RADIANT-2 MULTIFACTORIAL ANALYSIS-REFINING USE OF EVEROLIMUS IN NEUROENDOCRINE TUMORS

In patients with advanced neuroendocrine tumors that originate outside the pancreas, a new set of prognostic factors can help identify which patients are at greatest risk for progression and are more likely to need therapy sooner, say researchers.
The prognostic factors were identified in a reanalysis of the phase 3 multinational study known as RADIANT-2 (RAD001 in Advanced Neuroendocrine Tumors), said lead author James Yao, MD, assistant professor and deputy chair of gastrointestinal oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
He spoke at a press conference hosted by the 2012 Gastrointestinal Cancers Symposium, which begins this week.
The significant prognostic factors include elevated levels of the blood biomarker chromogranin A (CgA), neuroendocrine tumors that originate in the lung, bone metastases, and a World Health Organization (WHO) performance status of 1 or more.
There have not been any "great" studies of this rare form of neuroendocrine tumors that have identified prognostic factors, said Dr. Yao. The RADIANT-2 data revealed that the patient population is "quite heterogenous," he said. The newly defined prognostic factors help identify who is "likely to progress in a short time" and "who actually needs treatment."
Dr. Yao said that the reanalysis had another potentially important finding — that everolimus might be more effective in the treatment of these tumors than originally reported.
In RADIANT-2, Dr. Yao and colleagues originally showed that progression-free survival was a median of 5.1 months longer with the combination of everolimus (Afinitor, Novartis) plus the carcinoid syndrome drug octreotide (Sandostatin, Novartis) than with octreotide alone (16.4 vs 11.3 months); the study results were reported last year by Medscape Medical News.
But the phase 3 study was found to have imbalances in its patient randomization, which put more patients with a poor prognosis in the everolimus group.
After adjusting for randomization imbalances, the researchers found in an exploratory analysis that the reduction in the risk for progression in patients treated with everolimus plus octreotide was 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.51 to 0.87; P = .003). This is an improvement from the 23% risk reduction seen in the first analysis. Everolimus is likely "a little more active than previously thought," said Dr. Yao. A larger study to confirm these results is planned.
It is likely that the original study had randomization imbalances because the prognostic factors needed to stratify patients were not well defined at the start of the study, said Dr. Yao in a press statement.
In short, the researchers are learning as they go.
The subset of patients most likely in need of drug therapy is "all the more meaningful" because of the "limited treatment options" with this disease, said Morton Kahlenberg, MD, from the University of Texas Health Science Center at San Antonio, who moderated the press conference.
Everolimus was approved last year by the US Food and Drug Administration for the treatment of advanced pancreatic neuroendocrine tumors. The targeted therapy sunitinib (Sutent, Pfizer and Merck) was also approved for these tumors last year.
However, it is not known whether everolimus is effective in treating neuroendocrine tumors that do not originate in the pancreas. Currently, there are no approved therapies for the oncologic control of these types of neuroendocrine tumor, said Dr. Yao.
Study Details
In RADIANT-2, Dr. Yao and colleagues sought to assess the effectiveness of the combination of everolimus plus octreotide in patients with low- or intermediate-grade neuroendocrine tumors associated with carcinoid syndrome.
In the study, 429 patients with unresectable locally advanced or distant metastatic neuroendocrine tumors were randomized to receive either oral everolimus 10 mg daily (n = 216) or placebo (n = 213), both in conjunction with intramuscular octreotide LAR (long-acting repeatable) 30 mg every 28 days. Treatment was continued until disease progression, withdrawal from treatment because of adverse effects, or withdrawal of consent.
Of these patients, 357 discontinued study treatment and 1 was lost to follow-up.
The initial analysis of the study found that median progression-free survival was 16.4 months (95% CI, 13.7 to 21.2) in the combination group and 11.3 months (95% CI, 8.4 to 14.6) in the monotherapy group (HR, 0.77; 95% CI, 0.59 to 1.00; P = .026).
In the reanalysis, the investigators identified prognostic factors that predicted both good and poor outcomes in the trial.
They now report that median progression-free survival was significantly longer for patients with nonelevated CgA (27 vs 11 months; P < .001) and nonelevated 5-HIAA (17 vs 11 months; P < .001). The analyses also indicated the prognostic potential of age (14 vs 12 years; P = .01), WHO performance status of 0 vs 1 or more (17 vs 11; P = .004), liver involvement (14 vs not reached;P = .02), bone metastases (8 vs 15; P < .001), and lung as the primary site (11 vs 14; P = .06).
A multivariate analysis found that some factors were significantly associated with a greater likelihood of neuroendocrine tumor progression.
This analysis indicated that bone involvement (HR, 1.52; 95% CI, 1.06 to 2.18; P = .02) and lung as the primary site (HR, 1.55; 95% CI, 1.01 to 2.36; P = .04) were especially strong prognostic factors for progression-free survival, and that baseline CgA (HR, 0.47; 95% CI, 0.34 to 0.65; P < .001) and WHO performance status (HR, 0.69; 95% CI, 0.52 to 0.90; P = .006) were also significant.
Randomization in the trial also resulted patient group imbalances, especially in baseline CgA (median, 251 ng/mL for everolimus plus octreotide vs 137 ng/mL for octreotide alone), Dr. Yao reported.
Other randomization imbalances also favored the octreotide group, which had more patients with a WHO performance status of 1 or more and more with lung as the primary tumor site.
Dr. Yao reports receiving research funding and honoraria from Novartis, which sponsored the trial. Other authors report receiving research funding and honoraria or being employees of and owning stock in Novartis.
2012 Gastrointestinal Cancers Symposium (GICS): Abstract 157. To be presented January 20, 2012.

