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Chemotalk NewsletterChemotalk Newsletter, Vol. 67: November 1, 2013 A good November to you all. For anyone who has to make medical decisions, this article deserves attention: WHY WE MAKE BAD DECISIONS By Noreena Hertz* Six years ago, I was struck down with a mystery illness. My weight dropped by 30 pounds in three months, I experienced searing stomach pain, felt utterly exhausted and no matter how much I ate, I couldn't gain an ounce. I went from slim to thin to emaciated. The pain got worse, a white heat in my belly that made me double up unexpectedly in public and in private. Delivering on my academic and professional commitments became increasingly challenging. It was terrifying. I did not know whether I had an illness that would kill me or stay with me for the rest of my life or whether what was wrong with me was something that could be cured if I could just find out what on earth it was. Trying to find the answer, I saw doctors in London, New York, Minnesota and Chicago. I was offered a vast range of potential diagnoses. Cancer was quickly and thankfully ruled out. But many other possibilities remained on the table, from autoimmune diseases to rare viruses to spinal conditions to debilitating neural illnesses. Treatments suggested ranged from a five-hour, high-risk surgery to remove a portion of my stomach, to lumbar spine injections to numb nerve paths, to a prescription of anti-depressants. Faced with all these confusing and conflicting opinions, I had to work out which expert to trust, whom to believe and whose advice to follow. As an economist specializing in the global economy, international trade and debt, I have spent most of my career helping others make big decisions -- prime ministers, presidents and chief executives -- much about the process of decision making. So in between M.R.I.'s, CT scans and spinal taps, I dove into the academic literature on decision making. Not just in my field but also in neuroscience, psychology, sociology, information science, political science and history. What did I learn? Physicians do get things wrong, remarkably often. Studies have shown that up to one in five patients are misdiagnosed. In the United States and Canada, it is estimated that 50,000 hospital deaths each year could have ben prevented if th real cause of illness had been correctly identified. Yet people are loath to challenge experts. In a 2009 experiment carried out at Emory University, a group of adults was asked to make a decision while contemplating an expert's claims, in this case, a financial expert. A functional M.R.I. scanner gauged their brain activity as they did so. The results were extraordinary: when confronted with the expert, it was as if the independent decision-making parts of many subjects brains pretty much switched off. They simply ceded their power to decide to the expert. If we are to control our own destinies, we have to switch our brains back on and come to our medical consultations with plenty of research done, able to use the relevant jargon. If we can't do this ourselves we need to identify someone in our social or family network who can do so on our behalf. Anxiety, stress and fear -- emotions that are part and parcel of serious illness -- can distort our choices. Stress makes us prone to tunnel vision, less likely to take in the information we need. Anxiety makes us more risk-averse than we would be regularly and more deferential. We need to know how we are feeling. Mindfully acknowledging our feelings serves as an "emotional thermostat" that recalibrates our decision making. It's not that we can't be anxious, it's that we need to acknowledge to ourselves that we are. It is also crucial to ask probing questions not only of the experts but of ourselves. This is because we bring into our decision-making process flaws and errors of our own. All of us show bias when it comes to what information we take in. We typically focus on anything that agrees with th outcome we want. We need to be aware of our natural born optimism, for that harms good decision making, too. The neuroscientist Tali Sharot conducted a study in which she asked volunteers what they believed the chances were of various unpleasant events' occurring -- events like being robbed or developing Parkinson's disease. She then told them what the real chances of such an event happening actually were. What she discovered was fascinating. When the volunteers were given information that was better than they hoped or expected -- say, for example, that the risk of complications in surgery was only 10% when they thought it was 30% -- they