Doctor Healthy

PET-CT HAS PREDICTIVE VALUE AFTER RADIOCHEMOTHERAPY FOR HEAD AND NECK CANCERS

2012-02-07T06:43:00.000-08:00

Oncologists at St. John Hospital in Grosse Pointe Woods, Michigan, routinely perform a surveillance positron emission tomography (PET)/computed tomography (CT) scan 6 to 9 weeks after the definitive chemoradiation treatment of patients with squamous cell carcinoma of the head and neck — even when a recurrence is not clinically suspected.
And these clinicians will continue to do so in light of the results from a small study conducted at their center, despite the "controversy" surrounding such routine follow-up, said study author Yasir Rudha, MD, MBChB, a radiation oncologist at the hospital.
"We will keep doing it because of the high negative predictive value," said Dr. Rudha during a press conference at the 2012 Multidisciplinary Head and Neck Cancer Symposium. He was referring to the fact that, in their study, about half of the patients with no clinical evidence of recurrence had a subsequent negative surveillance scan and that all of them remained free of locoregional recurrence on further follow-up.
"Almost all of those patients will be able to avoid neck dissection," predicted David Raben, MD, from the University of Colorado in Aurora, about patients with negative surveillance scans. He was moderator of the press conference. In the past, most of these patients would have automatically gone on to a neck dissection as part of treatment, he said.
The surveillance scans had another benefit — they identified patients with disease recurrence that preceded any clinical manifestation of recurrence. The rate for finding these "true positives" was 53%, Dr. Rudha reported. However, this benefit was somewhat offset by the "high false-positive rate" of 46%, he admitted.
"The routine use of PET/CT scanning in the follow-up of patients with squamous cell carcinoma of the head and neck may be useful for the detection of locoregional recurrences before they become clinically apparent," he summarized.
Study Results and Controversies
Dr. Rudha and colleagues identified 234 patients with head and neck cancer at their center who were treated with chemoradiation and then underwent a posttherapy PET/CT scan from 2006 to 2010.
A retrospective chart review was performed for 45 of those cases, all of whom had a "clinical no-evidence-of-disease " status at the time of the surveillance PET/CT scan.
Of these 45 patients, 30 had a negative PET/CT scan, and all 30 remained free from locoregional relapse at the time of last follow-up. However, the median time of follow-up for the 30 patients was not presented by Dr. Rudha.
The scans identified 15 patients with abnormalities requiring further evaluation. Biopsy showed malignancies in 8 of the 15 patients (53%). (Six of the 8 showed occult persistent disease at the primary site.)
The other 7 cases of abnormalities turned out to be false positives (46%). Thus, patients underwent "unnecessary work-up and/or biopsy evaluation," he said. "Caution should be shown when ordering biopsies after abnormal scans to prevent excessive unnecessary biopsies," he added.
However, overall, the study results provide "support for the routine use of PET scanning as a surveillance method following treatment of head and neck cancer," Dr. Rudha summarized.
Dr. Rudha suggested that this is an uncommon finding in the literature.
He acknowledged that, in most studies, PET scans are performed only when recurrent disease is clinically suspected. "Only a few publications report the value of PET examination at a fixed time after the end of treatment," he told reporters at the press conference.
Dr. Raben endorsed using PET after treatment. The scans are "absolutely critical" for the monitoring and follow-up of these patients. But he added that the use of PET scans in head and neck cancer "continues to evolve."

10% RATE OF ORAL HPV INFECTION

2012-02-01T01:49:00.001-08:00

A major study of oral infection with human papillomavirus (HPV) — now known to cause of a subset of oropharyngeal cancer — has found a much higher incidence in men than in women and has established sexual transmission as the main way it spreads. It also raises questions about whether existing HPV vaccines offer protection.
There is a rising incidence in oral HPV infection and in HPV-positive oropharyngeal cancer in the United States. "The curves are a little bit frightening," said lead author Maura Gillison, MD, PhD, from Ohio State University in Columbus. But she pointed out that vaccines against HPV are already marketed, so "we have the means to prevent this already sitting on our pharmacy shelves."
The HPV vaccines (Gardasil and Cervarix) were developed to offer protection against cervical cancer after the link between cervical HPV infection and cervical cancer was firmly established, and are targeted mainly to girls.
The link between oral HPV infection and oral HPV cancer was established more recently; Dr. Gillison reported that the research is about 20 years behind that for cervical cancer. There is speculation — although no hard data — that the same vaccines could offer protection against HPV-associated oral cancer. Because this is more prevalent in men, it would make sense to vaccinate boys as well as girls.
"We need to have thorough and accurate discussions about HPV vaccination," Dr. Gillison said. "We have identified a new cancer...and we have identified its Achilles heel," she added.
Dr. Gillison spoke at a presscast at the 2012 Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Therapeutic and Radiation Oncology and held in Phoenix, Arizona. The study was published online January 26 in JAMA: The Journal of the American Medical Association to coincide with its presentation.
Sexual Transmission
This the first major prevalence study of oral HPV infection in the United States, according to anaccompanying editorial, subtitled "Hazard of Intimacy."
Editorialist Hans Schlecht, MD, MMSc, from Drexel University College of Medicine in Philadelphia, Pennsylvania, writes that the "results are remarkable for a number of reasons," including the fact that they allow estimation of oral HPV prevalence based on sexual experience, smoking status, and immune suppression.
One of the main findings from this study is that the main method of transmission is sexual, and that the prevalence of oral HPV infection increases with the number of sexual partners reported.
Another finding is "a striking bimodal pattern with age" in men, with peaks in men 30 to 34 and 60 to 64 years of age.
During the presscast, Dr. Gillison speculated that these peaks in oral HPV infection might be partially explained by a "birth cohort" effect. The peak in older men could be related to the fact that they would have been making their sexual debut during the sexual revolution of the 1960s; the dip in middle-aged men could be the result of the dampening impact that the HIV epidemic had on sexual behavior. The peak in younger men could be related to one result of that epidemic — the perception that oral sex is "safe sex."
The new data showing a rising incidence of HPV oropharyngeal cancer raise questions about exactly how safe oral sex is.
In his editorial, Dr. Schlecht suggests that "clinicians should encourage their patients who engage in oral sex to use barrier protection."
First Major Prevalence Study
This study used 2009/10 data from the National Health and Nutrition Examination Survey (NHANES), and analyzed tissue collected from an oral rinse and gargle collected from 5579 people 14 to 69 years of age.
The overall prevalence of HPV oral infection was 6.9%; the particular strain associated with oropharyngeal cancer, HPV16, was found in 1%. "Although this 1% may sound small, this means that around 2.1 million individuals in the United States are infected," Dr. Gillison explained.
However, the incidence in men is significantly higher than it is in women (10.0% vs 3.6%; P < .001).
In addition, the bimodal distribution, with peaks in younger and older individuals, was seen only in men. Why the incidence of oral HPV infection in men is so much higher is not clear, Dr. Gillison said.
Men did report having more sexual partners than women, but this difference in sexual behavior explains only about 16% of the difference in prevalence, the authors note. Another explanation could be higher rate of transmission to men performing oral sex on woman than to women performing oral sex on men; there is some evidence for this in the data. But there are also many other factors, including the fact that women who have already been exposed to cervical HPV infection have greater protection against subsequent oral HPV infection.
The bimodal distribution of oral HPV infection in men is different than that of cervical HPV infection, which peaks in women in their 20s and then generally drops off, although a later peak in older women is seen in some populations.
"It is clear that the natural history of HPV is different in the 2 genders," Dr. Gillison reported.
There was a higher prevalence of oral HPV infection in black than in white people, although this did not reach statistical significance (10.5% vs 6.5%; P = .06). There was also a higher prevalence in current smokers and heavy consumers of alcohol (which increased with intensity of use for both), as well as in current and former marijuana users.
There was little HPV oral infection in individuals who had no history of any sexual contact. Compared with this group, the prevalence was 8 times higher in sexually experienced individuals, and increased significantly with the number of sexual partners. For instance, the prevalence was 20% in people who reported having more than 20 sexual partners.
"These data indicate that transmission by casual, nonsexual contact is likely to be unusual," the authors write.
They note that previous studies have suggested a link between oral sexual behavior and an increased risk for HPV-positive oropharyngeal cancer, but the way the data were collected in the current study precluded association with any particular behavior. However, the data did show that oral HPV infection is more common in sexually experienced people who do not report performing oral sex than in those who were not sexually experienced, which suggests that transmission occurs through other sexually associated contact, such as deep kissing.
This adds weight to the notion that HPV vaccination should be targeted at individuals who are 9 to 13 years of age, in an effort to reach them before any sexual behavior, including deep kissing, begins. This suggestion has been made previously by Dr. Gillison, although she emphasized that protection against oral HPV infection with the existing HPV vaccines has not been proven. She has been trying to conduct such a study for the past 5 years, but has run into funding problems; she hopes to hear soon about funding from the National Cancer Institute, she told journalists in the audience.
Extending HPV vaccination to offer protection against oropharyngeal cancer was discussed by several experts, in addition to Dr. Gillison, last year when it was highlighted by the American Society for Clinical Oncology.
The study was supported by an unrestricted grant from Merck, and was also funded by Ohio University and the Intramural Research Program of the National Cancer Institute. Dr. Gillison reports acting as a consultant to Merck and GlaxoSmithKline, both manufacturers of HPV vaccines. Dr. Schlecht has disclosed no relevant financial relationships.

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

2012-01-25T09:13:00.000-08:00

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

2012-01-20T05:35:00.000-08:00

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

2012-01-20T05:34:00.000-08:00

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

2012-01-17T06:55:00.000-08:00

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

2012-01-14T01:07:00.000-08:00

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.”

Sex Hormones Are Not Just for Baby-Making

2012-01-08T01:09:00.001-08:00

The preceding discussion notwithstanding, the ovary is more than just a storehouse for eggs. Thebioidentical hormonesthat it produces ensure that our bodies will function properly throughout our lives, not just during our reproductive years.
I mentioned earlier that bioidentical hormones travel in the bloodstream to cells and tissues throughout the body, powerfully affecting our health. But once hormones reach their intended destinations, you may wonder, how do they actually exert their effects? Cells that depend on hormones to function properly have protein molecules called hormone receptors that act like tiny ignition starters. And the hormones, logically enough, act like tiny keys. When a hormone—say estrogen— encounters a cell that has a receptor for estrogen, it’s like when you put your key into your car’s ignition and turn it on to start the engine. When estrogen binds to and turns on the estrogen receptor, it stimulates the cell to produce a cascade of proteins that influence its behavior.
Estrogen receptors are found not only in the cells of reproductive organs, such as the uterus and breast, but also in the cells of the liver, digestive system, urinary tract, heart, blood vessels, bone, skin, and the brain.
The exact effect of estrogen depends on the type of cell that it encounters. For example, in the uterus and breast, estrogen’s main effect is to cause the cells that line the uterus and the milk ducts to grow and divide in preparation for pregnancy. In the liver, estrogen acts to control the production of cholesterol in ways that influence the buildup of harmful fatty deposits in the arteries. In the skeleton, estrogen preserves bone strength by helping to maintain the proper balance between bone buildup and bone breakdown. And in other parts of the body, estrogen appears to play a role in the regulation of body temperature, the ability to recall information from memory, and the elasticity of arteries and skin. This is only a partial list of estrogen’s effects.
When estrogen levels drop, the rate of bone loss accelerates rapidly. Indeed, the average woman loses 2 to 3 percent of bone mass a year for the first three years after menopause. As a result, osteoporosis is much more common in the decades after menopause. A woman’s risk of heart disease also increases sharply after menopause, but estrogen’s role in this process is still under study.
Two types of estrogen receptors—alpha and beta—have been identified. Scientists have known about the alpha receptor since the 1950s, but the beta receptor was identified only in 1996. In general, there are more alpha receptors in the reproductive organs (e.g., uterus and breast) and the liver, while beta receptors are more abundant in other tissues, such as bone and blood vessels. Estradiol appears to bind equally well to both types of receptors, while estrone binds preferentially to the alpha receptor and estriol to the beta receptor. We do not fully understand the role of the two types of estrogen receptors, their exact functions, or how they relate to the benefits and risks of our natural estrogen or the estrogen in traditional hormone therapies for menopause.
Nevertheless, recognition of differences in receptors has allowed pharmaceutical companies to manufacture a new class of medicines called selective estrogen receptor modulators (SERMs)—or, to use the more glamorous name, “designer hormones”—that act on one or the other of these receptors to selectively block or stimulate estrogen-like action in various tissues.
One of the first SERMs to be developed was tamoxifen. Known by its trade name Nolvadex and also available as a generic, tamoxifen is prescribed to treat breast cancer and prevent its recurrence in women with a history of the disease and to prevent its development in women at high risk. In the breast, tamoxifen acts as an antiestrogen by binding to the alpha receptor, thus preventing estrogen from accessing it. In other parts of the body, however, tamoxifen acts like estrogen. Another SERM, raloxifene, known by its trade name Evista, is approved for prevention of bone thinning in women after menopause and is being studied as a way to prevent breast cancer. In a recent “head-to-head” trial, raloxifene and tamoxifen provided similar protection against breast cancer but raloxifene had fewer risks. Both of theseSERMs increase hot flashes and the risk of blood clots, however. In the future, watch for additional developments with SERMs, which could eventually be designed to ease symptoms of menopause and protect bone and heart health without adding to the risk of breast cancer.
As with estrogen, receptors for progesterone also come in at least two forms. However, even less is known about their precise roles and functions, or how this information could be used to develop safer or more effective forms ofhormone replacement therapy.
In addition to estrogen and progesterone, generally known as the female sex hormones, the ovaries, along with the adrenal glands, produce small amounts of male sex hormones known as androgens, including testosterone. Testosterone levels in women are only one-tenth as high as in men. Androgens are thought to work in concert with estrogen to maintain a woman’s sex drive, bone and muscle health, energy level, and psychological well-being. Indeed, androgen receptors are found in many of the same cells that have estrogen receptors.
Interestingly, a large proportion of the androgens produced by the ovary and adrenal gland are converted to estrogen by an enzyme called aromatase found in fat and muscle. (Other organs that contain aromatase include the brain, hair, skin, and bone marrow.) After menopause, this conversion actually represents the main source of estrogen in women. Because aromatase is found in fat cells, women who are overweight or obese tend to have higher levels of estrogen than thinner women.
At the same time, because muscle cells are also rich in aromatase, women with more muscle mass are more likely to have higher estrogen levels than their scrawnier counterparts. This is thought to be why heavier women, and women who keep their muscles active with physical activity, may be less likely to suffer from certain symptoms of menopause.
In recent years, medicines called aromatase inhibitors—anastrozole (Arimidex) and letrozole (Femara)—have been approved to treat women with early-stage breast cancer. These medicines work by blocking the aromatase enzyme, thus preventing the conversion of androgens to estrogen in fat, muscle, and other tissues. Together with tamoxifen, aromatase inhibitors form a powerful new arsenal to fight breast cancer. (Not all breast cancer cells have estrogen receptors, though. These medicines stifle the growth of breast cancer cells that have estrogen receptors but do not affect the growth of breast cancers that lack estrogen receptors.)