ASPIRIN IN PRIMARY CVD PREVENTION-BENEFITS AND RISKS

A new meta-analysis said to provide "the largest evidence to date regarding the wider effects of aspirin treatment in primary prevention" has shown that cardiovascular benefits are offset by an elevated risk of bleeding [1].
Senior author Dr Kausik Ray (St George's University of London, UK) commented to heartwire : "On a routine basis I would not recommend aspirin use in primary prevention. And it certainly should not be put in a polypill for mass use."
The current study did not find a significant reduction in cancer mortality. However, the lead author of a previous meta-analysis that did show a reduction in cancer death with aspirin says follow-up in the current study was not long enough to show such an effect.
The new analysis, published online January 9, 2012 in the Archives of Internal Medicine, included nine randomized placebo-controlled trials with a total of 100 000 participants. Results showed that during a mean follow-up of six years, aspirin treatment reduced total cardiovascular events by 10%, driven primarily by a reduction in nonfatal MI, but there was a 30% increased risk of nontrivial bleeding events. The number needed to treat to prevent one cardiovascular event was 120, compared with 73 for causing a nontrivial bleed.
Effect of Aspirin on Vascular and Nonvascular Outcomes or Death

Event	Odds ratio (95% CI)
Cardiovascular events	0.90 (0.85–0.96)
Nonfatal MI	0.80 (0.67–0.96)
Cardiovascular death	0.99 (0.85–1.15)
Cancer mortality	0.93 (0.84–1.03)
Nontrivial bleed	1.31 (1.14–1.50)