adjusted closer to the new risk percentages presented. But if it was worse, they tended to ignore this new information. This could explain why smokers often persist with smoking despite the overwhelming evidence that it's bad for them. If their unconscious belief is that they won't get LUNG CANCER, for every warning from an antismoking campaigner, their brain is giving a lot more weight to that story of the 99-year-old lady who smokes 50 cigarettes a day but is still going strong. We need to acknowledge our tendency to incorrectly process challenging news an actively push ourselves to hear the bad as well as the good. It felt great when I stumbled across information that implied I didn't need any serious treatment at all. When we find data that supports our hopes we appear to get a dopamine rush similar to the one we get if we eat chocolate, have sex or fall in love. But it's often information that challenges our existing opinions or wishful desires that yields the greatest insights. I was lucky that my boyfriend alerted me to my most dopamine-drugged moments. The dangerous allure of the information we want to hear is something we need to be more vigilant about, in the medical consulting room and beyond. My own health story had a happy ending. I was finally given a diagnosis of a rare lymphatic vessel condition, and decided that surgery made sense. Not the five-hour surgical intervention that would have left me in bed recovering for more than three months, but a much less intrusive keyhole surgery with a quick recovery. I chose a surgeon who wasn't overly confident. I'd learned in my research that the super-confident, doctor-as-god types did not always perform well. One study of radiologists for example, reveals that those who perform poorly on diagnostic tests are also those most confident in their diagnostic prowess. My surgery went well. The pain subsided, the pounds gradually came back on. I am now cured. With brain switched on and eyes wide open, we can't always guarantee a positive outcome when it comes to a medical decision, but we can at least stack the odds in our favor. * A professor of economics at University College London and the autor of "Eyes Wide Open: How to Make Smart Decisions in a Confusing World." * * *
HYPERFRACTIONATED RADIOTHERAPY IMPROVED SURVIVAL FOR HEAD AND NECK CANCERS By Leah Lawrence The use of altered fractionation radiotherapy increased overall survival in patients with locally advanced head and neck cancers when compared with standard radiation, according to the results of a meta-analysis presented at the 2013 European Cancer Congress in Amsterdam. $B!H(BThe improvement in survival is marked for patients in the hyperfractionated regimen, with an absolute benefit of 8.1% at 5 years,$B!I(B said Pierre Blanchard, MD, a radiation oncologist from the Institut Gustave Roussy, Villejuif, France, who presented the results. Blanchard and colleagues undertook a meta-analysis that examined randomized trials comparing standard radiation therapy with altered fractionation radiation therapy with or without concomitant CHEMOTHERAPY in patients with local HEAD AND NECK SQUAMOUS CELL CARCINOMAS. Fractionation was defined as either standard, 5 fractions per week for 7 weeks, or altered. Altered therapy could have been either hyperfractionated; (10 fractions per week for 7 weeks resulting in a higher dose); accelerated, which is the same dose given over 6 weeks; or very accelerated, which is a low dose given in about 3 weeks. The researchers collected data from 31 trials representing more than 11,500 patients. After 7 years of follow-up, the data show that the higher dose intensity of altered fractionation radiotherapy improved outcomes in these patients. Altered fractionation radiotherapy improved overall survival (3.1% gained at 5 years, corresponding to a reduction of the risk of death of 6%) and progression-free survival (reduction of the risk of progression or death of 10% at 5 years). $B!H(BWhile the acute side-effects of altered fractionation radiotherapy are increased compared to those experienced by patients on standard fractionation radiotherapy, the late side-effects are comparable and, overall, side effects are more than compensated for by the significant increase in survival in the altered fractionation radiotherapy group,$B!I(B Blanchard said. Finally, a secondary analysis has shown that altered fractionation radiotherapy was inferior for overall survival to standard fractionation radiotherapy when the latter is associated with concomitant chemotherapy. Therefore, Blanchard said that in order to use altered fractionation radiotherapy in advanced cases of