MAJOR ADVANCES IN CANCER IN 2011

2011-12-26T10:11:00.001-08:00

The annual Clinical Cancer Advances 2011 report from the American Society of Clinical Oncology (ASCO), now in its seventh year, highlights 12 major advances made in 2011 and 42 advances that it considers "notable."
The report was compiled by 18 prominent oncologists, and covers the period from October 2010 to September 2011. The research highlighted in this report is considered by the experts to have had a significant impact on the way a cancer is understood or to have had a direct effect on patient care. Most of the advances were covered by Medscape Medical News.
Major Clinical Advances
Lung cancer deaths reduced by low-dose computed tomography (CT) scanning of people at high risk. These results come from the landmark National Lung Screening Trial, which was halted early because of benefit. The study followed 53,454 people at high risk for lung cancer (they had smoked the equivalent of a pack of cigarettes a day for 30 years), and showed that anannual CT scan reduced the risk of dying from lung cancer by 20%, compared with an annual chest x-ray, over the course of 3 years (N Engl J Med. 2011:365:395-409). "This was the first randomized trial to find a definitive reduction in lung cancer deaths with screening," according to the report.
Crizotinib (Xalkori) approved for rare type of lung cancer in August 2011 by the US Food and Drug Administration (FDA). This drug, indicated for use in patients with advanced nonsmall-cell lung cancer who harbor a specific type of alternation in the anaplastic lymphoma kinase (ALK) gene, is "one of the latest examples of a successful personalized medicine approach," says the report.
Exemestane (Aromasin) reduced risk for breast cancer in high-risk postmenopausal women in the MAP.3 (Mammary Prevention Trial). The trial followed 4560 women 60 years and or older who were at high risk for breast cancer, and 3-year results showed that exemestane reduced the risk for invasive breast cancer by 65% (N Engl J Med. 2011:364:2381-2391). "This is the first conclusive evidence that an aromatase inhibitor reduced the risk of a first breast cancer," the report notes, adding that exemestane now offers an alternative to tamoxifen and raloxifene, which are approved for chemoprevention but not widely used because of concerns about toxicity.
In early breast cancer, adding regional nodal irradiation decreases recurrences. In women with early-stage breast cancer who have 1 to 3 positive lymph nodes or who are node-negative but at high risk, the addition of regional nodal irradiation reduces the risk for both local recurrence and distant metastases. These results should encourage radiation oncologists to discuss with their patients a more extended radiotherapy field to reduce the risk for recurrences, the report notes.
Vemurafenib (Zelboraf) improves survival in advanced melanoma in patients with BRAFmutations, compared with standard chemotherapy (New Engl J Med. 2011;364:2507-2516).The drug was approved by the FDA in August, and the report notes that it is "a new standard treatment" for patients with melanoma and BRAF mutations (about half of all patients with melanoma).
First-line ipilimumab (Yervoy) plus chemotherapy improves survival in metastatic melanoma in a phase 3 study (N Engl J Med. 2011;364:2517-2526). The new drug is an immunotherapeutic that activates T cells, and was approved by the FDA in March. "This is the first study showing the benefit in prolonging life by combining chemotherapy and immunotherapy in patients with advanced melanoma," the report notes.
Bevacizumab (Avastin) has been shown to delay progression in both recurrent and newly diagnosed ovarian cancer in 2 separate phase 3 trials. The report considers this to be 2 separate major clinical advances. The data in recurrent ovarian cancer come from the phase 3 OCEANS trial, and show a 52% reduction in the risk for disease progression when bevacizumab is added to chemotherapy, compared with chemotherapy alone. The other study, known as ICON 7, found an improvement in overall survival in some women with newly diagnosed ovarian cancer. The report notes that researchers are waiting for longer-term data from both of these trials.
A new high-dose chemotherapy regimen improves survival in neuroblastoma. In children with high-risk metastatic neuroblastoma, an intense dosing with busulphan plus melphalan improved the event-free survival rate to 49% at 3 years, compared with 33% with the standard regimen of carboplatin, etoposide, and melphalan. These findings establish a new standard of care, the report notes.
A new chemotherapy regimen boosts event-free survival in acute lymphoblastic leukemia (ALL). The results from a phase 3 study of nearly 2500 children and young adults showed that giving methotrexate in large consistent doses, rather than gradually increasing the dose (as happens in the standard regimen) is more effective at preventing relapses and extended survival. These findings set a new standard of care and push cure rates for pediatric patients with ALL up to more than 80%, the report notes, adding that "this disease was once considered one of the most deadly pediatric cancers, but today is seen as one of the most curable."
Imatanib (Gleevec) for 3 years improves survival in patients with high-risk gastrointestinal stromal tumors. After surgery, patients who took imatanib for 3 years had significantlyimproved overall and recurrence-free survival, compared with those who took the drug for 1 year.
Abiraterone acetate (Zytiga) was approved for prostate cancer in April by the FDA. The drug is used in combination with prednisolone in patients with metastatic prostate cancer who have previously been treated with docetaxel. According to the report, it offers a much-needed new option for these patients.
Notable Advances
Brentuximab vedotin (Adcetris) shows tumor shrinkage in lymphomas. This novel antibody–drug combination was granted accelerated approval by the FDA in August for use in refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma. This is the first drug for Hodgkin's lymphoma to be approved by the FDA in more than 30 years, the report notes.
Ruxolitinib (Jakafi) used for high-risk myelofibrosis. The drug showed increased response rates, decreased spleen size, and improved symptoms such as fatigue, night sweats, weight loss, and bone pain in the COMFORT I and II studies (2011 ASCO annual meeting, abstract 6500 andabstract LBA6501). These are the first-ever randomized trials conducted in patients with myelofibrosis, and the findings promise to change the standard of care, the report notes. Ruxolitinib, a JAK inhibitor, was recently approved by the FDA for myelofibrosis.
Treating HER2 breast cancer with drug combinations is more effective than treating with single agents. Although trastuzumab (Herceptin) is effective in treating HER2-positive breast cancer, a significant number of tumors do not respond or become resistant. Two studies have shown that adding another agent improves or extends treatment response — trastuzumab was used with lapatinib (Tykerb) in the CHER-LOB study (2011 ASCO annual meeting, abstract 507) and with docetaxel and pertuzumab (Omnitarg) in the NeoSphere study (2010 San Antonio Breast Cancer Symposium, abstract S3-2). The report notes that larger, longer-term trials (ALTTO and Neo-ALTTO) are currently evaluating whether this approach ultimately extends survival.
PARP inhibitor did not improve survival in metastatic triple-negative breast cancer. The investigational drug iniparib, which acts as an inhibitor of the PARP enzyme that is involved in tumor cell DNA repair, showed promising activity in a randomized phase 2 study (n = 123) when it was added to gemcitabine and carboplatin, increasing overall survival from 8 to 12 months. However, a larger phase 3 study (n = 519) with the same drug combination failed to show any improvement in survival (2011 ASCO annual meeting, abstract 1007). The contrasting results underscore the need to conduct carefully controlled, adequately powered studies to clarify promising results in a preliminary study, the report noted.
Gene biomarkers linked to glioblastoma survival. Analysis of data collected during a phase 3 trial of temozolomide with radiation in patients with newly diagnosed glioblastoma showed that patients with tumors that carried the "silenced" gene for methyl guanine methyltransferase (MGMT) had better overall survival. Further study revealed several more biomarkers or groups of biomarkers that could predict clinical outcome (2011 ASCO annual meeting, abstract LBA2000).
Gene deletion linked to poor glioblastoma survival. Previous studies have shown that nearly all glioblastomas have alterations in the epidermal growth-factor receptor (EGFR) gene, but drugs targeting this pathway have not been effective. One study has shown that the deletion ofNFKBIA, a gene that inhibits the EGFR signaling pathway, affects tumor formation, increases chemotherapy resistance, and worsens survival. It might provide a new target for treatment (N Engl J Med 2011; 364:627-637).
New mutation patterns were found in medulloblastoma. Researchers characterized the most common genetic alterations in medulloblastoma, making it the first pediatric solid tumor to be genetically sequenced (Science 2011;331:435-439). This might allow for better molecular classification of the disease and better prognosis, and might lead to the identification of new drug targets, the report notes.
Trastuzumab was approved for HER2-positive gastric cancer by the FDA in late 2010. The drug is indicated for use in patients with metastatic gastric cancer with tumors that express high levels of HER2 (about 15% to 18% of patients). Adding trastuzumab to chemotherapy (cisplatin and either capecitabine or 5-fluorouracil) was shown to improve survival in the ToGA trial(Lancet 2010;376:687-697). This trial was the first to show a median survival of more than 1 year in this patient population, the report notes.
Sunitinib (Sutent) and everolimus (Afinitor) were approved for pancreatic neuroendocrine tumors in patients with unresectable or metastatic disease. Both drugs were shown to more than double the time it took for the cancer to progress, compared with placebo, the report notes, and they offer new options for the treatment of this cancer, which previously was treated with interferon and chemotherapy. The indication for pancreatic neuroendocrine tumors was approved for sunitinib and everolimus within weeks of each another in May 2010.
Cabozantinib shows benefit in advanced prostate cancer in a phase 2 trial. This investigational drug showed impressive activity in a phase 2 trial in patients with progressive metastatic hormone-refractory prostate cancer (2011 ASCO annual meeting, abstract 4516). Results from 100 evaluable patients showed tumor shrinkage in 84% and disease control in 71% of patients. In addition, the researchers reported that 56 of 65 patients (86%) with bone metastases experienced either partial or complete disappearance of the bone metastases on scans, often with a drop in blood biomarkers that are indicative of bone damage, leading to significant pain relief.
Cabozantinib shows significant effect in melanoma and other cancers. The same investigational agent showed impressive activity in another phase 2 trial — this time in patients with a variety of advanced solid tumors (including liver, ovarian, and prostate cancer) and in melanoma (2011 ASCO annual meeting, abstract 3010). Cabozantinib, which also showed suppression of bone metastases, is a novel multitargeted agent, with activity against MET, VEGFR2, RET, KIT — protein kinases that are involved in the development and progression of many cancers, the report notes.
Axitinib (Inlyta) used as second-line therapy for advanced kidney cancer. Results from the phase 3 AXIS trial of 723 patients with metastatic renal cell carcinoma in whom previous treatment had failed showed that axitinib improved progression-free survival to 7 months, compared with 5 months with sorafenib (Nexavar) (2011 ASCO annual meeting, abstract 4503). Axitinib is not marketed yet, but an FDA Oncologic Drugs Advisory Committee recently voted unanimously to recommend its approval for second-line treatment in renal cell carcinoma.
Denosumab (Xgeva) prevents skeletal-related events in metastatic cancer patients. This novel bone drug, a monoclonal antibody that targets a protein (RANK ligand) involved in cancer-related bone destruction, was approved by the FDA in November 2010 for preventing skeletal-related events in cancer patients with solid tumors and bone metastases. In 2 clinical trials, denosumab was significantly better at reducing skeletal-related events in patients with advanced breast and prostate cancer than the bisphosphonate zoledronic acid (Zometa).
The Cancer Genome Atlas provides details on ovarian cancer and points to potential drug targets. The first comprehensive effort to map the genome of ovarian cancer focused on serous ovarian adenocarcinoma (which accounts for about 70% of deaths), and found several molecular features: TP53 mutations in 96% of cases, BRCA mutations in 22%, and defects that interfere with DNA repair (which could be susceptible to PARP inhibitors) in about 50% of tumors (Nature. 2011;474:609-615). These findings reinforce the promise of ongoing research on PARP inhibitors, which are being evaluated in late-stage clinical trials in ovarian cancer, the report notes.
PARP inhibitors and maintenance therapy used in ovarian cancer. A phase 2 study of 265 women with relapsed high-grade serous ovarian cancer showed that the investigational PARP inhibitor olaparib used after standard chemotherapy improved progression-free survival to 8 months, compared with 5 months for placebo (2011 ASCO annual meeting, abstract 5003). If these results are confirmed in larger trials, which are underway, olaparib could become an important treatment for women with advanced or high-risk ovarian cancer, the report notes.
The Lung Cancer Mutation Consortium matched tumor mutation to drug selection. Aprospective study identified at least 1 of 10 recognized "driver" mutations in tumors of nearly two thirds of patients with adenocarcinoma, many of which are targeted with drugs that are already marketed or in clinical trials. As a result of this program, "multiplex testing" for many tumor mutations at the same time is now routine at some of the 14 American centers that took part, and is also applicable to other cancers, the report notes.
Maintenance pemetrexed extends survival in advanced lung cancer. The phase 3 PARAMOUNT study showed that after initial treatment with pemetrexed and cisplatin, patients who continued on maintenance pemetrexed had a longer progression-free survival than those who did not (4 vs 3 months). This is the first trial to show that longer-term maintenance with one of the drugs used in the initial treatment can improve outcomes, the report notes. Pemetrexed maintenance was recently approved in Europe and has been approved in the United States since 2009, after a previous trial showed benefit.
Combination of investigational oral therapies used in melanoma. A phase 1/2 trial showed that a combination of 2 oral targeted therapies — the MEK inhibitor GSK1120212 and the BRAF inhibitor GSK2118436 — appears to have substantial antitumor activity in advanced melanoma. The results suggested promising synergistic anticancer activity (2011 ASCO annual meeting,abstract CRA8503).
Pazopanib (Votrient) and brivanib show benefit in advanced sarcoma. Pazopanib is already marketed for advanced kidney cancer, but has also shown benefit in patients with metastatic soft-tissue sarcoma in the phase 3 PALETTE trial. Second-line pazopanib improved progression-free survival, compared with placebo (5 vs 2 months) (2011 ASCO annual meeting,abstract LBA10002). The investigational drug brivanib, which blocks both vascular endothelial growth factor and the fibroblast growth factor, significantly improved progression-free survival, compared with placebo, in a phase 2 discontinuation study (2011 ASCO annual meeting,abstract 10000).
Other Notable Advances
Other notable advances covered in the report are related to strides that have been made in advanced cancer care, in patient and survivor care, and in prevention and screening.

CHEMOTHERAPY ALONE FOR HODGKIN LYMPHOMA?

2011-12-20T06:41:00.001-08:00

New long-term data have shifted the debate over the best treatment for patients with limited-stage Hodgkin's disease in favor of chemotherapy alone, and have highlighted the risk for late complications from radiotherapy.
The new long-term data, from a 12-year follow-up of the Hodgkin's Disease 6 trial (HD6), were presented here at the American Society of Hematology (ASH) 53rd Annual Meeting and published simultaneously online December 11 in the New England Journal of Medicine.
Chemotherapy alone was associated with a higher overall survival when compared with radiation with or without chemotherapy (94% vs 87% of patients were still alive at 12 years; hazard ratio, 0.50; 95% confidence interval, 0.25 - 0.99; P = .04). The main reason was fewer deaths from causes other than Hodgkin's lymphoma, including secondary cancers and cardiovascular events, said lead investigator Ralph Meyer, MD, from Queen's University, Kingston, Ontario, Canada.
Commenting on the study for Medscape Medical News, ASH President J. Evan Sadler, MD, PhD, professor of medicine in the Division of Hematology at Washington University in St. Louis, Missouri, said: "I interpret this study as evidence that the long-term complications of radiotherapy are not necessarily worth the short-term efficacy".
In the shorter term, the results from radiotherapy in combination with chemotherapy do look better, he said. "Now, looking at the very long-term data, the morbidity and mortality associated with late complications from radiotherapy may well trump this short-term effectiveness," he added.
Long-term survival is the most important treatment outcome, and "this is the first trial that used late survival as the primary end point," noted David Strauss, MD from the lymphoma service at the Memorial Sloan-Kettering Cancer Center, New York City, in an editorial accompanying the New England Journal of Medicine article.
Patients treated with radiation developed more secondary cancers and cardiovascular events, he noted, adding that deaths from these causes increase dramatically after 10 years, and so it could be expected that the rate of survival in these patients may decrease even further in the future.
Long Wait for Results
The HD6 trialists have been very patient, waiting for 17 years for assessment of the primary end-point, and "the results have been well worth the wait," the editorialist comments.
When the study began in 1994, the standard of care for these patients with early-stage Hodgkin's lymphoma was radiotherapy, which in the trial was delivered as extended field subtotal nodal radiation (up to 35 Gy in 20 daily fractions). "This is no longer practiced today," Dr. Meyer commented at a press briefing, "and it would now be considered excessive."
How the results from this radiotherapy compare with modern radiotherapy approaches used now is one of the "core issues" with these data, and is discussed at length in both the published paper and the editorial, he noted.
The experimental group in the trial was chemotherapy alone, in which patients were given up to 4 or 6 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients assigned to radiotherapy who had an unfavorable risk profile (139/203 patients) also received chemotherapy, given as 2 cycles of ABVD.
At 12 years' follow-up, there were significantly fewer deaths in the group treated with chemotherapy alone compared with those treated with radiotherapy (12 vs 24).
The difference was primarily a result of death from causes other than Hodgkin's lymphoma, Dr. Meyers noted. There were 6 deaths from Hodgkin's lymphoma or an early-treatment complication of treatment in the chemotherapy-alone group, and 4 such deaths in the radiotherapy group, but there were only 6 deaths from other causes (4 from secondary cancers and 2 from cardiac events) in the chemotherapy-alone group compared with 20 such deaths in the radiotherapy groups (of which 10 were caused by secondary cancers and 2 by cardiac events).
When considering all patients, and not just those who died, secondary cancers were more common among those treated with radiotherapy (23 patients vs 10 receiving chemotherapy alone), as were cardiac events (26 vs 16).
Better Disease Control
Patients treated with radiotherapy showed a benefit over those treated with chemotherapy alone in one aspect: they had better disease control. The rate of freedom from disease progression was significantly lower (12-year estimates, 87% vs 92%; hazard ratio for disease progression, 1.91; 95% confidence interval, 0.99 - 3.69; P = .05) among patients who had received radiotherapy.
However, these results challenge the notion that "keeping the disease away will keep patients living for longer," commented Dr. Myers, and these 12-year data show that this is not the case. Hodgkin's lymphoma is a "highly curable disease," and the mean age of patients is around 35 years. Thus, these new data "emphasize the importance of frontline treatment that is provided," he commented.
"The results of our study suggest that in the long term, patients with limited-stage Hodgkin's lymphoma may be better served by a treatment approach that uses chemotherapy without radiation, as this method seems to be associated with fewer deaths from other causes," Dr. Meyer concluded.
Debate Continues, but Practice Will Shift
The debate over whether to use radiation as well as chemotherapy has raged fiercely for some years now, as previously reported by Medscape Medical News.
At present there is a split worldwide in how clinicians treat these patients, Dr. Meyers commented at the press briefing, with some using radiotherapy and others not. Although the old-fashioned radiotherapy used in this trial will fuel further debate over how these results apply to modern radiotherapy, and whether the long-term complications would be similar, Dr. Myers predicted that these new results will have an effect on clinical practice. He predicted that the proportion of physicians opting for each of the 2 approaches will change, and that clinicians more will now opt to use chemotherapy alone.
ASH Secretary Charles Abrams, MD, who was coordinator of the abstracts review and is associate chief of the Division of Hematology/Oncology at the University of Pennsylvania in Philadelphia, commented that this was a very well-designed study with very long-term follow-up. In answer to the question of whether this is a final answer, he said: "I doubt that there will be another trial like this."
The HD-6 trial was supported by a grant from the Canadian Cancer Society Research Institute. Dr. Myers reports receiving honoraria from Lilly and Cologne, and other coauthors also report relationships with industry, as detailed in the article.
American Society of Hematology (ASH) 53rd Annual Meeting: Abstract 590. Presented December 12, 2011.