Possible Benefit in Those at High Risk
The authors conclude that the "rather modest benefits" and the significant increase in risk of bleeding do not justify routine use of aspirin in the primary-prevention population. They say that further study is needed to identify subsets that may have a favorable risk/benefit ratio. They note that their results suggest an increased risk of nontrivial bleeding in individuals receiving daily (vs alternate-day) aspirin treatment and a particularly unfavorable risk/benefit ratio for individuals at lower baseline cardiovascular risk.
An editorial accompanying the paper suggests that aspirin may be considered in patients with a CHD risk of more than 1% per year [2], but Ray said he thought that was an "oversimplification" of the results.
"There may be a benefit in higher-risk individuals, and there is a case for personalized medicine here. But we showed that as the event rate increased in the placebo group, the reduction in MI with aspirin also increased, but so too did the bleeding risk. The bleeding risk is always greater than the MIs prevented, but it depends on whether you think a nonfatal MI is worse than a significant bleed. So we could do better if we knew who would bleed and who would have an event. I think we need a dual risk score as is done for warfarin."
The cardiovascular results from this latest analysis are in line with those from the 2009 Antithrombotic Trialists' (ATT) Collaboration, and there seems to be agreement on the conclusions regarding heart disease. But there is less agreement on the use of aspirin for the prevention of cancer.
Disagreement Over Cancer Data
Lead author of last year's analysis showing a reduction in cancer mortality with aspirin, Dr Peter Rothwell (University of Oxford, UK) commented to heartwire : "This new meta-analysis just looks at the overall study results, and most of the studies only had three to four years of follow-up. That is not long enough to see a major effect on cancer mortality. In contrast, in our meta-analysis published last year we obtained individual patient data and followed patients long-term after the trials had finished, and in this way we were able to show a significant and impressive effect on cancer mortality."
Rothwell estimates that it takes at least five years to show an effect on cancer deaths, "but after this point you see quite an impressive effect." He noted that the new study also included both alternate and daily aspirin trials, but "all previous work has suggested that aspirin needs to be given every day to prevent cancer."
He added: "Their results are completely compatible with our results. They did show a trend toward a reduction in cancer mortality, which we believe would have become significant if they had longer-term data or if they looked at individual patient data."
The UK newspapers were today full of reports saying there is no benefit of aspirin in cancer prevention, exactly the reverse of the headlines after Rothwell's study came out last year. Rothwell says he is concerned about this. "The message today that aspirin does not prevent cancer is premature. The current study should not change advice on taking aspirin as a healthy person. It does not offer any additional information that we don't already know. We need to think about both risk of heart disease and cancer, and in general heart disease risk is coming down while cancer risk is increasing. There does appear to be a cancer benefit with long-term use, so if there is a family history of cancer I would think about taking aspirin. We have more studies with individual patient data coming out soon that will shed more light on the issue."
More Data Coming Soon
Rothwell says official guidance on primary prevention varies from country to country. "At the moment, the guidelines on primary prevention are just focused on heart disease. They have not looked at the cancer data. There are some new guidelines due to come out over the next year, and these should start to discuss the cancer findings. "
Ray, however, is not so convinced by the cancer data. "Our meta-analysis is much larger than Rothwell's. They had 25 000 individuals whereas we have more than 100 000 patients. As usual, in this situation, when you see the bigger picture, you see 'regression to the truth.' "
Ray commented to heartwire that assuming the trend toward fewer cancer deaths in the current analysis was real, the use of aspirin would produce three and half extra nontrivial bleeds for one cancer death prevented. But he suggested that the cancer data may be biased. "Cancer often shows up as bleeding, and if you are taking aspirin, you are more likely to bleed so are more likely to be investigated, which could affect survival." He also points out that Rothwell's study mixed primary- and secondary-prevention populations, while his study looked at only healthy individuals.
He added: "The cancer data are far from certain. The major reason to give aspirin is to prevent heart attacks and strokes, and in healthy people this benefit is outweighed by the risk of bleeding. Aspirin is not the same as statins, which are known to reduce mortality in primary prevention. Aspirin doesn't affect atherosclerosis; it modifies plaque rupture, which is the final step. That is why it works better in patients with established heart disease. Primary-prevention efforts are much better directed at the basics of diet, exercise, and smoking and reducing cholesterol and blood pressure."