stage III or IV cancer, those patients cannot be candidates for concomitant chemotherapy. The meta-analysis was carried out by an international collaboration known as MARCH, including many countries in Europe, the USA, Canada, and Brazil, Egypt and developing countries through the International Atomic Energy Authority. The researchers said that the survival benefits are mostly related to improvements in locoregional control, the area located close to the primary tumor being by far the most common first site of relapse in this disease. $B!H(BThese data are a major advance for understanding the role in AFRT in head and neck squamous cell carcinoma,$B!I(B Blanchard said in a press release. $B!H(BBy carrying out a large-scale analysis such as this one, we believe that we have provided enough evidence to indicate that doctors should recommend AFRT as a validated treatment option for head and neck cancer patients.$B!I(B * * *
BREAKING CANCER'S SHIELD The recent discovery of how cancer survives in the human body comes with a bonus: A way to try to half the disease's progression. By Gina Kolata For more than a century, researchers were puzzled by the uncanny ability of CANCER cells to evade the immune system. They knew cancer cells were grotesquely abnormal and should be killed by white blood cells. In the laboratory, in Petri dishes, white blood cells could go on the attack against cancer cells. Why, then, could cancer survive in the body? The answer, when it finally came in recent years, arrived with a bonus: a way to thwart a cancer's strategy. Researchers discovered that cancers wrap themselves in an invisible protective shield. And they learned that they could break into that shield with the right drugs. When the immune system is free to attack, cancers can shrink and stop growing or even disappear in lucky patients with the best responses. It may not matter which type of cancer a person has. What matters is letting the immune system do its job. So far, the drugs have been tested and found to help[ patients with MELANOMA, KIDNEY and LUNG CANCER. In preliminary studies, they also appear to be effective in BREAST CANCER, OVARIAN CANCER and cancers of the COLON, STOMACH, HEAD and NECK, but not the PROSTATE. It is still early, of course, and questions remain. Why do only some patients respond to the new immunotherapies? Can these responses be predicted? Once beaten back by the immune system, how long do cancers remain at bay? Still, researchers think they are seeing the start of a new era in cancer medicine. "Amazing," said Dr. Drew Pardoll, the immunotherapy research director at Johns Hopkins School of Medicine. This period will be viewed as an inflection point, he said, a moment in medical history when everything changed. "A game-changer," said Dr. Renier J. Brentjens, a LEUKEMIA specialist at Memorial Sloan-Kettering Cancer Center. "A watershed moment," said his colleague, Dr. Michel Sadelain. (Both say they have no financial interests in the new drugs; Dr. Pardoll says he holds patents involving some immunotherapy rugs, but not the ones mentioned in this article.) Researchers and companies say they are only beginning to explore the new immunotherapies and develop others to attach cancers, like prostate, that seem to use different molecules to evade immune attacks. They are at the earliest stages of combining immunotherapies with other treatments in a bid to improve results. "I want to be very careful that we do not overhype and raise patients' expectations so high that we can never meet then," said Dr. Alise Reicin, a vice president at Merck for research and development. But the copanies have an incentive to speed development of the drugs. They are expected to be expensive, and the demand huge. Delays of even a few months mean a huge loss of potential income. Nils Lonberg, a senior vice president at Bristol-Myers Squibb, notes that immunotherapy carries a huge advantage over drugs that attack mutated genes. The later approach all but invites the cancer to escape, in the same way bacteria develop resistance to antibiotics. By contrast, immunotherapy drugs are simply encouraging the immune system to do what it is meant to do; it is not going to adapt to evade the drugs. "We are hoping to set up a fair fight between the immune system and the cancer," Dr. Lonberg said. Lowering Defenses The story of the new cancer treatments started with the discovery of how cancers evade attacks. It turned out that they use the body's own brakes, which normally shut down the immune system after it has done its job killing virus-infected cells. One braking system, for example, uses a molecule, PD-1, on the