TOP ONCOLOGY ADVANCES IN 2011

2011-12-10T09:01:00.000-08:00

Counting Down: Game Changers 10 Through 6

In 2011, great progress was made in the science and management of a variety of cancers. Our Medscape commentators selected and ranked the top 10 game changers in oncology for 2011. Here are their selections.

10. New Regimen Improves Outcomes in Neuroblastoma

A provocative European study^[1] showed improved outcomes in high-risk neuroblastoma using a high-dose myeloablative regimen. Until now, the best outcome in neuroblastoma has hovered around the 50% survival threshold, but the new regimen tested has pushed this up to 60%. European investigators say this regimen should be the new standard of care. "This is an incredible success and a great achievement for pediatric oncology," said Julie Park, MD, from Seattle Children's Hospital in Washington, who acted as discussant for the study.
The results are important for patients with this extremely difficult-to-treat disease," said principal investigator Ruth Ladenstein, MD, MBA, Associate Professor of Pediatrics at the University of Vienna, Austria.
Treatment for neuroblastoma comprises several steps. It begins with intense upfront chemotherapy to induce remission (induction) and is followed by surgery and radiation, myeloablative therapy with stem cell transplantation, and then consolidation therapy with 13-cis-retinoic acid and immunotherapy, if available.
The European trial used an induction regimen known as rapid COJEC, which consists of both cisplatin and carboplatin, and then compared a high-dose myeloablative regimen known as BuMel (busulphan plus melphalan) with carboplatin, etoposide, and melphalan (control group).
The BuMel group led to significantly improved survival at 3 years compared with the control group (60% vs 48%). "The superiority was based on a lower relapse rate," noted Dr. Ladenstein.
Read the complete Medscape News article on this trial, which was presented during the plenary sessions of the 2011 American Society for Clinical Oncology (ASCO®) annual meeting.

9. A Shooting Gallery of Targets in Lung Cancer

The treatment of non-small cell lung cancer (NSCLC) is undergoing a revolution driven by a greater understanding of the genetic factors fueling this disease. In personalized therapy, drugs are chosen according to the mutations found in the patient's tumor rather than chemotherapy chosen for the organ where the tumor is located.
Contributing to the growing knowledge of genetic targets is a landmark study by the Lung Cancer Mutation Consortium (LCMC),^[2] which involves 14 centers across the United States. The LCMC conducted a prospective study in which lung cancer tissue was assessed using a multiplex assay that identified 10 known driver mutations. In addition to EGFR and ALK, they are testing for KRAS,HER2, BRAF, PIK3CA, AKTI, MEKI, NRAS, and MET. Many of these mutations have targeted agents under development or, in the case of HER2, have targeted drugs already on the market (trastuzumab and lapatinib, which are used in breast cancer). The results so far show that 54% of the tested tumor samples have single-driver mutations. This information is now being used to select patients for first-line therapy with erlotinib or to place these patients into clinical trials with experimental targeted therapies specifically directed at their tumor mutation.
"Although an individual driver mutation may have a single-digit percentage incidence, when you look at all of the possible mutations that exist in lung cancer, you are likely to find a mutation," said Mark G. Kris, MD, lead author and Chief of Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York City, in a Medscape commentary. "Even in individuals who did not have a mutation that would suggest a certain clinical trial, we knew what treatments not to give those patients." This study, Dr. Kris added, "brings us one step closer to our goal of personalized medicine."
View the complete commentary by Mark G. Kris, MD, and read the original Medscape News storyon this trial, which was reported at the 2011 ASCO® annual meeting.

8. Strongest Data Ever for ER-Positive Breast Cancer

The combination of everolimus plus exemestane produced "the strongest data ever seen in estrogen receptor [ER]-positive breast cancer," principal investigator José Baselga, MD, from the Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News. The pivotal phase 3 study, known as BOLERO-2,^[3]was stopped early because of the benefit observed. Results were unveiled at the 2011 European Multidisciplinary Cancer Congress (EMCC).
"Everolimus is the most important advance in breast cancer since trastuzumab," said Fabrice André, MD, PhD, from the Institut Gustave Roussy, Paris, France, who acted as discussant. "The data are robust and are clinically relevant," he said, adding that "the efficacy is in the range of the most important recent advances in the field of medical oncology."
Everolimus is an mTOR inhibitor that has already been approved in the United States for the treatment of progressive neuroendocrine tumors of pancreatic origin and advanced renal cell carcinoma in certain patients. Exemestane is an aromatase inhibitor that is already widely used as adjuvant therapy for ER-positive breast cancer. Both drugs are taken orally.
Read the complete Medscape News story on this trial.

7. Extended Adjuvant Treatment Improves Survival in GIST

Extended adjuvant treatment with imatinib improves survival in patients with high-risk gastrointestinal stromal tumors (GIST). Imatinib administered for 3 years improved both relapse-free survival and overall survival in patients after surgery, compared with 1 year of adjuvant treatment.^[4]
Previous data showed that initiating adjuvant imatinib therapy reduces the risk for GIST recurrence compared with placebo. "But the effect of imatinib on overall survival is not known," said lead author Heikki Joensuu, MD, Professor of Oncology at Helsinki University Central Hospital in Finland, who presented the findings during the plenary session here at the ASCO® 2011 annual meeting.
The 5-year relapse-free survival in patients was higher in those who received 3 years of treatment than in those who received 1 year (65.6% vs 47.9%; hazard ratio [HR], 0.46; P < .0001). The 5-year overall survival was also better in patients who received 3 years of therapy (92.0% vs 81.7%; HR. 0.45; P = .019).
Kathy Miller, MD, Chair of the scientific program for the 2011 ASCO® annual meeting, said in a Medscape commentary, "There had been a lot of debate in the GIST community that perhaps the drug was so effective in people with metastatic disease that you didn't really need to give adjuvant therapy for a longer time or maybe you didn't need to give it at all. You could just catch up and treat these folks when they recurred, and that was definitely not true. A longer duration of therapy, 3 years instead of 1, improved survival."
"We are looking at 92% in the 3-year group, and that is very high," said Dr. Joensuu. "We are making substantial improvement here."
View the complete commentary by Kathy D. Miller, MD, and read the original Medscape News story on this trial.

6. New Hope for Patients With Refractory Lymphoma

The experimental agent brentuximab vedotin, which has shown strong responses in patients with resistant and refractory Hodgkin lymphoma, was the first drug approved for lymphoma in 30 years. The results were reported at the 52nd annual meeting of the American Society of Hematology by Robert Chen, MD, Assistant Professor at the City of Hope National Medical Center in Duarte, California.^[5] The data come from a single-group multicenter study of 102 patients, all of whom had failed autologous stem cell transplantation and a median of 4 chemotherapy regimens (range, 1-13). The median age of patients was 31 years (range, 15-77 years).
Brentuximab 1.8 mg/kg was administered as a 30-minute outpatient intravenous infusion once every 3 weeks for up to 16 cycles of therapy (median, 9 cycles).
Responses were "dramatic," Dr. Chen said. The objective response rate was 75%, and tumor reduction was demonstrated in 94 patients (96%). Around one third of patients (34%) achieved complete remission.
In August, the US Food and Drug Administration (FDA) granted accelerated approval of brentuximab vedotin infusion for the treatment of relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, as reported at the time by Medscape.
"Why are we so excited about this?" asked Bruce D. Cheson, MD, Professor of Medicine, Georgetown University, Washington, DC, in a Medscape commentary. "Not only is this a great drug, it is also a proof of concept. We now have demonstrated that you can take an antibody and link it strongly to a poison. It will get in the cells and kill them, without doing much damage to the rest of the body. This will be one of many to follow in its footsteps."

5. Improved Survival in Metastatic Pancreatic Cancer

A chemotherapy combination provided the best survival time ever reported in metastatic pancreatic cancer, according to a study from French researchers, but the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) was considerably more toxic than gemcitabine. Data from the study, which were first presented at the 2010 annual meeting of ASCO® and reported by Medscape Medical News at that time, were published in May in The New England Journal of Medicine.^[6]Although the data are largely the same, the published paper includes new information on quality-of-life measures, said lead author Thierry Conroy, MD, from the Centre Alexis Vautrin, Vandoeurve les Nancy, France.
Gemcitabine, used alone or in combination with other agents, has been the "reference regimen" for advanced pancreatic cancer treatment for an extended period of time, according to Dr. Conroy and colleagues from 48 centers in France. However, the study authors propose that FOLFIRINOX is now a first-line option for patients with metastatic pancreatic cancer "who are younger than 76 years, and who have a good performance status (Eastern Cooperative Oncology Group score [ECOG] 0 or 1), no cardiac ischemia, and normal or nearly normal bilirubin levels."
"This is the first study to show substantial improvements in survival in advanced pancreatic cancer," said Alok A. Khorana, MD, Associate Professor and Vice-Chief of Hematology-Oncology at the University of Rochester, Rochester, New York, in a Medscape viewpoint. "It is unfortunate, however, that this gain occurs with an aggressive multichemotherapy regimen rather than with the addition of targeted therapy as many had hoped for. Although the efficacy of the regimen is clear and substantial, concerns about toxicity and tolerability are ongoing."

4. New Standard of Care for High-Risk ALL

A regimen of high-dose methotrexate was found to be superior to the standard protocol of escalating methotrexate in children and young adults with high-risk B-precursor acute lymphoblastic leukemia. The results of a phase 3 trial,^[7]which were presented at the 2011 ASCO® annual meeting, established a new standard of treatment for this population.
In a planned interim analysis, 5-year event-free survival for patients who received the high-dose regimen was 82% compared with 75% for those receiving the escalation protocol.
"We feel that it is the standard of care to receive high-dose methotrexate in this population," said lead author Eric C. Larsen, MD, Director of the Maine Children's Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children's Hospital at Maine Medical Center in Portland, adding that "high-dose methotrexate will be incorporated in current and future Children's Oncology Group trials for children and young adults."

3. Increased Survival in Metastatic HER2-Positive Breast Cancer

The first randomized trial to compare the novel agent trastuzumab emtansine (T-DM1) with standard therapy shows that it significantly increased progression-free survival in women with metastatic breast cancer.^[8] The study was presented at the 2011 EMCC in Stockholm, Sweden.
"First-line treatment with T-DM1 was associated with a statistically significant improvement in progression-free survival and was also associated with a reduction in the risk for toxicity," said lead author Sara Hurvitz, MD, Director of the Breast Oncology Program, Division of Hematology/Oncology, University of California, Los Angeles.
Median progression-free survival was 14.2 months for women who received T-DM1 and 9.2 months for those who received standard therapy with trastuzumab plus docetaxel. The hazard ratio was 0.59, indicating that treatment with T-DM1 reduced the probability of disease progression or death by 41% compared with standard therapy, noted Dr. Hurvitz.
"These results validate the hypothesis that the unique targeted delivery of chemotherapy through T-DM1 may lead to an improved therapeutic index," she said.
Fabrice André, MD, PhD, Associate Professor at the Institut Gustave Roussy, Villejuif, France, as reported in a Medscape commentary, finds T-DM1 interesting for 3 distinct reasons. "The first is conceptual -- This is the first time that an immunoconjugate (a combination of a monoclonal antibody and a cytotoxic agent) has shown efficacy in cancer. It's a new concept, and we have the proof of concept. The second reason is the finding that immunoconjugate is safer compared with conventional chemotherapy. We had the presentation today, during which we heard that the frequency of grade 3 adverse events was lower in patients treated with T-DM1. The third reason it is so important is that these drugs can be delivered for a long time. Because of this prolongation of the treatment, we had a better progression-free survival, specifically in HER2-positive breast cancer."
Because T-DM1 is not toxic, it can be administered for a long period of time, which leads to long-term progression-free survival.
"We are entering in a new era with this trial," said Dr. André. "At the very beginning, to obtain a response the drug is not better. Once we have a response and once the drug is working, we can administer the drug for a longer time period and know that the patient is not going to present with progressive disease, but at the opposite end -- in patients treated with trastuzumab and docetaxel -- we have to stop both the chemotherapy agents. Then the patient is going to have a progressive disease. In terms of induction of the response, there is not any major difference between T-DM1 and a combination of trastuzumab and docetaxel, but then duration of the response is very long. We are going through a scenario where we have induction with T-DM1, and once the patient has a response, then the response can be long lasting."

2. Lung Cancer Screening Comes of Age

The landmark National Lung Screening Trial,^[9] which enrolled 53,000 persons,showed that screening with low-dose spiral CT reduced mortality from lung cancer by 20%. CT screening was compared with chest radiographs, which have not shown any mortality reduction in previous trials.
The study was accompanied by expressions of enthusiasm from the American oncology community. "It's gratifying. We've been looking for this kind of good news in lung cancer for a long time," Otis Brawley, MD, Chief Medical Officer at the American Cancer Society, told Medscape Medical News. "It's simply an amazing result with an immediate impact on this disease," Mark G. Kris, MD, Chief of Thoracic Oncology at Memorial Sloan-Kettering Cancer Center, reported in a Medscape commentary.
"Finally we have a screening test that meets that gold standard and has a substantial opportunity to decrease the death rate for lung cancer," said Dr. Kris. "In the group that was screened, all patients had smoked 30 pack-years, which is the equivalent of 1 pack per day for 30 years, 2 packs per day for 15 years, and so on. Based on these data, it makes sense to recommend screening with a low-dose helical CT for any person who has smoked 30 pack-years."
In November, the National Comprehensive Cancer Network in an updated set of guidelines came out in favor of lung cancer screening, recommending the use of low-dose CT screening for select patients at high risk for disease.

1. The Top Game Changer for 2011 in Oncology

Unprecedented Advances in Melanoma

In 2011, 2 studies and 2 drug approvals revolutionized therapy for patients with metastatic melanoma. Vemurafenib and ipilimumab quickly became household names after studies on their efficacies in metastatic melanoma were highlighted in the plenary session of the 2011 ASCO® annual meeting.
In a phase 3 study^[10] that was accompanied by much praise and grand declarations, the targeted therapy vemurafenib was shown to dramatically improve progression-free and overall survival, compared with standard chemotherapy, in patients with advanced melanoma with no previous treatment.
Vemurafenib targets the V600E mutations in the BRAF gene, and an estimated 40%-60% of melanoma patients have this type of BRAF mutation.
The progression-free survival data constitute "an unprecedented level of difference," said lead author Paul Chapman, MD, from Memorial Sloan-Kettering Cancer Center.
This study is "practice changing," said Lynn Schuchter, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. Responses with the new oral therapy can be dramatic -- patients can have improvement within 72 hours of treatment, she said.
In August, vemurafenib was approved by the FDA for the first-line treatment of both metastatic and unresectable melanomas, as reported at the time by Medscape News. The drug is specifically indicated for patients with melanoma whose tumors have V600E mutations in the BRAF gene.
A phase 3, international, multicenter study showed ipilimumab, a human monoclonal antibody, to be effective as first-line therapy in melanoma,^[11] increasing the number of patients who can benefit from the drug, which has just been approved for use as second-line therapy.
The data on first-line use were presented at the 2011 ASCO® annual meeting and published online in The New England Journal of Medicine to coincide with the presentation.
Ipilimumab in combination with dacarbazine improved overall survival in patients with previously untreated metastatic melanoma, compared with dacarbazine plus placebo, said senior author Jedd Wolchok, MD, from Memorial Sloan-Kettering Cancer Center. The drug was approved in March by the FDA as second-line therapy for patients with advanced melanoma, based on a study of previously treated patients. At the time of its approval, ipilimumab was the first agent ever proven to improve survival in advanced melanoma, as reported at the time by Medscape.
Overall survival in the study was significantly longer in the ipilimumab group than in the placebo group (11.2 vs 9.1 months; hazard ratio [HR] for death, 0.72; P < .001), Dr. Wolchok and his coauthors reported. The ipilimumab group had higher survival rates than the placebo group at 1 year (47.3% vs 36.3%), 2 years (28.5% vs 17.9%), and 3 years (20.8% vs 12.2%). The 3-year results are "very mature," commented Dr. Wolchok.
"Today we are in the very fortunate position of having 2 medicines approved for metastatic melanoma, the first time in 13 years that any medicine has been approved by the FDA for melanoma," said Dr. Wolchok. "Importantly, both of these medicines were approved on the basis of the gold standard endpoint -- namely, improvement of overall survival. We believe these newly approved treatments are a source of great hope to patients, their families, and their physicians."

FOOD WITH ORAL CANCER DRUGS?

