus muscle strengthening activities on 2 or more days per week that work all major muscle groups; or
1 hour and 15 minutes of vigorous-intensity aerobic activity (eg, jogging or running) every week and muscle-strengthening activities on 2 or more days per week that work all major muscle groups; or
An equivalent mix of moderate- and vigorous-intensity aerobic activity and muscle-strengthening activities on 2 or more days per week that work all major muscle groups.

As for the type of exercise, that is an individual choice that considers existing medical conditions and leisure-time preferences, said Dr Fleischman. "I think that the important message, and the one that I give to my patients, is that they do not have to be marathon runners to maintain cognitive and motor function through physical activity as they age."

Other studies by Dr Fleischman and her research group showed that participants with the highest level of total daily activity, no matter how this is accumulated, are at the lowest risk for cognitive and motor impairment and decline as they age. "So the message is to just keep moving in any way that is safe and enjoyable."

This is particularly important because, unlike many age-related conditions that impair motor function, such as Parkinson disease and arthritis, age-related motor impairment is usually left untreated, said Dr Fleischman.

"Until we have a more complete understanding of the biological mechanisms underlying chronic late-life motor impairment, and have developed effective pharmacological treatments to lessen the effects of brain pathology on motor function, efforts to encourage and facilitate an active lifestyle in older adults will be a critical element in meeting this public health challenge."

The research group is acquiring longitudinal scans that will allow them to measure changes in all the primary variables and compare them with baseline, said Dr Fleischman.

Physical Activity a "Panacea"?

The study is yet another example of how physical activity is a kind of "panacea" in medicine, commented Glen Finney, MD, assistant professor, neurology, University of Florida College of Medicine, Gainesville, and a member of the American Academy of Neurology.

"We have seen similar effects for cognitive function and now they have found it in the motor domain. This supports the idea that physical activity is good for everything."

He noted that the motor function in this case is determined by the brain. "The research clearly shows that lower levels of physical activity are correlating with brain disease burden, so clearly this is brain-driven motor function. But once you get to a high level of physical activity, it actually helps to overcome and sort of negate that white matter burden."

Although the authors speculate that this is because of a motor reserve, Dr Finney said he would like to see a prospective study look at whether it is really a reserve or an actual treatment effect. "At this point, it's correlation; it's not causation. It's a definite possible way this works," he said.

According to an accompanying editorial, the "pooled approach" of using a composite motor score and a range of cognitive tests is statistically powerful but needs further development to be accessible in routine clinical practice.

The editorial writers, Richard Camicioli, MD, Department of Medicine, Division of Neurology, University of Alberta, Edmonton, Canada, and Joe Verghese, MB BS, MS, Departments of Neurology and Medicine, Albert Einstein College of Medicine, Bronx, New York, noted that the 167 participants were more educated and cognitively healthy although slightly older than the overall sample of 1545 persons originally recruited for the study.

They also commented that because the study was cross-sectional, it cannot determine causality. In addition, they note, actigraphy measures total activity, so it is difficult to know which aspects of the activities were protective.

"The nature (aerobic or resistance), complexity (dancing), or frequency of the physical activity may all have a role," they said.

Measuring WMHs by fluid-attenuated inversion recovery imaging may not completely reflect white matter damage, they said. Diffusion tensor imaging or magnetization transfer imaging may better depict white matter damage, might provide complementary measures, and may be related to physical activity.

The study was supported by the National Institute on Aging, National Institute of Minority Health and Health Disparities, Illinois Department of Public Health, and Rush Translational Science Consortium. The study authors and editorial writers have disclosed no relevant financial relationships.

Neurology. 2015;84:1294-1300, 1288-1289. Abstract, Editorial