surface of T-cells of the immune system. If a target cell has molecules known as PD-L1 or PD-1.2 on its surface, the T-cell cannot attack it. So some cancer cells drape themselves in those molecules. The effect, whn t-cells are near, is like turning off a light switch. The T-cells just shut down. Cancers that do not use PD-L1 or PD-1.2 are thought to use other similar systems, just starting to be explored. Body systems have a lot of redundancy to tamp down immune attacks. But for now, the PD system showed researchers how cancer cells can evade destruction. "That is what has been realized in the past few years," said Ira Mellman, vice president of research oncology at Genentech. "Tumor cells are making use of this brake." The discovery led to an idea: Perhaps a drug that covered up any of those PD molecules, on the cancer cells or on white blood cells, would allow the immune system to do its job. (There is another immunotherapy stratgey -- to take white clood cells out of the body and program them with genetic engineering to attack a cancer. Studies have just begun and are promising. But researchers note that thie is a very different sort of treatment that is highly labor-intensive and has been successful so far in only a few types of cancer.) The first indication that a cancer's protective shield night be breached came in 2010, after a trial of the drug ipilimumab n patients with otherwise untreatable melanoma. The drug unleashes the immune system, letting it overwhelm tumors even if they have a protective shield. Patients who took the drug survived an average of 10 months, or 4 months longer than those randomly assigned to a different treatment. And about 20% of patients who responded have now survived up to 10 years. It was the first drug to improve survival for patients with metastic melanoma in a randomized trial. "It was spectacular," said Dr. Axel Hoos, vice president for oncology research and development at GlaxoSmithKline, who helped develop the drug when he was at Bristol-Myers Squibb. "Until that tipping point, immunotherapy had a bad name. It didn't work." The drug was approved for melanoma in March 2011, with a high price tab -- 4120,000 for a course of therapy. It had another drawback. By unleashing the immune system, it sometimes led to attacks on normal cells. In some cases, the reaction was fatal. But the trial was a proof of concept. It showed that cancers can succumb to an attack by the immune system. "That opened the door a crack," said Dr. Pardoll, of Johns Hopkins. "People stood up and took notice." A Signal Emerges Dr. Suzanne Topalia, a professor of surg3ery and oncology at Johns Hopkins, was one of the first to test the new drugs in patients. The trial began in 2006, with 39 patients who got a PD-1 blocker, made by Medarex, since bought by Bristol-Myers Squibb. The study included patients with a variety of advanced cancers, who had failed all traditional treatments; most had tried at least three, without any luck. The study looked at safety, not effectiveness. But Dr. Topalian noticed something intriguing. One patient with lung cancer treated at a collaborating medical center had a partial regression of her tumor. "It was very temporary; it was not enough to call it a response." Dr. Topalian said. "But it was a signal; it was there." That was surprising because researchers had assumed the cancers most colnerable to an immune system attack were melanoma and kidney cancer. Lung cancer was supposed to be out of the question. "Julie and I got on the phone with Mdarex and said, 'You have to incude lung cancer in your next clinical trial,'" Dr. topalian said, referring to her colleague Dr. Julie Brahmer. That led to studies of two Bristol-Myers drugs: one that blocks Pd-1 and another that blocks PD-L1. The studies included 503 patients with a variety of advanced cancers who had exhausted other options. The findings, presented in October last year at a meeting of the American Society of Clinical Oncology, were striking. A significant proportion of patients responded, including 18% of the 76 lung cancer patients who got the PD-1 drug, and 10% of 49 who got PD-L1 drug. Dr. Pardoll, who is married to Dr. Topalian, said that when she and her colleagues presented the data, "it was almost like a hush fell over the room: 'Can this really be?'" Emblems of Hope As researchers continue to study the new drugs and ask if they can improve their results by combining them with other therapies, they are heartened by some of the rare patients whose cancers were halted by the drugs. They caution that these patients are unusual; critical studies to reveal the drugs' effects on populations