2011-11-21T10:13:00.000-08:00

Are oral oncology drugs being mislabeled? Maybe.
Most oral cancer drugs stipulate that they should be taken in a fasting state, but some actually have better bioavailability when taken with food. This is particularly true for the new prostate cancer drug abiraterone acetate (Zytiga), which has a greater interaction with food than any other marketed drug, yet it is labeled to be taken when fasting.
These points are highlighted in a comment published in the October 20 issue of the Journal of Clinical Oncology by Mark J. Ratain, MD, professor of medicine and director of the Center for Personalized Therapeutics at the University of Chicago, Illinois.
"My major concern is safety," Dr. Ratain told Medscape Medical News. "Very few patients would anticipate that the consequences of taking their medications with food...would be an effective overdose."
In the case of abiraterone acetate, the dose of the drug could be increased 10-fold by eating breakfast half an hour after taking the drug, he writes.
Dr. Ratain notes that food interactions are described in the labeling of many drugs, but are notably absent in the labeling of new oral cancer agents.
Most drugs can be taken either with or without food, he explains, because the effects of food are not clinically significant to drug absorption. There are cases in which absorption is decreased by food; generally, the labeling on those drugs instructs that they be taken on an empty stomach. Similarly, labeling on drugs for which absorption is enhanced by food typically instructs that they be ingested with meals.
"However, a recent study of oral agents approved by the US Food and Drug Administration [FDA] in the last 10 years demonstrated that oral oncology drugs have generally been labeled fasting, despite food effects as large as a 4-fold increase in bioavailability," Dr. Ratain notes.
Bias in Labeling?
This apparent bias for fasting labeling in cancer drugs is exemplified with abiraterone, he notes. Abiraterone, which was approved earlier this year in the United States for the treatment of metastatic prostate cancer, has a greater food interaction than any drug currently on the market. Depending on the fat content, food can increase drug exposure 5- to 10-fold, yet it is labeled to be taken in a fasting state, Dr. Ratain points out.
The effect of a high-fat meal indicates "that absolute bioavailability in the fasting state is no more than 10%," says Dr. Ratain, and is likely due to the low absorption rate under fasting conditions; 77% of the drug is excreted as abiraterone (or its prodrug acetate) in the stool.
"In addition, there is marked interindividual pharmacokinetic variability, with a coefficient of variation in the plasma concentration area under the curve of 59% under labeled conditions," he notes.
It is unclear why this faulty labeling is occurring, or why the FDA has not been more stringent about proper labeling for oral oncology drugs, Dr. Ratain said. He told Medscape Medical Newsthat the FDA has not responded to his inquiries and "essentially stonewalled" him because of the confidentiality of their discussions with sponsors.
"The blame could be assigned to sponsors, the Office of Oncology Drug Products, and/or the Office of Clinical Pharmacology and Biopharmaceutics," he said. "Given that there are multiple sponsors, all of whom who have a different approach to oncology..., the evidence points to an FDA origin."
Oral Drugs Relatively New
Alex Adjei, MD, PhD, who was approached by Medscape Medical News for independent comment, explained that until recently, oncology drugs have generally been given intravenously; for other diseases, oral drugs have been in common use for many years.
Perhaps that is why there has not been that much attention on the food-effect data, Dr. Adjei hypothesized. He is chair of the Department of Medicine at Roswell Park Cancer Institute, in Buffalo, New York.
"In clinical trials, we tend to give the drugs on an empty stomach," he said. "So that was how the drug was tested and that was how it was approved. We don't go back and change the label."
Dr. Adjei pointed out that unlike intravenous drugs, there is considerable variation in the way oral drugs are absorbed. "We try to simplify it by giving them on an empty stomach," he said.
Food-Effect Data Ignored
In a study published last year (Clin Cancer Res. 2010;16:4446-4451), Dr. Ratain and his colleague, Soonmo Peter Kang, MD, also from the University of Chicago, evaluated the effect of food on 99 oral agents that received FDA approval from January 2000 to May 2009. They compared food-labeling patterns between oncology and nononcology drugs using Fisher's exact test.
Food had a significant effect on drug bioavailability in 34 of the 99 drugs evaluated. In cases where food markedly enhanced bioavailability, 8 of 9 nononcology drugs were labeled to be taken with food to take advantage of the food–drug interaction. However, all oncology agents were labeled to be taken in "fasted" states (P = .01).
"The food-labeling pattern of recently approved oral oncology drug products is inconsistent with fundamental principles of oral drug delivery," they write. "The labels of 3 agents (erlotinib, nilotinib, and lapatinib) minimized bioavailability through food restrictions, which is in contrast to the labeling principles used for all other classes of oral agents."
In an editorial that accompanied the study by Drs. Ratain and Kang (Clin Cancer Res. 2010;16:4305-4307), Rajul K. Jain, MD, from the University of Texas M.D. Anderson Cancer Center, Houston, and colleagues explained that the effects of food are complex, and that multiple factors determine final labeling recommendations. "When analyzing the label given to any product or product class, all of the potential influencing factors should be considered," they said.
They also noted that "sponsors are encouraged to conduct food-effect studies early in a product's development so the results can be implemented into larger clinical trials."
In his comment, Dr. Ratain refers back to that editorial, and points out that the agency has "expressed concern about the potential for high intraindividual variability in cancer patients resulting from variability in oral intake secondary to disease or concurrent medications." This appears to indicate a preference for labeling drugs to be used when fasting, even if their bioavailability would be substantially increased when taken with food.
He explains that there isn't any evidence that this concern applies to all oral oncology drugs, and that there is no evidence that intraindividual variability in diet is greater for cancer patients than for those with other life-threatening conditions who also take daily oral drugs.
"If the US Food and Drug Administration were truly concerned about intraindividual variability in diet, why has this never come up in the labeling of nononcology drugs?" he asks.
He notes that the FDA was aware of the food-effect data from early studies of abiraterone and could have required at least 1 randomized study to be conducted to review this, so that it could have been labeled to be taken with food. The FDA has the authority to require such studies as a postmarketing requirement, but chose not to.
With the risk for poor adherence to food-effect labeling, there is a risk for overdose or underdose of a given drug, with the more serious being overdose, Dr. Ratain says.
In addition to this safety issue, there are economic implications, Dr. Ratain notes.
The standard dose of abiraterone for men without liver problems is 1000 mg once daily. But because the bioavailability of the drug is greatly increased when taken with food, it would be interesting to have studies of abiraterone at a dose of 250 mg once daily, administered with a standard breakfast. If this approach is shown to be safe and effective, it could save patients and their payers approximately $3750 per month at current prices.
"It also would send a message to the pharmaceutical industry that flawed drug development has financial consequences," he notes, "along with potential risks of product liability because of defective labeling."
He concludes: "After all, given the high attrition rate for oncology drugs, do we really need to flush our few successful products down the toilet?"
Impracticalities of Dosing and Diet
Lawrence J. Lesko, PhD, FCP, former director of the Office of Clinical Pharmacology at the FDA's Center for Drug Evaluation and Research, and a coauthor of the editorial by Dr. Jain, pointed out that the principal of labeling is consistent safety.
"The most consistent way to take drugs is on an empty stomach," said Dr. Lesko, who is now at the Department of Pharmaceutics at the College of Pharmacy at the University of Florida in Gainesville. "It would be impractical to expect that patients are going to adhere to a specific diet when taking these drugs. And it is often unclear what 'food' may mean to the patient. Is it a glass of juice, breakfast cereal, a cheeseburger?"
The goal is to minimize the variability, he told Medscape Medical News. "Food studies are generally conducted in healthy volunteers and not cancer patients. Labeling can't be done on a theoretical basis; it has to reflect what was done in the study."
Dr. Lesko noted that another problem with tying an oral drug dose to food is that many cancer patients have problems with appetite, nausea and vomiting, and gastrointestinal motility. "Their appetite can change on any given day," he said. "Some days, they may not be able to tolerate a high-fat meal, for example, which raises the bioavailability of abiraterone. It would just be impractical to do this on a day-to-day basis."
The other issue that Dr. Ratain focuses on in his comment is the comparison of oncology and nononcology drugs, Dr. Lesko pointed out. "But you really can't compare them."
For most nononcologic agents, food doesn't matter, so it isn't that important how the product is labeled, he said.
But that is not the case with oral oncologic agents. "Every drug in oncology has a narrow therapeutic index, and taking the drug with food could affect the therapeutic range," he said. "The labels are intended to minimize variability and mimic approval data."

CANCER DEATHS OVERTAKE HEART DISEASE IN CANADA

2011-11-12T01:08:00.000-08:00

For the first time, cancer has overtaken heart disease as the number-one cause of death across Canada, according to the latest statistics here [1].
According to numbers released yesterday, cancer accounted for 29.6% of deaths (70 558) in 2008--the latest year for which stats have been made available by heath authorities. Heart disease caused 21.3% of deaths (50 722).
Stroke, in third place, caused 5.8% (13 870) of deaths.
Statistics from the previous year had cancer leading heart disease in every province and territory with the exception of Prince Edward Island and the Northwest Territories. In the 2008 statistics, heart disease has now moved into second place in every province/territory, with the exception of Nunavut, where suicide ranks second.
Between 2007 and 2008, cancer deaths climbed 1.4% nationally, continuing a trend seen since 2000. By contrast, heart-disease deaths declined between 2000 and 2006 but actually crept upward between 2007 and 2008.
Preliminary US numbers published by the US Centers for Disease Control and Prevention show that heart disease was still the leading cause of death for both 2008 and 2009, followed by malignant neoplasms, with both diseases declining in this period, although that decline was three times greater for heart disease [2].
In the UK, which has published 2010 causes of death for England and Wales, it is more difficult to draw comparisons, due to how diseases are grouped by statisticians there [3]. "Circulatory diseases" (which include heart disease and stroke, as well as venous and arterial diseases) were the leading cause of death and had declined since 2009. By contrast, deaths due to cancers and neoplasms, in the number-two position, had climbed slightly over the past year.
Commenting on the newly released Canadian statistics for heartwire , Dr Paul Armstrong(University of Calgary, AB) observed that there is both good news and bad in the numbers.
"I guess it's good news that we're making some progress in cardiovascular disease. And obviously if the burden of cardiovascular disease is relieved such that you are living longer, it's more likely that you're going to die of something else," he said.
But before anyone celebrates these numbers, Armstrong points out that despite progress in controlling risk factors such as hypertension and elevated cholesterol, Canada and other countries have not done so well in curbing the upward march of obesity and diabetes. Diabetes, he points out, is the number-six cause of death in Canada, and the number of diabetes deaths has climbed since 2000.
"I worry we could still see a second wave of [increased] heart-disease deaths as a result of the increasing prevalence of diabetes and obesity, although it's too soon to know," Armstrong said.
In response to a poll question on theheart.org this summer, 52% of respondents said they expected cancer to surpass heart disease as the world's number-one killer within the next 10 years.

NEW GUIDELINES FOR REIRRADIATION OF HEAD AND NECK CANCER

2011-10-27T10:20:00.001-07:00

When head and neck cancer recurs and surgery is not an option, reirradiation provides the only potentially curative option. However, because the tumor often recurs in the same place or very close to tissue that has already been irradiated, this treatment approach represents a "significant challenge."
For this reason, it should be handled at a tertiary-care center, according to a new guideline issued by the American College of Radiology. Specifically, it stipulates that the tertiary center should have a head and neck oncology team that is equipped with the resources and the experience to manage the complexities and toxicities of retreatment.
In the guideline, published in the International Journal of Radiation Oncology, Biology and Physics, a panel of experts outline appropriateness criteria for various clinical scenarios that arise with such patients.
"This is an important document because it is the first set of guidelines for the potentially curative treatment of patients who have regrowth of head and neck tumors. It provides a consensus on how patients should be managed," coauthor Madhur Kumar Garg, MD, said in a statement. Dr. Garg is from the Department of Radiation Oncology at Montefiore Medical Center, in the Bronx, New York, where about a dozen reirradiation procedures are performed annually.
Commitment to Retreatment
Retreatment is justified because clinical trial results have shown that local treatment improves overall survival, the panel of experts notes.
However, they emphasize that, before a commitment to retreatment is made, patients presenting with recurrent or second primary tumors need to undergo careful restaging evaluation. In addition to computed tomography (CT) or magnetic resonance imaging to evaluate the extent of the recurrent tumor, the panel urges that strong consideration be given to positron emission tomography with CT to evaluate for metastatic disease, or "at a minimum, a CT scan of the chest should be performed."
In addition, a detailed history and assessment is needed, which includes documentation of the sequelae of previous treatment, such as fibrosis, carotid stenosis, dysphagia, xerostomia, and osteoradionecrosis.
Retreatment options include surgical resection and palliative chemotherapy — both are regarded as standard of care, the panel writes. But for patients with unresectable disease, reirradiation is the "only potentially curative treatment," they add.
Two phase 2 clinical trials conducted by the Radiation Therapy Oncology Group (RTOG) have shown survival outcomes with reirradiation plus chemotherapy that appear to be superior to those seen with chemotherapy alone in other studies. However, "whether this apparent improvement is the result of selection bias is uncertain," the panel explains. A larger phase 3 comparing reirradiation plus chemotherapy with chemotherapy alone was closed because of poor accrual.
In terms of the dose of radiation delivered in the second treatment course, it appears that at least 50 to 60 Gy is needed, the experts report. Both of the phase 2 studies conducted by the RTOG delivered a total dose of 60 Gy, using an accelerated hyperfractionated regimen delivering 1.4 Gy twice daily in 4 week-on/week-off cycles. Multiple single-institution reports of reirradiation have used once-daily standard fractionation in a planned continuous treatment course with less toxicity, they note. However, differences in study designs and in the chemotherapy regimens make it difficult to discern what independent effect, if any, differences in radiation fractionation had on the toxicity that was seen.

CHEMOTHERAPY CAN BE USED SAFELY AFTER FIRST TRIMESTER OF PREGNANCY

2011-10-04T10:20:00.000-07:00

A cancer diagnosis can be devastating, but is even more traumatic when the patient is pregnant. A new study offers some reassurance to pregnant patients and their physicians.
The results of the small study, presented during a presidential session here at the 2011 European Multidisciplinary Cancer Congress, show that children who were exposed to chemotherapy in utero did not appear to suffer any detrimental effects in terms of general health and neurologic and cardiac functioning.
Treating cancer in pregnant women is complex. One issue, in particular, is the ethics of treating a woman with chemotherapy, "but there are no good data that describe the ethics," said lead author Frederic Amant, MD, PhD, assistant professor, gynecologic oncologist, and head of the scientific section of gynecologic oncology at Katholieke Universiteit in Leuven, Belgium.
In Europe, there are approximately 2500 to 5000 cases of cancer diagnosed during pregnancy every year; however, it remains unclear how systemic chemotherapy affects the development of the fetus, he said.
This is a common situation, and one that many doctors face, said Michael Baumann, MD, PhD, a radiation oncologist from the University of Technology, Dresden, Germany, and president of the European CanCer Organisation. "That is why this study is so important," he said.
There are a lot of data related to radiotherapy and its use in pregnancy, said Dr. Baumann, who moderated a press briefing during which the highlights of this study were presented. " That there are now good data on chemotherapy.... This is a paradigm shift that we see here."
Neuro and Cardiac Function Normal
In their study, Dr. Amant and colleagues looked at the potential negative effects of in utero exposure to chemotherapy. Participants ranged in age from 18 months to 18 years. Of the 140 children currently in the study, complete data are available for 70.
The children were all evaluated at birth and approximately every 2 years after. Their general health was assessed, and they underwent neuropsychologic testing to assess intelligence, verbal and nonverbal memory, attention, working memory, and behavior.
The mean gestational age at cancer diagnosis was 18.1 weeks, and a total of 236 cycles of chemotherapy were given in the cohort.
About half of the women were diagnosed with breast cancer (51%), and 26% were diagnosed with hematologic cancers. Other diagnoses included cervical cancer, ovarian cancer, and malignancies of the brain, skin, and colorectum. Half of the patients (50%) received chemotherapy, and 38% underwent surgery and received chemotherapy. Treatment was given at a median gestational age of 17 weeks (range, 12 to 37 weeks).
The median gestational age of the children at birth was 35.7 weeks, and intrauterine growth retardation was observed in almost 21% of the children.
Cardiac function was evaluated by electrocardiography and echocardiography. It was necessary to assess for possible cardiac problems because the majority of these women were given anthracyclines, explained Dr. Amant. In breast and gynecologic cancers, "anthracyclines are very important. The majority of children — almost 80% — were exposed to anthracyclines, which can pass through the placenta, so it is very important to assess heart function."
The median follow-up was almost 2 years, although some were followed for up to 18 years.
At birth, no congenital heart defects were observed, and cardiac function was normal. Most of the children had adequate neurologic function and normal cardiac function, explained Dr. Amant; rates were similar to those seen in the general population.
High Rate of Premature Birth
Premature birth was very common in this population, with 47 of the 70 children born before 40 weeks of gestation (66%), and 7 born at 26 to 32 weeks.
Although cognitive development was in the normal range for the majority of the cohort, children who fell below the normal parameters tended to be premature. Because developmental delay is common in children who are premature, Dr. Amant explained, they are unable to tell if these issues are related to chemotherapy exposure.
"We can't exclude the effects of chemotherapy in preterm children," he told Medscape Medical News. "They do worse, we know that, but whether it's the prematurity or the chemotherapy — that is an unanswered question."
Because the majority of the children have done well, Dr. Amant surmised that the cognitive issues in those born premature are not related to the chemotherapy.
Normal findings were observed in 64 children (91.4%), which conforms to the general population.
Developmental Issues in Twins
Two serious problems emerged with a set of twins who were born at 32.5 weeks of gestation. The mother had been treated for leukemia. The male twin was autistic and had other serious neurodevelopmental delays and problems; the female twin also had some degree of neurodevelopmental delay.
Although prenatal exposure to chemotherapeutic agents cannot be completely ruled out, Dr. Amant feels that it was probably not the cause of the severe problems observed in the male twin. Geneticists who studied the data tend to think that the child had some sort of syndrome, he pointed out, which was not related to the chemotherapy. "But we can't rule it out right now," he said.
The high rate of prematurity seen in this study was not caused by chemotherapy, but was most likely related to the strategy of delivering the baby as soon as it becomes viable and then beginning chemotherapy, explained Dr. Amant.
Chemotherapy Should Not Be Feared
"Our message is that we prefer to give chemotherapy until the baby is mature; after the baby is delivered, we continue maternal treatment," said Dr. Amant. "The baby loses 2.5 IQ points for each week that he or she is delivered early."
"We think that the baby has less trauma from chemotherapy than from prematurity," he explained. "In our setting, this changes how we treat patients."
This is not a perfect study, Dr. Amant acknowledged; it was both retrospective and prospective, and had a relatively short follow-up.
"But we think that the fear of chemotherapy should no longer be an indication to terminate a pregnancy, and it should no longer be a reason to delay maternal treatment, which can affect maternal prognosis," Dr. Amant explained.
More Data Needed
"We are quite confident that these children will continue to perform normally, but we need more follow-up and more children," he said. "Right now, the group is too small to make a statement on clinical practice change."
George Pentheroudakis, MD, PhD, who acted as discussant for the paper, agrees that a longer follow-up is needed.
Although the study showed that chemotherapy can be administered with reasonable safety after the first trimester of pregnancy, there are still a number of unanswered questions, noted Dr. Pentheroudakis, who is from the University of Ioannina, Greece.
There are a few children in the study with severe neurocognitive deficits, he pointed out, noting that more careful interpretation of the results is needed. In addition, the "course of these deficits over time" need to be determined.
Undetected cardiac toxicity is a potential problem for these children. Although the electrocardiogram and echocardiogram are good tools, they might not be sensitive enough for the early detection of subclinical cardiac damage, he said.
Also, there was a high incidence of prematurity in the cohort. "What are the causes of prematurity," he wondered. "Is it maternal age, the presence of cancer,...or the cancer treatment that was administered?
Much is still unknown about the long-term effects of chemotherapy exposure, said Dr. Pentheroudakis. "We don't know about fertility or germ cell mutagenesis in the children and their future offspring. More data are needed."
For now, on the basis of these data, the fear of chemotherapy is not a reason to delay treatment that can affect maternal prognosis, he said. "It seems that chemotherapy can be administered with reasonable safety after the first trimester, and there is emerging evidence that the mid- and long-term health of these children is normal."