A RARE MUTATION THAT INCREASE PROSTATE CANCER RISK

Researchers have discovered a "rare but recurrent" genetic mutation that is associated with a significantly higher risk for hereditary prostate cancer.
A report on the finding appears in the January 12 issue of The New England Journal of Medicine.
The discovery has no immediate impact on clinical practice because a commercial test is not available.
"Our findings need to be reproduced in additional populations before...there are sufficient data to support developing a clinical test," Kathleen Cooney, MD, one of the study's senior authors, toldMedscape Medical News. She is professor of internal medicine and urology at the University of Michigan Medical School in Ann Arbor.
Still, the discovery is big news. "This is the first major genetic variant associated with inherited prostate cancer," said Dr. Cooney in a press statement.
Prostate cancer has long been identified as having a "strong familial component," but identifying a genetic basis for the phenomenon has been elusive in the past, write Dr. Cooney and her coauthors in their paper.
In their preliminary work, the investigators found that in 4 selected families with a pronounced history of prostate cancer, all 18 males with the disease had a G84E mutation in the HOXB13 gene, which is important in prostate development.
This HOXB13 G84E mutation, now also identified as rs138213197, is novel; it has not been reported elsewhere in major gene sequencing databases.
Dr. Cooney and colleagues looked for the newly documented mutation in 5083 white men who had prostate cancer (but who were unrelated to each other) and in 1401 control subjects without prostate cancer.
They found the mutation in 72 men (1.4%) with and in 1 man without (0.1%) prostate cancer. Thus, the carrier rate was 20 times higher in men with than in men without prostate cancer.
The investigators analyzed these 5083 men with prostate cancer by age at disease onset and by the presence of any history of prostate cancer in their families. The mutation was significantly more common in men with early-onset familial prostate cancer (3.1%) than in those with late-onset nonfamilial prostate cancer (0.6%) (P = 2.0 × 10⁻⁶).
The HOXB13 G84E mutation is rare, the authors point out; it apparently occurs in only 1.4% of all men with prostate cancer. However, the relative rarity of the mutation has not dampened the spirits of the investigators.
"It's what we've been looking for over the past 20 years," said William B. Isaacs, PhD, the study's other senior author. He is professor of urology and oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. "It's long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging, and previous studies have provided inconsistent results."
The investigators hope that other groups will attempt to validate their findings. Dr. Cooney and her team are already doing further studies. But a test for the genetic mutation will have to overcome some hurdles, she explained.
"If our findings hold up, it may be possible to offer testing to unaffected men within a family in which the proband [the first member identified with prostate cancer] carries a HOXB13 mutation," she said.
But this is currently "premature," given the unknowns at the moment. "Because we do not know the penetrance of any of the HOXB13 mutations, we would not be able to offer clinical advice to men found to be mutation carriers. In other words, we would not be able to tell them the likelihood of being diagnosed with prostate cancer in their lifetime or if PSA testing would be useful," she said.
Other Rare Variants Could Be Found
This study might lead to more discoveries of the genetic causes of inherited prostate cancer, say the authors.
"This work suggests that future DNA sequencing studies using next-generation technology and study populations enriched for genetic influence (as evidenced by an early age at onset and positive family history) may identify additional rare variants that will contribute to familial clustering of prostate cancer," they write.
This "next-generation technology" was pivotal to the discovery of the HOXB13 G84E mutation.
Improved gene sequencing technologies allow for more "rapid and comprehensive" investigation of genomics, the authors say. In this case, the researchers sequenced the DNA of more than 200 genes in a human chromosome region known as 17q21–22. This has been "one of the most intensely investigated regions of the genome for prostate cancer susceptibility," they point out.
The study received funding support from William Gerrard, Mario Duhon, John and Jennifer Chalsty, P. Kevin Jaffe, and the Patrick C. Walsh Prostate Cancer research fund. The Department of Network and Computing Systems at TGen, with support from National Institutes of Health grants, facilitated the use of supercomputing resources.

How to Lose Weight All Day Long

Timing your workouts and meals may be the secret to your weight loss success

Understanding and working with your body's natural hunger and sleep rhythms will vanquish cravings, increase energy, and help you lose more weight.

It's not just what you eat or how much you exercise that matters; it's the timing of each component that is the true secret to weight loss success. Research shows that our bodies' inner eat-and-sleep clocks have been thrown completely out of whack, thanks to all-day food cues and too much nighttime artificial light. The result: You're caught in a "fat cycle": a constant flow of hunger hormones that makes you prone to cravings. By tuning in to your body's natural eat/sleep schedule, you can finally say good-bye to your belly.

The Perfect Day of Eating

Drop Around The Clock! Follow this hour-by-hour slim-down schedule to control hunger hormones, banish cravings, and get trim and toned--fast!