of cancer patients are still under way. "What you really want to know," said Dr. Roger M. Perlmutter, the president of Merck Research Laboratories, "is, are people living longer?" For that, "you just have to wait," he continued, adding, "What I don't want to do is give people false hope." But some patients, like two treated at Hopkins, have become emblems of hope. In 2007, Dennis M. Sisolak, who is 72 and a retired engineer from Bel Air, Md., learned he had kidney cancer. The tumor was huge, and the cancer had spread. After he tried two new drugs to no avail, his doctor, Dr. Charles G. Drake, a kidney cancer specialist at Johns Hopkins, enrolled him in an early phase clinical trial of a P-1 inhibitor. His cancer disappeared on scans and has not returned, even though he has had no treatment for a year. "I have a lot of people praying for me," Mr. Sisolak said. Dr. Drake said three of his patients had similar responses, including one who was treated five years ago in the first study. All, with advanced disease, would have been dead by now, he said, adding, "I have never seen anything like this, personally." David Gobin, 63, a retired Baltimore police officer, has a similar story. He learned he had lung cancer in2008. He had surgery to remove the two lower lobes of his right lung, then radiation and CHEMOTHERAPY. The treatment was grueling: he lost 70 pounds. Two years later, the cancer was back, and it had spread to the wall of his chest. He had more surgery, more chemotherapy, more radiation. In 2010, Mr. Gobin entered a clinical trial of an experimental drug that interferes with cell growth, but had no success. Then his doctor at Johns Hopkins suggested a Phase 1 trial of an anti-PD-1 drug. "Sure, I'll do it," Mr. Gobin recalled saying. "What do I have to lose?" His tumors shrank significantly and have not grown, even though he stopped taking the drug eight months ago. "Every day I have my feet on the grass is a good day, Mr. Gobin said. "I was in the right place at the right time. I will always have cancer, but you know what, I can live with it. "The Lord wanted me to be alive, and I am alive." * * * HIGH RETENTION, IMPROVEMENTS IN RHEUMATOID ARTHRITIS WITH GOLIMUMAB + METHOTREXATE The final 5-year results from the GO-FORWARD trial showed a high retention rate and improvements in signs/symptoms of RHEUMATOID ARTHRITIS (RA) and in physical function were maintained long-term with golimumab + methotrexate therapy. GO-FORWARD, a Phase 3, 2-year randomized trial, evaluated the safety and efficacy of subcutaneous golimumab $B!^(B methotrexate in patients with active RA despite methotrexate therapy. Patients were randomized to placebo + methotrexate, golimumab 100mg + placebo, golimumab 50mg + methotrexate, or golimumab 100mg + methotrexate every 4 weeks. At Week 16, the placebo + methotrexate group crossed over to golimumab + methotrexate ($B!H(Bblinded early escape$B!I(B) or at Week 24 ($B!H(Bcrossover$B!I(B). At Week 52, patients continued treatment with the start of the long-term extension. The last golimumab injection was at Week 252. Edward Keystone, MD, of the University of Toronto/Mount Sinai Hospital, Toronto, Ontario, Canada, and colleagues analyzed the final safety and efficacy results through 5 years. Observed efficacy results by randomized treatment group and cumulative safety data were reported through Week 256 and Week 268, respectively. Of the 444 patients randomized, 313 continued treatment through Week 52 and 301 patients completed the safety follow-up through Week 268. At Week 256, 76.0% of all patients achieved ACR20, 89.5% had a DAS28-CRP EULAR response, and 68.5% had improvement in HAQ-DI $B!f(B0.25. Changes from baseline in mean total vdH-S scores were small (3.3$B!^(B9.4); 54% of patients randomized to golimumab + methotrexate had no radiographic progression ($B&$(BvdH-S$B!e(B0). The most common adverse events were upper respiratory tract infection (32.9%), nasopharyngitis (17.1%), and bronchitis (17.1%); 9.2% of patients had an injection-site reaction. Through Week 268, 172/434 patients (39.6%) had a serious AE and 14.1% of patients discontinued the study drug due to AEs. $B!H(BThe retention rate was high (70.5%) through 5 years, and improvements in signs/symptoms of RA and in physical function were maintained long-term in patients continuing golimumab + methotrexate therapy,$B!I(B Dr. Keystone concluded. Overall, researchers noted long-term safety of golimumab is consistent with other anti-tumor necrosis factor-$B&A(B agents. * * * Until next month ... * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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