TWICE DAILY ASPIRIN MAY BE BETTER FOR DIABETICS

2011-09-24T01:03:00.000-07:00

Twice-daily aspirin administration, but not a once-daily doubling of the dose, appears to provide good inhibition of platelet cyclooxygenase (COX)-1 in diabetic patients who have rapid recovery of COX-1 activity and might enhance cardiovascular protection, Francesco Zaccardi, MD, a diabetology fellow at Catholic University of Sacred Heart in Rome, Italy, reported here at the European Association for the Study of Diabetes (EASD) 47th Annual Meeting.
Aspirin is currently recommended for cardiovascular protection for patients with type 2 diabetes mellitus, regardless of prior vascular events. But primary prevention trials have failed to demonstrate its efficacy in this population, possibly because of incomplete platelet inhibition. Italian researchers, led by Dr. Zaccardi, investigated glycemic control and other factors as possible reasons for the incomplete inhibition of thromboxane A₂ by low-dose aspirin over 24 hours. Thromboxane A₂, a product of COX-1 activity, is prothrombotic.
The investigators recruited 100 patients with type 2 diabetes who were taking 100 mg of aspirin daily. They measured thromboxane B₂, the hydrolysis product of thromboxane A₂ and a marker of platelet COX-1 activity, every 3 hours, between 12 and 24 hours after an observed aspirin administration, to assess the kinetics of recovery of COX-1 activity. In addition, a subset of 46 patients underwent 24-hour continuous glucose monitoring. Of them, the 33 patients with the steepest slopes of recovery of COX-1 activity were randomly assigned to receive aspirin 100 mg daily (n = 11), 200 mg daily (n = 11), or 100 mg twice daily for 28 days (n = 11). Recovery of COX-1 activity was determined on day 29 during the 12- to 24-hour dosing period.
The researchers found that COX-1 activity showed linear kinetics with large variability among individuals in the slope of recovery of enzyme activity. For the patients in the lowest tertile of recovery of activity, serum thromboxane B₂ increased in the 12- to 24-hour period by 0.02 ng/mL per hour (range, 0.01 to 0.03 ng/mL per hour), compared with an increase of 0.14 ng/mL per hour (range, 0.11 to 0.20 ng/mL per hour) for the tertile with the fastest recovery.
Independent predictors of the slope of thromboxane B₂ recovery were mean platelet volume (MPV) (P < .0001), higher body mass index (BMI) (P = .007), and age (P = .049). None of the parameters studied in continuous glucose monitoring (e.g., mean 24-hour glycemic value, mean amplitude of glycemic excursions), nor glycated hemoglobin or fasting glucose level, predicted the slope of recovery of thromboxane B₂.
In the cohort with the steepest slopes of return of COX-1 activity, the subjects taking 100 mg of aspirin twice daily showed complete normalization of the slope of platelet COX-1 activity; the administration of 200 mg daily did not have such an effect. Compared with 100 mg once daily, the once-daily administration of 200 mg of aspirin reduced the slope of the recovery line by 55%, and 100 mg of aspirin twice daily reduced the slope by 88% (P < .05 for each vs 100 mg once daily).
Considering the predictive effect of MPV, Dr. Zaccardi surmised that the interindividual variability in the return of COX-1 activity probably reflects abnormal megakaryopoiesis associated with type 2 diabetes. Furthermore, BMI might affect the pharmacokinetics after aspirin dosing. He concluded that twice-daily aspirin administration can overcome the inadequate thromboxane B₂ inhibition seen with once-daily dosing. He advised performing larger, randomized clinical trials to test the safety and effectiveness of this approach.
Since it is not feasible to measure COX-1 activity or thromboxane B₂ in routine clinical practice, Dr. Zaccardi told Medscape Medical News that in the future, we will likely "have to focus more attention on BMI, on age, and on MPV, because it's very easy to measure BMI and to obtain the value of MPV from a single blood analysis."
In summary, he said that an important finding of the study is that "one third of type 2 diabetic patients are poor responders to aspirin, and probably they need twice-daily administration of aspirin." He speculated that the one third of patients who are poor responders to aspirin might have diluted out an effect in the other two thirds in primary prevention trials, possibly accounting for the failure of those trials to show efficacy.
With twice-daily dosing, compliance could be a problem. A slow-release formulation of 200 mg of aspirin could be helpful, but does not now exist, Dr. Zaccardi said. Session cochair Michael Cummings, MD, professor of diabetes and endocrinology in Portsmouth, United Kingdom, said he doubts that adding 1 more pill a day for an elderly type 2 diabetic patient on multiple medications already would present much of an additional problem.
He noted that guidelines in the United States and in Europe focus on using once-daily aspirin, so the study is intriguing for its use of twice-daily dosing, which has not been studied previously. "The implications of the study could be that a simple change to the way that we dose aspirin at the moment — [twice-daily] dosing — could lead to different clinical outcomes, and could perhaps have more pronounced cardiovascular benefits than we're seeing with once-daily aspirin," he said, "particularly in patients with type 2 diabetes."
Dr. Cummings noted that it is becoming increasingly apparent that how and when drugs are administered can change outcomes. As an example, he cited recent work showing that nighttime dosing of antihypertension drugs is probably better than taking them in the morning.
Dr. Cummings advised that future trials of aspirin in people with type 2 diabetes will need to look at cardiovascular outcomes, not just mechanisms of platelet inhibition. Dr. Zaccardi agreed, and said that in light of current good regimens for glycemic, cholesterol, and blood pressure control, "what we have to improve is the problem of [platelet] aggregation in diabetic patients. It is probable that this study could represent a solution...[to] the reduced ability of aspirin to block COX-1."

MASTECTOMY OFFERS NO SURVIVAL ADVANTAGE IN YOUNG WOMEN

2011-09-14T11:30:00.000-07:00

Lumpectomy with adjuvant radiation and mastectomy provide "equivalent" overall and disease-specific survival in young women with early breast cancer, according to a new study presented at a press conference today in advance of the start of the 2011 Breast Cancer Symposium.
Young women "should not choose a mastectomy based on the assumption of improved survival," said lead investigator Usama Mahmood, MD, who was at the University of Maryland in Baltimore when the study was undertaken.
"Young age alone does not mandate mastectomy," commented Andrew Seidman, MD, from Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press briefing. His comments related to this study and another reported at the briefing, which found similar rates of local recurrence with the 2 competing surgical approaches.
Using the Surveillance, Epidemiology, and End Results (SEER) database, Dr. Mahmood and colleagues reviewed outcomes among 14,760 women aged 20 to 39 years who were diagnosed with early-stage breast cancer (T1-2, N0-1, M0) between 1990 and 2007.
The women underwent breast-conserving therapy (45%; lumpectomy and radiation treatment) or mastectomy (55%). Everyone in the breast conservation group received adjuvant radiation, but only 17% of the mastectomy group received radiation.
A multivariable analysis that included tumor characteristics found that breast-conserving therapy resulted in similar overall survival (hazard ratio [HR], 0.93; P = .16) and breast cancer–specific survival (HR, 0.93; P = .26) as mastectomy, said Dr. Mahmood, who is now a fellow in radiation oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Median follow-up duration was 5.7 years.
A matched-pair analysis involving a subset of 4644 of the patients confirmed no difference in overall survival and disease-specific survival, he also said. The patients were matched according to specific factors such as tumor size, tumor grade, and number of positive nodes.
In this analysis, at 5, 10, and 15 years, the overall survival rates for the breast conservation group were 92.5%, 83.5%, and 77%, respectively. For patients who underwent mastectomy, overall survival rates were 91.9%, 83.6%, and 79.1%, respectively. Breast cancer–specific survival rates were also similar between the 2 groups of women, said Dr. Mahmood.
The study's importance is, in part, due to other research findings, suggested Dr. Mahmood. A series of studies presented in the 1980s comparing breast-conserving therapy and mastectomy found equivalent survival among women with early breast cancer. But the number of young women in those studies was small, he said.
Other research has not encouraged the use of breast-conserving therapy in young women, he suggested.
"Previous studies have shown that young women with breast cancer treated with breast-conservation therapy experience higher local recurrence rates," he said. However, those findings were challenged by another study presented at the press conference. The combination of 2 new studies "should make us question that mastectomy is the only option for young women with breast cancer," said Dr. Seidman, who added the caveat that BRCA status is also a key to decision-making in young women.
The new study "serves as a reminder that women should be counseled appropriately about their treatment options," said Dr. Mahmood.
"The data is the data"
The factors included in the multivariate analysis included year of diagnosis, age, race/ethnicity, tumor grade, progesterone receptor status, tumor size, and lymph node status, noted the study authors. Patients had no more than 3 positive nodes, added Dr. Mahmood.
These are standard factors to consider when assessing breast cancer, suggested Dr. Seidman.
The new analysis did not include a number of factors that might also be used to make treatment decisions in the clinic, he further suggested. For instance, there are biological and luminal subtypes, as well the oncotype recurrence score, all of which may help clinicians and patients in their decision-making, he said.
"But most of us don't think about using that information as a decisive factor in the decision to undergo mastectomy or breast conservation therapy," Dr. Seidman said about these more recently identified breast cancer characteristics and newer tests.
Magnetic resonance imaging (MRI) may or may not have an important role to play in this decision-making process, he suggested. It is used to evaluate breast cancer in the preoperative setting to "better select" patients for the type of surgery, he said.
However, whether or not the use of MRI confers a survival advantage is "not settled," according to Dr. Seidman. "There is an epidemic of breast MRI," he said, quoting his colleague Monica Morrow, MD, from Memorial-Sloan Kettering Cancer Center.
"The data is the data," he said about the study, suggesting that any equivocations about the results and any missing factors in the analysis were not merited.
The investigators have disclosed no relevant financial relationships.

STATINS-A GOOD MEDICINE

2011-09-05T07:38:00.000-07:00

Long-term results of the Anglo-Scandinavian Cardiac Outcomes--Lipid-Lowering Arm (ASCOT-LLA) study, eight years after the trial officially stopped, showed that treatment with 10 mg of atorvastatin (Lipitor, Pfizer) reduced all-cause mortality compared with placebo, mainly through a reduction in noncardiovascular deaths [1].
Presenting the results at a hot-line session today at the European Society of Cardiology (ESC) 2011 Congress, investigators observed that reductions in the risk of death from respiratory illness and infection contributed to the overall reduction in all-cause mortality. "The numbers are large, the data are convincing, but we have no definitive explanation to date for the hypothesized legacy effect of atorvastatin on noncardiovascular-death risk reduction," said lead investigator Dr Peter Sever (Imperial College, London, UK).
The study was published online August 28, 2011 in the European Heart Journal to coincide with the ESC presentation.
Chair of the hot-line session, Dr George Parcharidis (Aristotle University of Thessaloniki, Greece), asked, somewhat tongue-in-cheek, whether the data were sufficiently strong to support prescribing all young adults a statin for long-term treatment in the hope of reducing all-cause mortality. "They say that one swallow does not make a summer, and I would never advocate atorvastatin to young people on the basis of these findings," responded Sever. "But what these findings do demand is a prospective study in patients at high risk for infection to determine whether the presence of a statin could reduce serious sepsis or death from serious infectious illness."
ASCOT-LLA and the Long-Term Effects of Atorvastatin
The results of ASCOT-LLA were first presented and simultaneously published online in theLancet in 2003 [2]. As reported by heartwire , lipid lowering with atorvastatin resulted in a significant 36% reduction in the primary end point of fatal coronary heart disease and nonfatal MI after a median follow-up of 3.3 years. At the time the study was stopped, there was a nonsignificant trend toward reduction in all-cause mortality. Upon completion of ASCOT-LLA, investigators continued to collect mortality data and evaluated the mortality outcomes in participants originally randomized to atorvastatin or placebo in the ASCOT-LLA arm for a median of 11 years.
At the end of the extended follow-up, all-cause mortality was significantly reduced by 14% (hazard ratio [HR] 0.86; 95% CI 0.76–0.98), and noncardiovascular mortality was significantly reduced by 15% (HR 0.85; 95% CI 0.73–0.99). There was no difference in death from cardiovascular causes.
Looking more closely at deaths from noncardiovascular causes, investigators found that deaths due to cancer were not statistically significant between those treated with atorvastatin vs placebo. There was, however, a significant 36% reduction in deaths due to infection and respiratory illness (HR 0.64; 95% CI 0.42–0.97), driven primarily by deaths due to infection.
During the session, Sever noted there are emerging data on the effects of statins on infection, with preclinical studies showing statins modulate neutrophil function, reduce proinflammatory cytokine release, improve vascular function, have antithrombotic properties, and improve outcomes from pneumonia and sepsis. Results of other observational studies have suggested that prior statin use reduces mortality from sepsis. Despite these observations, Sever said that there is still the possibility of confounding bias in some of the observational studies that have shown a benefit of statins in pneumonia and sepsis and that caution should be used when interpreting such results until a randomized clinical trial is performed.
Serious Decision for Primary Prevention Patients
Dr Guy De Backer (University Hospital, Ghent, Belgium), the discussant who also wrote an editorial that accompanies the published study [3], said that the introduction of statins into primary prevention is a serious decision considering that asymptomatic patients would be advised to take a drug for the rest of their lives and the only treatment benefit would be that "nothing happens." Moreover, there is little long-term safety data. For these primary-prevention trials, the mean patient age is 55 to 66 years old and the median length of statin use is just under five years, and yet primary-prevention patients would likely be treated with a statin for 15 to 20 years.
For this reason, the long-term ASCOT-LLA study is welcome, said De Backer. In primary-prevention studies, the most important clinical outcome is total mortality and quality of life, he added. One of the reassuring results of ASCOT-LLA is that the results confirm the benefits observed in the Scandinavian Simvastatin Survival Study (4S) and West of Scotland Prevention Study (WOSCOPS). In 4S, WOSCOPS, and ASCOT-LLA, there were significant 15%, 12%, and 14% reductions in all-cause mortality, respectively--all achieving statistical significance. He added that data suggesting a therapeutic role for statins in the management of pneumonia and sepsis are supported by observational studies.
Still, De Backer, like Sever, urges caution in interpreting the findings, especially because there is no explanation for the long-term carryover effect of statins on all-cause mortality but not on cardiovascular mortality. The data are essentially a subgroup analysis, and the reduction in all-cause mortality might be the result of chance, De Backer added. Quoting Dr Peter Sleight (Oxford University, UK), De Backer said, "Subgroup analyses are fun to look at, but don't believe them."