6 TO 8 AM: GET MOVING.
Within a half hour of rising and before you eat breakfast, do 20 minutes of cardio. Research has found that exercising before breakfast may help you burn fat more efficiently. If you can get outside, even better. Early morning sunlight helps your body naturally reset itself to a healthier sleep/wake cycle (regular indoor lights don't have the same effect).

How to Burn More Calories with Every Workout

6:55 TO 8:55 AM: DRINK UP.
Before every meal, drink two 8-ounce glasses of water. Research shows that people who drank this amount lost 5 pounds more than nonguzzlers.

Try Refreshing Sassy Water Recipe to De-Bloat Your Belly

7 TO 9 AM: EAT BREAKFAST.
The alarm clock also wakes up ghrelin, the "feed me" hormone made in your stomach. Ignore ghrelin and your body will produce even more, eventually making you ravenous. To suppress ghrelin's effect, eat a mix of complex carbs and protein, such as eggs and whole grain toast, within an hour of waking.

Get 8 Healthy Breakfast Ideas

10 TO 11 AM: MUNCH MIDMORNING.

Ghrelin begins to rise again a couple of hours before lunch. It turns off when you chow down, particularly on carbs and protein, so have a small combo snack, like blueberries and Greek-style yogurt.

Get 30 Healthy Snack Suggestions

12 TO 1 PM: HAVE YOUR MIDDAY MEAL.

Galanin, another hunger hormone that makes you crave fat, rises around lunchtime. However, dietary fat causes you to produce more galanin, which then tells you to eat more fat. Instead, fill up with complex carbs and protein, such as chicken-vegetable soup or black bean chili.

The Best Sandwiches for Weight Loss

2 TO 3 PM: TAKE A NAP.
Instead of hitting the vending machines, find a quiet place to grab a few Zzzs. (Hint: Your parked car is the perfect impromptu sleep pod!) Just set an alarm--15 to 20 minutes will energize your body without affecting your ability to sleep at night.

3:30 PM: GET BUZZED.
Need a boost? This is your last chance to have a cup of joe. Drinking coffee after 4 PM disturbs circadian rhythms and can keep you from falling asleep at night.

4 TO 8 PM: TRIM AND TONE.
Now's the time to do your strength training, plus any additional cardio. This is when your body temperature is highest, so you're primed for peak performance. In one study, subjects who worked out in the late afternoon or early evening built 22% more muscle than morning exercisers.

7 Strength Moves You've Got to Learn

5 TO 7 PM: TIME TO DINE.
To ensure you don't wake up hungry in the middle of the night, add a serving of healthy fats, such as flaxseed or fish oil, to your meal. If you're a wine drinker, pour a glass now. Drinking later can delay dream (REM) sleep, waking you frequently during the night.

9 TO PM: HAVE A PRESLEEP SNACK.
Enjoy a carb-based bedtime snack, such as a serving of low-fat frozen yogurt. Nighttime carbs create tryptophan, which helps your brain produce serotonin. This feel-good chemical triggers your body to make melatonin, the sleep hormone.

9 TO 10:30 PM: POWER DOWN.
Step away from digital devices, including the TV. They emit a blue spectrum of light that's even more disruptive to sleep than regular bulbs. Do something calming--read, take a bath--in dim light so you're ready to nod off when you hit the sheets.

10 Reasons You Can't Fall Asleep

9:30 TO 11 PM: GO TO SLEEP.
Crawl under the covers at the same time each night and get up at the same time each morning, even on weekends. Having a regular sleep-and-wake schedule helps you fall asleep faster over time.

Get 3 Days of Recipes from the Belly Melt Diet

TELL US: What time of day do you find the hardest to stick to your diet?

--By the editors of Prevention

10 Surprising Health Benefits of Beer

Beer drinkers rejoice: Your favorite brew may be healthier than you think.

For years, wine drinkers have indulged without guilt, reveling in the news that red wine can help protect against heart disease. Recent research shows that beer can also be good for what ails you, from reducing risk for broken bones to helping warding off diabetes and mental decline. It can even increase longevity, a large study suggests.

However, the key to tapping into beer’s benefits is moderation, meaning just one 12-ounce beer per day for women and two for men. Heavy drinking ups the threat of liver damage, some cancers, and heart problems. Bingeing on brewskis can also make you fat, since a 12-ounce regular beer has about 150 calories, while light beer has about 100.