ACTIVE SURVEILLANCE IN LOW RISK PROSTATE CANCER

2011-09-01T10:27:00.001-07:00

There is now an "emerging consensus" that supports the use of initial active surveillance in low-risk prostate cancer, according to an essay published online August 8 in the Journal of Clinical Oncology.
At the same time, active surveillance is a "relatively uncommon management strategy," admit the essayists, led by Matthew Cooperberg, MD, from the University of California, San Francisco (UCSF).
Two related challenges have limited the widespread acceptance of active surveillance, say Dr. Cooperberg and his prominent coauthors, Peter Carroll, MD, also from UCSF, and Laurence Klotz, MD, from the University Toronto in Ontario, Canada.
In their essay on the "progress and promise" of active surveillance, the trio identify these 2 big challenges as problems in "defining eligibility" (i.e., who should be followed with active surveillance) and "identifying progression" (i.e., when this strategy should be stopped and replaced with active treatment).
They also introduce a host of other impediments to acceptance of the strategy, including economics. "Active surveillance is labor intensive and reimbursed relatively poorly," they write.
The essayists dramatically cite another retarding factor: patients. For some men, despite all educational efforts of a clinician, "the conversation about surveillance ends at the word cancer," they say.
Dr. Cooperberg and colleagues do not directly say that the practice of urology is at fault for the lack of uptake of active surveillance, but they allude to some responsibility, saying that "cultural biases in favor of aggressive treatment" might be at play.
The behavior of urologists is an important consideration, suggested a medical oncologist not involved with the essay.
"Urologists have been taught that the right way to treat cancer is to take it out," said Richard Lam, MD, from Prostate Oncology Specialists in Marina del Rey, California. This 3-physician practice, which treats about 1500 men with prostate cancer, is headed by medical director Mark Scholz, MD, author of Invasion of the Prostate Snatchers (2010, Other Press), a scathing indictment of the mainstream approach to prostate cancer.
Dr. Lam maintains that urologists "have not been taught to not take out prostate cancer."
"It's almost in their DNA to take it out," he told Medscape Medical News.
"Active surveillance is not a concept that they cannot grasp," said Dr. Lam about urologists. "The question is," he continued, "whether or not the basic principles [of active surveillance] are followed."
"There is very little likelihood that a cancer that is destined to be cured will not be cured if active surveillance is done," Dr. Lam asserts.
However, this is a major concern, as Brantley Thrasher, MD, from the University of Kansas Medical Center in Kansas City, and a spokesperson for the American Urological Association, pointed out in a previous interview with Medscape Medical News.
"Once you know there is a cancer, you have to be very careful," Dr. Thrasher noted. If the patient opts for active surveillance but then is noncompliant with regular follow-up tests, and a metastatic prostate cancer is discovered after a few years, then there is danger — especially in the litigious environment of the United States — of a claim of medical negligence, because there might have been a window of opportunity for curative treatment that was missed, he explained.
Dr. Cooperberg and colleagues also cite "medicolegal" risks as a retardant to the uptake of active surveillance.
But Dr. Lam said that, with a patient who is carefully oriented to active surveillance, "we are not very concerned about lawsuits."
Patient Education Could Change Things
Dr. Lam said that the essay by Dr. Cooperberg and colleagues is "well balanced," and adds that he has admired and followed Dr. Klotz's pioneering work in active surveillance "for years."
But Dr. Lam emphasized the need for patient education about active surveillance, and said that he and his colleagues at Prostate Oncology Specialists work hard to educate patients.
Among the 1500 men with prostate cancer attending their practice, about 400 are on active surveillance.
"It takes a lot of time and empathy to communicate the concept that most prostate cancer is a slow growing disease that doesn't kill people," he said.
"Urologists don't do this," Dr. Lam said.
Education is the key to patient acceptance of active surveillance, he asserted. Foremost, patients need to know that active surveillance is "not a case of writing them off," said Dr. Lam, who provided an example of the kind of simple teaching he uses.
He explains to patients that one of the criteria for judging the appropriateness of active surveillance is the "amount" of cancer. Patients with low-risk cancer are told that as the amount increases, their risk increases. They are asked to think of low-risk prostate cancer as a "marble."
"People don't die of a cancer that is the size of a marble," he explains to patients. If it increases to the size of a "ping pong ball," they will continue to watch and biopsy it. And they take out the cancer that is "like a basketball."
One of the investigators in the Surveillance Therapy Against Radical Treatment (START) trial, the first-ever North American phase 3 trial comparing active surveillance and treatment, also suggested that education can shape patients' attitudes.
When enrolling men for START, Adam Kibel, MD, from the Washington University School of Medicine in St. Louis, Missouri, found that, once educated, "many patients end up being concerned about possibly being randomized to treatment."
Reflecting on "Reflexive" Treatment
Dr. Cooperberg and colleagues make numerous references to the fact that the current approach to the care of men with low-risk prostate cancer is in need of repair.
"In contemporary practice in the United States, diagnosis tends to lead to treatment; thus, as the proportion of prostate cancers diagnosed with low-risk characteristics has grown, overdiagnosis has been associated with high rates of overtreatment," they write.
Overdiagnosis and overtreatment are likely to increase with the American Urological Association's new recommendation to begin screening at age 40 years for most men, they suggest.
Autopsy series have shown that 30% of men in their 30s have histologic evidence of prostate cancer, Dr. Cooperberg and his coauthors point out. Thus, it is especially important that "reflexive treatment should be avoided for young men with low-risk disease, whose period of tumor latency may be prolonged."
In general, urologists need to stop offering surgery to everyone with prostate cancer, suggest the essayists. "Reflexive radical treatment of all new diagnoses is increasingly difficult to justify," they write.
There is evidence now that active surveillance is a sound initial strategy in low-risk prostate cancer. "The data to date are sufficient to conclude that most men with low-risk disease — and likely most with intermediate-risk disease and significant comorbidity — should be offered at least a trial of active surveillance," they write.
Who are the best candidates?
"The obvious candidate for active surveillance is an older man with low-risk prostate cancer," the essayists write. Dr. Lam pointed out that older men with comorbidities such as heart disease, who are less likely to be referred to surgery as a result, are especially obvious candidates.
The essayists concur and further qualify this point. "Cancer risk, comorbidity, and life expectancy should receive greater consideration than chronologic age per se in treatment decision making."
How to define risk progression in this setting is "equally challenging," say the essayists. "Overall, grade progression seems to be the most consistent driver of progression," they write. However, "none" of the end points used to measure progression is "entirely satisfactory."

CANCER PREVENTION-DOGS CAN PROBABLY HELP!!!

2011-08-22T12:12:00.000-07:00

German researchers say that highly trained dogs are able to reliably sniff out lung cancer in human breath.
In its early stages, lung cancer has few symptoms, making it difficult for doctors to catch it early, when it's still treatable.
"This is the holy grail," says Suresh S. Ramalingam, MD, associate professor and director of the lung program at Emory University's Winship Cancer Institute in Atlanta.
"The whole field is focused on using something that's readily available that does not involve an expensive surgery or scan that would allow us to find early cancers," says Ramalingam, who is developing technology that aims to replicate the ability of dogs to smell trace amount of chemicals produced by cancerous tumors. He was not involved in the research.
Recently a large, government-funded study found that longtime smokers at high risk for lung cancer who received annual rapid computed tomography (CT) scans of their lungs cut their risk of dying of the disease by 20%.
But that test has caused controversy because it falsely detects cancer in about one out of four people, leading to further invasive procedures.
Checking for Lung Cancer
The new study, which is published in the European Respiratory Journal, found that four trained dogs -- two German shepherds, an Australian shepherd, and a Labrador retriever -- correctly identified cancer in 71 of 100 samples from lung cancer patients.
They also ruled out cancer in 372 out of 400 samples that were known not to have cancer, giving them a very low rate of false positives, about 7%.
"The surprising result of our study is the very high specificity of our dogs to identify lung cancer," says study researcher Thorsten Walles, MD, a lung surgeon at Schillerhoehe Hospital in Gerlingen, Germany.
"It even surpasses the combination of chest computed tomography (CT) scan and bronchoscopy, which is an invasive procedure that needs some form of anesthesia," Walles tells WebMD in an email.
Doctors have previously reported cases in which dogs have alerted their owners to undiagnosed skin, breast, and lung cancers by repeatedly pawing or nosing an affected body part. Some dogs have even been trained to smell low blood sugar levels in people who have diabetes.
But dogs have had more mixed success in carefully controlled studies, where samples from healthy people and sick people have been mixed.
A study published in BMJ in 2004 found that dogs correctly identified bladder cancer an average of about 40% of the time, a rate that was better than the 14% accuracy that could be expected by chance, but was lower than available tests.
But in June, researchers in Japan reported that dogs could detect the presence of colon cancer in human breath and stool samples with nearly 90% accuracy, a success rate only slightly lower than colonoscopy.
The length of time the dogs are trained may be an important difference between the studies, Walles says. In his study, the four dogs were trained for nine months. Other studies have used dogs trained for as little as three weeks.
The kind of sample the dogs are asked to smell -- urine, breath, blood, or stool -- may also influence the results, he says.
In his study, 220 volunteers -- 110 who were healthy, 60 who had lung cancer, and 50 with chronic obstructive pulmonary disease (COPD) -- were asked to exhale into a glass tube filled with fleece.
The tubes were mixed up so neither the dogs' handlers nor two observers who placed the samples on the floor in front of the dogs knew the status of the person they were from, to avoid inadvertently giving the dogs clues about what they should find.
The dogs were presented with five tubes at a time. Only one contained a sample from a person with cancer.
The dogs were trained to lie down and put their nose to the tube if they detected lung cancer.
The dogs appeared to be able to accurately identify the samples from cancer patients, even when they were in very early stages of the disease. And they were able to pick up the scent despite competing odors of cigarette smoke or food on a person's breath.

How Dogs Detect Cancer

Researchers think dogs and other animals are able to smell disease by picking up on minute changes in compounds called volatile organic compounds (VOCs) that comprise chemical signatures in the body.
As many as 4,000 different VOCs, for example, have been identified in human breath.
A dog's sense of smell has been estimated to be 100 to 1,000 times more powerful than a human's, says Gary K. Beauchamp, PhD, director of the Monell Chemical Senses Center in Philadelphia.
"It's not just how sensitive their nose is. It's how they process this into a recognition pattern," Beauchamp says. "The reason dogs can do this is that they're recognizing a complex picture, and that's the big trick, to find out how to mimic that in some sort of device that could be useful for diagnostic purposes in human disease."
Other researchers agree.
Ramalingam says because success rates vary between dogs and between samples, the real value of knowing dogs can detect cancer will likely be in building technology that can reliably repeat what they can do.
"The dogs show that it can be done. We need to find out what the dogs are sniffing so we can do it in a more scientific manner."

URINE GENETIC TEST FOR PROSTATE CANCER

2011-08-16T12:53:00.000-07:00

An investigational urine test stratifies prostate cancer risk in men with elevated levels of prostate specific antigen (PSA), according to newly reported results from more than 1000 men.
Previous research has indicated that the urine test is 100% accurate in detecting a gene fusion directly linked to prostate cancer, say the authors.
However, the urine test, which detects the fusion of 2 genes (TMPRSS2 and ERG), has a weakness: this tell-tale gene fusion occurs in only about 50% of prostate cancers.
For this reason, in the new prospective study, the urine test was combined with another marker, prostate cancer antigen 3 (PCA3).
The study was published online August 3 in Science Translational Medicine.
All of the men in this study had elevated PSA levels and had undergone either biopsy or prostatectomy, report the researchers, headed by Scott Tomlins, MD, PhD, from the University of Michigan Health System in Ann Arbor.
The men in the study were also evaluated for TMPRSS2:ERG and PCA3, but some were tested with the initial version of the gene fusion test and others with the second-generation test. Hence, the researchers chose not to directly compare individual men; instead, they stratified patients into risk groups by score (low, intermediate, and high).
Of 1065 men who received biopsies, 363 (34%), 346 (32%), and 356 (33%) were in the lowest, intermediate, and highest TMPRSS2:ERG + PCA3 score groups, respectively.
These scores were then compared to biopsy results.
Biopsies indicated cancer in 21% of men in the low-score group, 43% in the intermediate-score group, and 69% in the high-score group. The difference between the low- and high-score groups was significant (P < .001).
"Testing for TMPRSS2:ERG and PCA3 significantly improves the ability to predict whether a man has prostate cancer," said Dr. Tomlins in a press statement. "We think this is going to be a tool to help men with elevated PSA decide if they need a biopsy, or if they can delay having a biopsy and follow their PSA and urine TMPRSS2:ERG and PCA3."
In effect, the test, if it reaches the clinic, would help improve the murky decision-making that plagues many men with elevated PSA levels as they consider a biopsy.
"Many more men have elevated PSA than actually have cancer, but it can be difficult to determine this without biopsy. This test will help in this regard. The hope is that this test will be an intermediate step before getting a biopsy," said senior study author Arul Chinnaiyan, MD, PhD, from the Michigan Center for Translational Pathology and University of Michigan Medical School in Ann Arbor.
In 2009 at the Genitourinary Cancers Symposium, when the first-ever clinical results of the urine test were presented, an expert not involved with the research praised the rapid development of the test.
"This is an amazingly short interval between the discovery [of the gene fusion] and [the emergence of a] possible clinical application in diagnosis," said Howard Sandler, MD, from the Samuel Oschin Comprehensive Cancer Institute, Cedars–Sinai Medical Center, in Los Angeles, California. The gene fusions quantified in the test were first reported in 2005, he said.
Scores Correlate with Aggressiveness
The men in the study were patients at 3 academic medical centers and 7 community-based hospitals, and had specimens collected from 2006 to 2009.
In addition to helping predict the likelihood of prostate cancer, the urine test scores correlated with aggressiveness, as indicated by Gleason score. Only 7% of men in the low-score group had an aggressive tumor (Gleason score above 6), compared with 20% in the intermediate-score group and 40% in the high-score group. The difference between the low- and high-score groups was significant (P < .001).
The researchers also found that, of the 966 men with enough information to determine the Epstein criteria for significance of cancer on biopsy, 15%, 33%, and 61% of men in the 3 groups, respectively, had Epstein-criteria-defined significant cancer.
The researchers also compared the TMPRSS2:ERG + PCA3 score with Prostate Cancer Prevention Trial (PCPT) risk calculator, a commonly used online tool.
"Calculated PCPT risks of cancer (or Gleason score >6 cancer) differed markedly from the actual risks observed in the lowest and highest TMPRSS2:ERG + PCA3 score groups of men," they write.
For instance, almost all of the men (90%) of PCPT-evaluable men in the highestTMPRSS2:ERG + PCA3 score group had PCPT risk scores less than their actual risk of cancer on biopsy, they say.
The combined TMPRSS2:ERG and PCA3 test is not yet available as a prostate cancer screening tool. The Michigan Center for Translational Pathology is working with Gen-Probe Inc., which has licensed the technology, to develop the testing strategy. The University of Michigan hopes to offer it to patients within the year, according to the press statement.
The study was funded by Gen-Probe Inc., the Early Detection Research Network, National Institutes of Health, Prostate Cancer Foundation, Burroughs Wellcome Fund, Doris Duke Foundation, and the Howard Hughes Medical Institute. Dr. Chinnaiyan reports serving as a consultant to Gen-Probe. Coauthor Yves Fradet, MD, from University of Laval Cancer Research Centre, in Québec City, Quebec, is cofounder of Diagnocure, which licensed diagnostic rights to the PCA3 gene to Gen-Probe.

TALL WOMEN AT HIGHER RISK FOR CANCER

2011-07-31T01:30:00.000-07:00

Taller women have an increased risk of developing many types of cancer, compared with their shorter counterparts, according to new research published online today in the Lancet Oncology.
"For a woman of any height, the risk of cancer was 16% greater than for a woman 10 cm shorter. The association was seen across the whole normal range of heights," lead author Jane Green, DPhil, University of Oxford, United Kingdom, told Medscape Medical News.
"Other people have found links between height and some common cancers," Dr. Green said in an interview. "We had a study large enough to examine this link in detail for a range of cancers, and taking into account factors such as smoking and socioeconomic factors, so we were able to extend the previous findings."
Dr. Green and her team assessed the association between height and cancer incidence in the Million Women Study, in which close to 1.3 million middle-aged women in the United Kingdom were enrolled between 1996 and 2001. Their mean age at recruitment was 56.1 years.
Taller women tended to be of higher socioeconomic status, drink more alcohol, be older at first menstruation, have fewer children, be more active, and have their first child later in life than shorter women. They were also less likely to be obese or to be current smokers.
The mean height of the study population was 160.9 cm. The mean height of the tallest women was 174 cm and of the shortest women was 153 cm, for a difference of 21 cm.
The women were followed for a total of 11.7 million person-years, or a median of 9.4 years per woman (interquartile range, 8.4 to 10.2 years). During this time, 97,376 incident cancers occurred.
The study found that the relative risk (RR) for total cancer was 1.16 (95% confidence interval [CI], 1.14 to 1.17; P < .0001) for every 10 cm increase in height.
The increased risk was statistically significant for 10 different cancers.
RR for Individual Cancers per 10 cm Increase in Height

Cancer Type	RR	95% CI
Colon	1.25	1.19–1.30
Rectal	1.14	1.07–1.22
Malignant melanoma	1.32	1.24–1.40
Breast	1.17	1.15–1.19
Endometrial	1.19	1.13–1.24
Ovary	1.17	1.11–1.23
Kidney	1.29	1.19–1.41
Central nervous system	1.20	1.12–1.29
Non-Hodgkin's lymphoma	1.21	1.14–1.29
Leukemia	1.26	1.15–1.38

The researchers also conducted a meta-analysis, combining their results with those from 10 published prospective studies, and found that the height-associated risk of developing cancer was similar in Europe, North America, Australasia, and Asia.
Asked why she thinks taller people have a greater cancer risk, Dr. Green said: "Taller people have more cells in their bodies, so will have a greater chance of one of those cells developing cancerous changes."
She added that growth hormones, which have been linked both to childhood growth and to cancer, might also play a part.
So What's a Tall Person to Do?
"You can't change your height, nor would most people want to," Dr. Green said. "Being tall has health advantages, including lower risk of heart disease. The increased cancer risk is just part of the picture. Most people are not a lot taller or shorter than average, and their cancer risks will not be greatly affected by their height."
She added that the single most important risk factor for cancer is smoking, "and that is something that can be changed."
Dr. Green said her hope is that the results of this study will contribute to knowledge of how cancers develop.
In an accompanying comment, Andrew G. Renehan, PhD, from the University of Manchester, United Kingdom, writes that attained adult height is unlikely to directly modify cancer risk. He calls for future research to explore the predictive value of nutrition, psychosocial stress, and illness during childhood, rather than final adult height.
"Extended follow-up of large childhood cohorts with longitudinal repeated exposure measurements are needed," Dr. Renehan states.
"Assessing these cohorts will need new methods (e.g., latent class analyses) to tease out key factors that influence the subsequent development of height-related cancers," he concludes.
The study was funded by Cancer Research UK and the UK Medical Research Council. Dr. Green has has disclosed no relevant financial relationships. Dr. Renehan reports financial relationships with Novo Nordisk.

BENEFITS OF OVARIAN SUPPRESION DURING BREAST CANCER CHEMOTHERAPY-BAD TRIAL DESIGN

2011-07-25T11:15:00.000-07:00

Temporary ovarian suppression during chemotherapy in young women with early-stage breast cancer reduced the occurrence of treatment-induced early menopause, according to Italian researchers.
In a phase 3 study, triptorelin, a gonadotropin-releasing hormone agonist (GnRH), was administered to suppress ovarian function during chemotherapy in the hope of protecting women 18 to 45 years of age from ovarian failure, say the authors, led by Lucia Del Mastro, MD, from the Istituto Nazionale per la Ricerca sul Cancro in Genova, Italy. They report their results in the July 20 issue of the Journal of the American Medical Association.
The exact mechanism through which this protection takes place is not known, admit the authors.
Nonetheless, patients randomized to the group that received chemotherapy plus triptorelin had a lower rate of early menopause than those randomized to the group that received chemotherapy alone, for an absolute difference of −17% (8.9% vs 25.9%; P <.001).
Early menopause was defined as either the failure to resume menses or to recover premenopausal levels of estradiol 12 months after the end of chemotherapy.
Triptorelin "can therefore be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy," conclude the authors.
However, a pair of American breast cancer experts suggest that this conclusion is overreaching.
"Recovery of a single menstrual cycle or premenopausal levels of estradiol are not definitive measures of recovery of ovarian function," write Hope Rugo, MD, and Mitchell Rosen, MD, from the University of California San Francisco, in an editorial accompanying the study.
Furthermore, the editorialists note that a large portion (82%) of the study participants had hormone-receptor-positive disease. If these women recovered their menses after treatment with triptorelin, the study protocol called for the immediate use of 2 more years of ovarian suppression with triptorelin, in addition to 5 years of tamoxifen, to avoid the adverse effects of ovarian-produced estrogen on disease outcome. As a result, "it is impossible to evaluate the effects of ovarian suppression on true recovery of ovarian function or on ovarian reserve," they write. True recovery means long-term recovery, they suggest.
Another problem with the study and its approach is that other research suggests that loss of menses is helpful in the treatment of hormone-receptor-positive breast cancer, the editorialists note.
They point out that "recent data have confirmed that amenorrhea 12 months after the start of therapy had an important effect on outcome, with an almost 50% relative improvement in risk of recurrence or death in women with hormone-receptor-positive disease and amenorrhea, compared with those with persistent menstrual function" (N Engl J Med. 2010;362:2053-2065).
Because the current study has no information about disease outcome and because women with hormone-receptor-positive disease who had evidence of recovery were immediately resuppressed, per the study protocol (and thus cannot be counted as having long-term recovery of ovarian function), the editorialists believe too much is unknown about ovarian suppression with triptorelin.
Thus, the use of triptorelin is not wholly advisable in women with hormone-sensitive disease, they argue.
The current study — and mixed results from other, smaller studies on this subject — indicate that, for women with hormone-sensitive disease, "the use of GnRH agonists concomitant with chemotherapy cannot be recommended as a standard treatment and should be approached with caution," they write.
The Matter of Fertility
The study, known as PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6), was conducted at 16 Italian centers. Between October 2003 and January 2008, the investigators enrolled 281 patients who were premenopausal with stage I to III breast cancer.
Patients received adjuvant or neoadjuvant treatment with anthracycline-based chemotherapy, anthracycline plus taxane-based chemotherapy, or CMF-based chemotherapy (100 mg/m² of oral cyclophosphamide on days 1 to 14 or 600 mg/m² of intravenous cyclophosphamide on days 1 and 8; 40 mg/m² of methotrexate on days 1 and 8; and 600 mg/m² of fluorouracil on days 1 and 8).
The patients randomized to receive triptorelin (n = 148) were given an intramuscular dose of 3.75 mg at least 1 week before starting chemotherapy, and then every 4 weeks for the duration of the treatment, according to the authors.
Women with hormone-receptor-positive disease received 20 mg/day of tamoxifen for 5 years starting after chemotherapy ended.
Predictably, recovery of menses was less common in women receiving tamoxifen, and the protection with triptorelin from early menopause was greater in women with hormone-receptor-negative disease than in those with hormone-receptor-positive disease.
Multivariate analysis showed that only treatment with triptorelin was associated with a significant reduction in the risk of developing early menopause (odds ratio, 0.28; 95% confidence interval, 0.14 to 0.59; P <.001). Patient age and the type of chemotherapy (taxane- or CMF-containing) did not significantly affect the risk, report the authors.
Although the incidence of early menopause was the primary outcome measure, the investigators say that infertility is another major concern for these young women.
"Young survivors of breast cancer consider premature menopause, sexual dysfunction, and infertility the most distressing aspects of their cancer experience," write the authors, referring to chemotherapy-induced adverse events.
As a strategy to preserve fertility, ovarian suppression has a number of advantages over cryopreservation. It "does not require a male partner, is simple to administer, does not require delaying chemotherapy, and is less invasive and less expensive," the authors say. These 2 approaches to preserving fertility are "not mutually exclusive," they write, adding that "they can be used together to increase the probability of preserving fertility."
The editorialists agree that GnRH agonist therapy during chemotherapy can "potentially expand fertility possibilities." However, they point out that "recovering menses is not the same as fertility preservation." Instead, what matters most is "ovarian reserve," which is an end point that "clearly affects reproductive potential but is more difficult to measure." In short, the resumption of menses is a surrogate marker for fertility.
The editorialists champion reproductive technology for women in the "difficult situation" of being treated with chemotherapy for breast cancer. They write: "The most effective option for fertility preservation is assisted reproductive technology with embryo or oocyte cryopreservation, and this option should be discussed with young women facing chemotherapy for breast cancer and other curable malignancies."
This study was sponsored by the Istituto Nazionale per la Ricerca sul Cancro, and partly supported by a grant from the Associazione Italiana per la Ricerca sul Cancro, Italy. The triptorelin used in the study was provided by Ipsen (Milan, Italy). Dr. Del Mastro reports receiving honoraria for speaking activity from Ipsen. Another author reports receiving payment for lectures from AstraZeneca. Dr. Rugo reports that her institution has received research funding from Pfizer, Novartis, Roche/Genentech, Abbott, Celgene, Merck, and Bristol-Meyers Squibb, and she reports receiving honoraria from Genomic Health. Dr. Rosen has disclosed no relevant financial relationships.

GASTRIC CANCER STAGING

2011-07-18T10:56:00.000-07:00

Tumor.
TX: The primary tumor cannot be evaluated.
T0 (T plus zero): There is no evidence of a primary tumor in the stomach.
Tis: This stage describes a condition called carcinoma (cancer) in situ. The cancer is found only in cells on the surface of the epithelium (the inner lining of the stomach) and has not spread to any other layers of the stomach.
T1: The tumor has invaded the lamina propria, muscularis mucosae, or the submucosa (the inner layers of the wall of the stomach).
T1a: The tumor has invaded the lamina propria or muscularis mucosae.
T1b: The tumor has invaded the submucosa.
T2: The tumor has invaded the muscularis propria (the muscle layer of the stomach).
T3: The tumor has grown through all of the layers of the muscle into the connective tissue outside the stomach, but it has not penetrated the peritoneal lining or serosa.
T4: The tumor has grown through all of the layers of the muscle into the connective tissue outside the stomach and has penetrated the peritoneal lining or serosa or the organs surrounding the stomach.
T4a: The tumor has invaded the serosa.
T4b: The tumor has invaded organs surrounding the stomach.

Node.
NX: Regional lymph nodes cannot be evaluated.
N0 (N plus zero): The cancer has not spread into the regional lymph nodes.
N1: The cancer has spread to one to two regional lymph nodes.
N2: The cancer has spread to three to six regional lymph nodes.
N3: The cancer has spread to seven or more regional lymph nodes.
N3a: The cancer has spread to seven to 15 regional lymph nodes.
N3b: The cancer has spread to more than 16 regional lymph nodes.

MX: Distant metastasis cannot be evaluated.
M0 (M plus zero): The cancer has not metastasized.
M1: The cancer has spread to another part or parts of the body.

Cancer stage grouping
Stage 0: This is also called carcinoma in situ.
Stage IA: T1N0M0
Stage IB: T1N1M0, T2N0M0
Stage IIA: T1N2M0, T2N1M0, T3N0M0
Stage IIB: T1N3M0, T2N2M0, T3N1M0, T4aN0M0
Stage IIIA: T2N3M0, T3N2M0, T4a, N1, M0
Stage IIIB: T3N3M0, T4a,N2M0, T4bN0N1M0).
Stage IV: any T, any N, M1

Do you really need 8 glasses of water a day?

2011-07-16T02:20:00.000-07:00

How much water do we really need? You may think six to eight glasses per day because you have probably read many articles and had discussions with your doctor to support that. But a Scottish physician has blasted that standard in a British Medical Journalarticle, stirring the debate about how much water we should drink and how much is too much and bad for our health. Dr. Margaret McCartney argues there is no quality scientific evidence to support the recommendation, which she says can lead to over-hydration problems for some people.

Here's what you need to know to sort hydration hype from good health advice.

Don't skimp
The eight-glass formula doesn't fit for everyone. It depends on your gender, size, and level of activity, other studies note. The Institute of Medicine calls for adult men to drink 13 cups of fluid daily (which totals three liters, or a little more than four tall reusable water bottles) and women to have nine cups (2.2 liters, or about the amount found in three reusable water bottles). That number changes according to lifestyle. The more active a person is, the more they will need to replace fluids. Larger people, pregnant and nursing women, and those who take dehydrating medications also will likely need to account for that by adding more water to their diet.

If you are active, it's also important to account for your environment when calculating how much fluid you need. If you are exercising in temperatures that are very hot (likely leading you sweat more) or very cold (which can stunt your ability to sense dehydration), are an endurance athlete, or are active in a high-altitude area, you will probably need to up your water intake.

Don't overdo it
The debate about how much water we really need to be drinking is centered around the risk of hyponatremia, or taking in more fluid that the body loses while sweating. It is a serious condition that occurs when there is not enough sodium (or salt) in the body fluids outside of the cells. This can cause swelling, including of the brain. Hyponatremia happens when a person sweats excessively in one stint, does not eat, does not urinate enough, and drinks a great deal of water. Symptoms include confusion, headaches, muscle spasms, vomiting, convulsions, and fatigue. In the worst cases, hyponatremia can lead to seizures, coma, and even death.

There are exceptions for medical conditions and other situations, but athletes are often watched for signs of hyponatremia, especially those participating in endurance events like a marathon or triathlon.

Experts advise taking in some electrolyte-replacement fluids in addition to drinking water while you are exercising. However, you really only need a minimal amount to keep your body in balance and give you an energy kick. For example, it is recommended that runners out for 30 minutes to an hour take in three to six ounces of fluid every 15 or 20 minutes, including one sports drink. There's also evidence that simply taking sips or swishing a sports drink will do the trick.

Don't get sucked in to the sports drink hype
The risks of hyponatremia are steep, but take the hype about over-hydrating with a grain of salt. The multi-billion-dollar sports drink industry has pushed the idea that most people need more than water when they are active. However, some experts say that most people don't need a lot of sports beverages, and that they often just add calories to diets. The CDC recommends choosing sports drinks that do not have added sugar, which can total 38 grams in just one bottle.

Count other drinks besides water as fluids
It's OK to include other drinks when you're measuring how many fluids you take in per day. However, that isn't a license to subsist on soda, coffee, and sugary drinks. Although caffeine in soda and coffee won't dehydrate you, they shouldn't be used to quench thirst or as a substitute for water. Add them to your fluid tally, but do reach for water more often than you pop open a can of bubbly stuff.

People who imbibe, particularly wine and hard liquors, should also be aware that those drinks with a high alcohol content can be dehydrating. Beer, however, is less dehydrating because it is predominantly water. Drinking a glass of water before and after alcohol can't hurt fluid intake or the chances of avoiding a headache the next day.

Eat your water
You don't always have to sip to stay hydrated. Experts say that 20 percent (or 2-1/2 cups) of the water we ingest comes from the foods we eat. Choosing the right water-rich fruits and vegetables will also add nutrients to your diet, fill you up, and may even give some oomph to your exercise.

Fruits like strawberries, cantaloupes, and peaches are packed full of water and potassium, which is the electrolyte shed when your body sweats. Adding more to your daily diet will help balance the fluids your body needs, regulate your heartbeat and circulation, and tastes better than chugging an energy drink.

Selecting foods that fuel your health while helping keep you hydrated will give you more bang for your buck. Watermelon offers a vitamin C boost, broccoli helps fight cancer, pineapple aids muscle recovery after a big workout, and yogurt ups immunity. (Read more about foods that keep you hydrated and healthy here.)

Sneak in the good stuff
If you're up to your ears in cucumber salad or can't manage to down another bottle of water, work in little ways to stay hydrated. Add slices of orange, lime, kiwi, or watermelon to a jug of water for a burst of natural flavor. Make a regular old glass of tap water feel fancier by adding fizz with a counter-top carbonator (sold for about $100 and marketed as home soda-makers, skip the added flavors to make sparkling water in your own reusable bottles). Take 10 minutes once a week to stock your fridge, car, gym bag, and desk with water bottles so it's convenient to grab water wherever you spend most of your day. Finally, you can up your fluid intake with one little step by simply adding a straw to your glass of water.