Here are 10 surprising—and healthy—reasons to cheer about your next beer.

1. Stronger Bones

Beer contains high levels of silicon, which is linked to bone health. In a 2009 studyat Tufts University and other centers, older men and women who swigged one or two drinks daily had higher bone density, with the greatest benefits found in those who favored beer or wine. However, downing more than two drinks was linked toincreased risk for fractures.

For the best bone-building benefits, reach for pale ale, since a 2010 study of 100 types of beer from around the word identified these brews as richest in silicon, while light lagers and non-alcoholic beers contained the least.

2. A Stronger Heart

A 2011 analysis of 16 earlier studies involving more than 200,000 people, conducted by researchers at Italy’s Fondazion di Ricerca e Cura, found a 31 percent reduced risk of heart disease in those who quaffed about a pint of beer daily, while risk surged in those who guzzled higher amounts of alcohol, whether beer, wine, or spirits.

More than 100 studies also show that moderate drinking trims risk of heart attacks and dying from cardiovascular disease by 25 to 40 percent, Harvard reports. A beer or two a day can help raise levels of HDL, the “good” cholesterol that helps keep arteries from getting clogged.

3. Healthier Kidneys

A study in Finland singled out beer among other alcoholic drinks, finding that each bottle of beer men drank daily lowered their risk of developing kidney stones by 40 percent. One theory is that beer’s high water content helped keep kidneys working, since dehydration increases kidney stone risk.

It’s also possible that the hops in beer help curb leeching of calcium from bones; that “lost” calcium also could end up in the kidneys as stones.

4. Boosting Brain Health

A beer a day may help keep Alzheimer’s disease and other dementia at bay, researchers say.

A 2005 study tracking the health of 11,000 older women showed that moderate drinkers (those who consumed about one drink a day) lowered their risk of mental decline by as much as 20 percent, compared to non-drinkers. In addition, older women who downed a drink a day scored as about 18 months “younger,” on average, on tests of mental skills than the non-drinkers.

5. Reduced Cancer Risk

A Portuguese study found that marinating steak in beer eliminates almost 70 percent of the carcinogens, called heterocyclic amines (HCAs) produced when the meat is pan-fried. Researchers theorize that beer’s sugars help block HCAs from forming.

Scientists also have found that beer and wine contain about the same levels of antioxidants, but the antioxidants are different because the flavonoids found in hops and grapes are different.

6. Boosting Vitamin Levels

A Dutch study, performed at the TNO Nutrition and Food Research Institute, found that beer-drinking participants had 30 percent higher levels of vitamin B6 levels in their blood than their non-drinking counterparts, and twice as much as wine drinkers. Beer also contains vitamin B12 and folic acid.

7. Guarding Against Stroke

Researchers at the Harvard School of Public Health found that moderate amounts of alcohol, including beer, help prevent blood clots that block blood flow to the heart, neck and brain—the clots that cause ischemic stroke, the most common type.

8. Reduced Risk for Diabetes

Drink up: A 2011 Harvard study of about 38,000 middle-aged men found that when those who only drank occasionally raised their alcohol intake to one to two beers or other drinks daily, their risk of developing type 2 diabetes dropped by 25 percent. The researchers found no benefit to quaffing more than two drinks. The researchers found that alcohol increases insulin sensitivity, thus helping protect against diabetes.

9. Lower Blood Pressure

Wine is fine for your heart, but beer may be even better: A Harvard study of 70,000 women ages 25 to 40 found that moderate beer drinkers were less likely to develop high blood pressure—a major risk factor for heart attack—than women who sipped wine or spirits.

10. Longer Life

In a 2005 review of 50 studies, the U.S. Department of Agriculture (USDA) reported that moderate drinkers live longer. The USDA also estimates that moderate drinking prevents about 26,000 deaths a year, due to lower rates of heart disease, stroke, and diabetes.

These benefits appear to apply in other countries as well, with an earlier studyreporting that, “if European beer drinkers stopped imbibing, there would be a decrease in life expectancy of two years—and much unhappiness.”