LUNG CANCER SCREENING-TIME TO BEGIN

2011-07-04T12:13:00.000-07:00

Results from the landmark National Lung Screening Trial (NLST), which indicate that screening with low-dose helical computed tomography (CT) reduces mortality from lung cancer, have been published online in the New England Journal of Medicine.
The 53,000-person trial found a 20% reduction in deaths from lung cancer among current and former heavy smokers screened with low-dose helical CT, compared with those screened with chest radiograph (P = .004); the study has a median follow-up of 6.5 years. These principal findings were first reported publicly in October 2010, and were covered at the time by Medscape Medical News.
The newly published paper includes previously unavailable details on the diagnostic procedures performed after positive screenings and their related complications rates, as well as details on the lung cancers that were diagnosed.
The study has been accompanied by expressions of enthusiasm and gratitude from the American oncology community.
"It's gratifying. We've been looking for this kind of good news in lung cancer for a long time," Otis Brawley, MD, chief medical officer at the American Cancer Society (ACS), told Medscape Medical News.
"This study fills a huge gap in lung cancer control," said Bruce Johnson, MD, in a press statement from the American Society of Clinical Oncology, where he is a board member. "This is a very exciting and important result," added Dr. Johnson, who is from the Dana-Farber Cancer Institute in Boston, Massachusetts.
The positive study results beg the question of whether or not it is time for lung cancer screening programs in the United States.
The study authors, led by Christine Berg, MD, from the National Cancer Institute, think the evidence is not complete enough yet. "The current NLST data alone are . . . insufficient to fully inform such important decisions [on lung cancer screening recommendations]."
The authors have estimated the immensity of the potential impact of such policies.
Although there are only 7 million adults in the United States who meet the entry criteria for the NLST, there are an estimated 94 million adults who are current or former smokers, and thus potential screens, they suggest.
Whatever the target population, "a national screening program of annual low-dose CT would be very expensive," writes Harold Sox, MD, from Dartmouth Medical School in West Lebanon, New Hampshire, in an editorial that accompanies the NLST study. "I agree with the authors that policy makers should wait for more information before endorsing lung cancer screening programs," he writes, citing cost as his principal objection.
However, one clinician has seen enough data to endorse screening.
"There should be a national screening policy, with CT offered to and even recommended for all patients who meet the same criteria as the eligibility for the NLST," said Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, and author of the Blowing Smokelung cancer blog.
If such a policy is not forthcoming, the lung cancer community, including medical professionals, "should ask the government and insurance company leadership why they so clearly devalue the lives of people with lung cancer, compared with those afflicted with other cancers," Dr. West toldMedscape Medical News.
Dr. West said that if results of this magnitude were seen in other cancers, especially breast cancer, there would be no questioning the cost of the screening. "Screening in other cancers that is widely accepted is based on far, far less impressive improvement in actual survival," he said.
"Our society routinely places a very different threshold for acceptance of lung cancer interventions than breast cancer interventions, which are often routinely and unquestioningly accepted as worthwhile interventions based on remarkably minimal absolute differences in outcomes," he pointed out.
"There is nothing less valuable about a life saved from lung cancer than a life saved from breast cancer or another cancer," said Dr. West.
Dr. Brawley suggested that professional opinion will influence forthcoming lung cancer screening policy. The ACS began drafting a lung cancer screening guideline when the NLST results were first announced. The ACS guideline will now be informed by the paper's new data, as well as by the medical communities' reaction to it, said Dr. Brawley. The ACS will be "monitoring the 'Letters to the Editor' reaction to the paper," he said.
Concerns About Harms
In NLST, participants were between 55 and 74 years of age and had a history of heavy smoking. They were screened once a year for 3 years, and were followed for 3.5 additional years with no screening.
There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, which is a relative reduction in mortality from lung cancer with low-dose CT screening of 20% (95% confidence interval [CI], 6.8 to 26.7).
The number needed to screen with low-dose CT to prevent 1 death from lung cancer was 320, Constantine Gatsonis, PhD, one of the study coauthors, told Medscape Medical News. He is from the Warren Alpert Medical School of Brown University in Providence, Rhode Island.
The rate of positive screening tests was more than 3 times higher with low-dose CT than with radiography (24.2% vs 6.9%) over all 3 rounds.
Most of the positive tests were false — 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false-positive results.
"The rate of false positives is very high, although the thoracic/pulmonology communities have certainly seen high rates of false positives with screening in the past," noted Dr. West.
The authors address the issue of false positives. "The vast majority of false-positive results were probably due to the presence of benign intrapulmonary lymph nodes or noncalcified granulomas," they write.
In a related concern, they note that the rates of complications after a diagnostic evaluation procedure for a positive screening test were "low." The rate of 1 complication or more was 1.4% in the low-dose CT group and 1.6% in the radiography group. The diagnostic methods and algorithms varied at the 33 sites and were not uniform per the protocol, the authors point out.
Dr. Sox observes that invasive diagnostic procedures were "few, suggesting that diagnostic CT and comparison with prior images usually sufficed to rule out lung cancer in participants with suspicious screening findings."
Dr. West said that lung screening is akin to prostate-specific antigen monitoring for prostate cancer. "Undergoing CT screening for lung cancer will require a careful discussion of the road that this may well lead people down, including the anxiety, additional imaging, and potentially invasive procedures that this pathway might well entail," he said.
The study authors point to another finding from the NLST as proof of the relative safety of lung cancer screening. The rate of death from any cause was reduced in the low-dose CT group, compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P = .02). "The decrease in the rate of death from any cause with the use of low-dose CT screening suggests that such screening is not, on the whole, deleterious," they conclude.
Another concern with CT screening is overdiagnosis, says Dr. Sox.
"Overdiagnosis probably occurred in the NLST," he writes. After 6 years of observation, there were 1060 lung cancers in the low-dose CT group and 941 in the radiography group. This may be evidence of overdiagnosis because, in a large clinical trial of screening tests, "the proportion of patients in whom cancer ultimately develops should be the same in the 2 study groups," he said. If the difference found to date between the 2 screening methods persists with more follow-up, this "suggests that one test is detecting cancers that would never grow large enough to be detected by the other test," Dr. Sox notes.
Finally, the study authors cite one last safety concern with CT screening — cancer caused by the CT scans themselves. "The association of low-dose CT with the development of radiation-induced cancers could not be measured directly," they write, adding that it is a "long-term phenomenon." Dr. Brawley said that previous research has indicated that for every 2000 spiral CT scans, there is at least 1 cancer caused (Radiology. 2004;232:735-738).
Cancers Detected
Low-dose CT screening fulfills an often-touted claim about cancer screening — that it detects more cancers earlier than would have been likely detected clinically. Indeed, 40% of the cancers in the low-dose CT group were stage 1A, whereas 21.7% were stage IV.
"Cancers discovered after a positive low-dose CT screening test were more likely to be early stage and less likely to be late stage than were those discovered after chest radiography," Dr. Sox explains.
Will the benefits of screening seen in the NLST be seen in community settings? Dr. Sox believes the applicability of the results is "mixed."
Diagnostic work-up and treatment did take place in the community, he acknowledged. "However, the images were interpreted by radiologists at the screening center who had extra training in the interpretation of low-dose CT scans and presumably a heavy low-dose CT workload," he writes.
Furthermore, both Dr. Sox and the study authors point out that the study population was not typical. Trial participants were younger and had a higher level of education than a random sample of men and women with a history of heavy smoking. This might have contributed to the high rate of adherence to the screening protocol in the study (more than 90%), says Dr. Sox.
The influential US Preventative Services Task Force (USPSTF) will make a determination about recommendations for lung cancer screening "by next year," said Dr. Brawley. In the meantime, while the USPSTF and organizations such as the ASC, which helped fund the study, and the American College of Radiology make their recommendations, physicians and patients should have a conversation about the harms and benefits of screening, he said.
Dr. Brawley, while emphasizing concerns about low-dose CT screening, said that "it's wonderful that we can say to high-risk people: 'We have something to offer you folks."
The study was conducted by the American College of Radiology Imaging Network and the National Cancer Institute's Lung Screening Study Group.

LUMPECTOMY BETTER THAN MASTECTOMY FOR TRIPLE NEGATIVE PATIENTS?

2011-06-28T11:58:00.000-07:00

NEW YORK (Reuters Health) Jun 16 - Breast-conserving therapy may provide better five-year locoregional control for women with triple-negative breast cancer than modified radical mastectomy without adjuvant radiation, according to a retrospective study from Canada.
National Comprehensive Cancer Network guidelines recommend adjuvant radiotherapy after modified radical mastectomy based only on tumor size and lymph node status, without regard to biologic subtype.
But the new results challenge the "paradigm in breast cancer that breast-conserving surgery followed by radiation therapy is equivalent to mastectomy alone" in all patients, said Dr. Jean-Philippe Pignol of Sunnybrook Health Sciences Centre in Toronto and colleagues in an editorial.
Instead, mastectomy for aggressive disease like triple-negative breast cancer may be the wrong approach, they wrote.
As reported online June 13 in the Journal of Clinical Oncology, Dr. Bassam Abdulkarim and colleagues at McGill University in Montreal reviewed all cases of triple-negative breast cancer at their institution from 1998-2008 (n=768), i.e., all women whose tumors didn't express receptors for estrogen, progesterone, or human epidermal growth factor receptor-2 (HER2).
As initial treatment, 42% of patients received breast-conserving therapy, 37% had modified radical mastectomy alone, and 21% had modified radical mastectomy plus adjuvant radiotherapy. Eighty-five percent received chemotherapy. The median follow-up in the study was 7.2 years.
Five-year, locoregional recurrence-free survival was 94%, 85%, and 87% for breast-conserving therapy, modified radical mastectomy and modified radical mastectomy plus radiotherapy, respectively (P<.001).
When investigators analyzed only the type of initial treatment, the rate of locoregional recurrence was significantly higher in the modified radical mastectomy group (HR, 2.61, P<.001) and the modified radical mastectomy plus radiotherapy group (HR, 2.38, P<.001) compared to patients receiving breast conserving therapy.
When they analyzed multiple variables, including tumor size, grade, lymph node status, lymph vascular invasion and adjuvant chemotherapy, modified radical mastectomy without radiotherapy was an independent predictor of local recurrence (HR 3.44, P<.001) however, there was no difference between those who also underwent radiotherapy and those who received breast conserving therapy.
The investigators also looked separately at 468 women with T1-2N0 disease. In this group, five-year locoregional recurrence-free survival was 96% after breast-conserving therapy and 90% after modified radical mastectomy without radiation (P=.022). On multivariate analysis, modified radical mastectomy without radiotherapy was the only independent factor associated with higher local recurrence (HR, 2.53, P=.027).
"Taken together, our findings emphasize that the current guidelines should take into account the intrinsic risk associated with this biologic subtype," the investigators, the authors say.
In their editorial, Dr. Pignol and colleagues say that clinically, the data should be used to inform triple-negative breast cancer patients of their likely outcomes. Also, they suggest, "adjuvant radiotherapy after mastectomy should at least be discussed" with such women.

PROSTATE CANCER KILLS 50% IN UK BU ONLY 15% IN USA-PSA TESTING MAY BE THE ANSWER

2011-06-19T00:58:00.001-07:00

New data from the United Kingdom show that prostate cancer kills half of the men diagnosed with this disease, and challenge the notion that prostate cancer patients "are more likely to die with, rather than of, their disease," according to the researchers.
The situation is much different in the United States, where recent estimates suggest that only about 15% of men diagnosed with prostate cancer die from this disease.
The main reason for this huge difference is the high uptake of testing for prostate-specific antigen (PSA) in asymptomatic men in the United States, and the low uptake in the United Kingdom, say experts on both sides of the Atlantic.
Both situations are described as extreme by those on the other side. British researchers say that routine PSA testing in the United States is picking up disease that might be clinically insignificant, leading to overdiagnosis and overtreatment of prostate cancer. American researchers argue that PSA testing is picking up prostate cancer at an earlier stage of disease, when it is still treatable and curable, which results in the much lower mortality rates.
"If you are screening too aggressively, there is no question that you will overtreat, but the other end of the spectrum is that you have a cancer that is very curable but you still end up having half of the patients dying of the disease because they are presenting at late stages" said Brantley Thrasher, MD, FACS, professor of urology at the University of Kansas in Kansas City, who acts as a spokesperson for the American Urological Association.
"I would rather have the potential — and I emphasize the potential — for overtreating than swing the other way and lose all of these patients to a disease that is curable," Dr. Thrasher explained in an interview with Medscape Medical News.
New British Analysis
The new British data come from an analysis of 50,066 men diagnosed with prostate cancer between 1997 and 2006 from the Thames Cancer Registry, which covers a population of 12 million in South East England. Subjects were followed to the end of 2007.
During that period of time, there was little uptake of PSA testing in asymptomatic men in the United Kingdom.
The situation is different in the United States, where there is a high uptake of PSA testing, and has been for some time, lead researcher Simon Chowdhury, MD, consultant oncologist at Guy's and St Thomas' NHS Foundation Trust in London, United Kingdom, told Medscape Medical News.
Dr. Chowdhury presented the findings at the 2011 Meeting of United Kingdom Association of Cancer Registries and National Cancer Intelligence Network (NCIN), held in London.
The analysis found that prostate cancer was the cause of death in 49.7% of the men who had been diagnosed with the disease. The other causes of death were cardiovascular disease (17.8%), other cancers (11.8%), pneumonia (7.5%), and other causes (13.25%).
Prostate cancer remained an important cause of death even when the data were analyzed according to age, cancer stage, and first treatment, the researchers note.
Prostate cancer was the cause of death in 74.3% of men who had stage IV cancer at diagnosis, in 46.4% of all men 75 years and older, and in 31.6% of all men who underwent radical prostatectomy.
"Prostate cancer was the underlying cause of death in a substantial proportion of men," the researchers conclude, "and remained an important cause of death in all subgroups, including those treated with curative intent and older men."
"Our data show that a high proportion of men with prostate cancer die from the cancer," commented study author Henrik Møller, BA, BSc, MSc, DM, FFPH, professor of epidemiology at King's College London, and director of the Thames Cancer Registry. Dr. Møller, who is also head of analysis and research at the NCIN, added: "Our findings challenge the commonly-held view that most men with prostate cancer will die with the disease, rather than from it."
Setting of Low PSA Testing
The British researchers point out that their findings pertain to settings where there is a low uptake of PSA testing in asymptomatic men. In such a setting, "our findings challenge the notion that prostate cancer is a negligible problem in any subgroup, as defined by age, stage, or treatment," they note.
Dr. Chowdhury explained in an interview with Medscape Medical News that PSA testing was introduced in the United Kingdom in the early 1990s, but it is not routinely performed in asymptomatic men.
The situation is different in the United States, where there is a high uptake of PSA testing, with reports that more than 50% of men older than 65 years of age are tested, and many of the men tested are asymptomatic. This PSA testing in asymptomatic men might result in overdiagnosis and overtreatment of prostate cancer, Dr. Chowdhury said, because "some of the prostate cancers that are picked up are small and some may be clinically insignificant."
Dr. Chowdhury noted that the ratio of prostate cancer deaths to prostate cancer diagnoses is very different in the 2 regions — about 1 to 6.0 in the United States (based on estimates from the 2010 SEER database, showing a diagnosis in 215,000 men and 30,000 deaths) and about 1 to 3.7 in the United Kingdom (based on 2008 Cancer Research UK data, which show that there were 37,000 diagnoses and 10,100 deaths from prostate cancer).
There is a difference in the stage of prostate cancer at diagnosis — some American reports suggest that about 80% of the disease is localized, whereas in the United Kingdom, although most disease is also localized, there is a higher proportion of cancers diagnosed at an advanced stage, Dr. Chowdhury explained. Widespread PSA testing picks up prostate cancer at an earlier stage, which might be less aggressive and less clinically significant, he said.
"Not a Trivial Disease"
This is an extremely important study, which highlights the fact that prostate cancer is not a trivial disease for a large number of men in the United Kingdom who suffer from it," said Malcolm Mason, MD, head of oncology and palliative medicine at Cardiff University School of Medicine, United Kingdom. Dr. Mason is also chair of the UK National Cancer Research Institute's Prostate Cancer Clinical Studies Group, and was commenting in a statement issued by Cancer Research UK.Particularly for men with advanced prostate cancer, their disease poses a significant threat to their health and their life, and the old notion that 'most men die with it, not of it' is simply not true."
Since that study was carried out, there have been a number of important advances in treatment, Dr. Mason noted. "It is possible that not all of the men in this study who died of prostate cancer would die of it today with modern treatment," he said. In addition, many more men are diagnosed at a much earlier stage; for these men, the outlook is excellent, even without treatment, he added.
Need for Earlier Diagnosis and Treatment
Dr. Thrasher agreed with the conclusion that prostate cancer is not a trivial disease. "This study highlights the fact that prostate cancer can be a deadly disease," he said. "It speaks volumes about what happens when the cancer is advanced and out of the confines of the organ — it will kill you."
These data add weight to the argument for screening for prostate cancer, he said. They reinforce the need for earlier diagnosis and earlier treatment of the disease, and although the PSA test has its problems, it does result in both.
"There is no question that this is happening in the United States; we are finding and treating prostate cancer earlier," he said.
Dr. Thrasher cited 2010 estimates, from the Cancer Journal for Clinicians,that there were 217,000 new cases of prostate cancer diagnosed in the United States and 32,500 cancer deaths, which gives a mortality rate from the disease of 15%. In the United Kingdom, the rate is 50%.
There is a similar situation in Japan, he noted, where there is no routine PSA screening. Dr. Thrasher explained that he recently had the opportunity to talk to Japanese urologists during a joint meeting of the American and Japanese urological associations in Hawaii, and they were saying that by the time they see prostate cancer, it has often advanced to a stage where it is inoperable and not suitable for radiation.
Dr. Thrasher acknowledged that routine PSA testing can lead to the overdiagnosis and overtreatment of prostate cancer that might not be clinically significant. "We are starting to see some pullback as a result of this," he said, and although it is slow to gain ground in the United States, there is more use now of active surveillance as a treatment option, he told Medscape Medical News."We are starting to do this, especially in older men with low-grade, low-volume disease," he said. "However, right now, that is not mainline, and it is not a standard of care," he emphasized: "It is one option."
The very real benefit from PSA testing — finding prostate cancer at an earlier stage of disease, when it is still curable, which saves lives — has to be weighed against the potential for overdiagnosis and overtreatment, and the potential for anxiety from routine testing, he concluded. These latest data from the United Kingdom show that when there is no PSA testing, "you are losing about half your patients to the disease, and so it lends credibility toward leaning the other way," he said.
2011 Meeting of United Kingdom Association of Cancer Registries and National Cancer Intelligence Network (NCIN): Abstract 86. Presented June 16, 2011.

TIME TO THINK ABOUT COST OF CANCER TREATMENT

2011-06-02T12:58:00.000-07:00