NEW GUIDELINES FOR non-STEMI:Hs-TROPONIN-TICAGRELOR-PRASURGEL IN CLOPIDOGREL OUT

August 31, 2011 (Paris, France) — The European task force for the management of ACS patients presenting with non-STEMI has released new guidelines here at the European Society of Cardiology (ESC) 2011 Congress [1]. The guidelines update a previous version issued in 2007, and according to members of the writing group, contain a number of important new recommendations.
Dr Christian Hamm (Kerchkhoff Heart and Thorax Center, Bad Nauheim, Germany), who chaired the task force, noted in a press release that there are a number of "practice-changing" recommendations.
The 56-page document carries through several recommendations from the 2007 update but also includes some novel items.
Chief among them, according to Hamm, is the inclusion of the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) risk score to estimate the risk of in-hospital bleeding.
"It’s probably the best validated score, because it's based on more than 70 000 patients of the CRUSADE registry and was validated in a cohort of [more than] 17 000 patients," Hamm said in a statement.
Dr Magnus Ohman, the sole American on the task force, observed that the new European guidelines, as a product of the timing of trial evidence and regulatory decisions, are also slightly more au courant than the American College of Cardiology (ACC)/American Heart Association (AHA) unstable angina/non-STEMI guidelines released earlier this year, as reported by heartwire .
High-Sensitivity Troponin and CT Angiography
Of note, says Ohman, the guidelines recommend the use of high-sensitivity (hs) troponin assays: a rapid rule-out protocol (within zero to three hours of symptoms) using hs-troponin is given a class Ib recommendation in the new guidelines.
They also, for the first time, support a role for coronary CT angiography (CTA) as an alternative to invasive angiography to exclude ACS in patients with a low to intermediate likelihood of CAD, when both troponin tests and an ECG are inconclusive (class IIa, level of recommendation B).
"Traditionally, when you come in for chest-pain evaluation, you get a stress test, but these new European guidelines have gone one step further in saying that you can use CTA to rule out CAD."
Prasugrel and Ticagrelor
Whereas the ACC/AHA guidelines earlier this year included the newer antiplatelet agent prasugrel (Effient, Lilly), the European guidelines make space for both prasugrel and the new, reversible, P2Y12 inhibitor ticagrelor (Brilique, AstraZeneca). Of note, clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) is now recommended only for patients who cannot take ticagrelor or prasugrel (class Ia).
A proton-pump inhibitor (but "preferably not omeprazole") is recommended for patients taking dual antiplatelet therapy with a history of gastrointestinal bleeding or ulcer and "is appropriate" for patients with multiple risk factors for a GI bleed, the new guidelines say.
To heartwire , Ohman also singled out the inclusion of an urgent invasive strategy based on risk scores in the ESC guidance, for patients who, following initial evaluation and validation, are determined to be at especially high risk. "Traditionally we've said cath within 24 hours for non-STEMI, but [the European guidelines] have done this a bit differently, saying that patients should go to the cath lab within 24 hours if they have a high-grade risk score, and that's new, and there's some new trials to support that."
For "very high-risk patients," an "urgent invasive strategy" (<120 minutes after first medical contact) is warranted, the guidelines state.
Physician: Watch Thyself
Finally, the European guidelines also stress the need for physicians to keep tabs on just how well they are actually adhering to evidence-based guidance. "Continuous monitoring of performance indicators is strongly encouraged to enhance the quality of treatment and minimize unwarranted variations in evidence-based care," Hamm et al write.
According to Ohman, that wording is slightly different from what their American counterparts urged, but the message is the same.
"That's a new concept: it's asking you to examine your practice and actually figure out if you are following guidelines or not. That's a healthy change: we're not just supporting physicians to help them do the right thing; we're saying we should actively examine our own practice and have that kind of internal audit of what we're doing. A similar recommendation was made for the first time in the ACC/AHA guidelines, and I think this is an important change."

CHOCOLATE IS GOOD FOR HEART AND BRAIN

August 29, 2011 (Paris, France) — In a city renowned for its love of food, it is only fitting that researchers presented the results of a new study in Paris, France, showing that chocolate is good for the heart and brain. In a presentation at the European Society of Cardiology (ESC) 2011 Congress, British investigators are reporting that individuals who ate the most chocolate had a 37% lower risk of cardiovascular disease and a 29% lower risk of stroke compared with individuals who ate the least amount of chocolate.
In the study, published online August 29, 2011 in BMJ to coincide with the ESC presentation, Dr Adriana Buitrago-Lopez (University of Cambridge, UK) and colleagues state: "Although overconsumption can have harmful effects, the existing studies generally agree on a potential beneficial association of chocolate consumption with a lower risk of cardiometabolic disorders. Our findings confirm this, and we found that higher levels of chocolate consumption might be associated with a one-third reduction in the risk of developing cardiovascular disease."
In this meta-analysis of six cohort studies and one cross-sectional study, overall chocolate consumption was reported, with investigators not differentiating between dark, milk, or white chocolate. Chocolate in any form was included, such as chocolate bars, chocolate drinks, and chocolate snacks, such as confectionary, biscuits, desserts, and nutritional supplements. Chocolate consumption was reported differently in the trials but ranged from never to more than once per day. Most patients included in the trials were white, although one study included Hispanic and African Americans and one study included Asian patients.
Of the seven studies, five trials reported a significant inverse association between chocolate intake and cardiometabolic disorders. For example, individual studies showed reductions in the risk of coronary heart disease (odds ratio 0.43; 95% CI 0.27–0.68), the risk of cardiovascular disease mortality (relative risk [RR] 0.50; 95% CI 0.32–0.78), and the risk of incident diabetes in men (hazard ratio 0.65; 95% CI 0.43–0.97).
Overall, the pooled meta-analysis results showed that high levels of chocolate consumption compared with the lowest levels of chocolate consumption reduced the risk of any cardiovascular disease 37% (RR 0.63; 0.44–0.90) and stroke 29% (RR 0.71; 0.52–0.98). There was no association between chocolate consumption and the risk of heart failure, and no association on the incidence of diabetes in women.
The researchers note that the findings corroborate the results of previous meta-analyses of experimental and observational studies in different populations showing a similar relationship between chocolate and cocoa consumption and cardiometabolic disorders.
"These favorable effects seem mainly mediated by the high content of polyphenols present in cocoa products and are probably accrued through the increasing bioavailability of nitric oxide, which subsequently might lead to improvements in endothelial function, reductions in platelet function, and additional beneficial effects on blood pressure, insulin resistance, and blood lipids," conclude Buitrago-Lopez and colleagues.

STATINS-A GOOD MEDICINE

August 28, 2011 (Paris, France) — 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 the Lancet 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."

IT HAPPENS EVERYWHERE

August 30, 2011 — Fourteen physicians in southern Florida have been indicted as members of what one agent with the Federal Bureau of Investigation calls "the nation's largest criminal organization" involved in illegally distributing opioid analgesics such as oxycodone.
Thirteen of the physicians, along with 19 other individuals, face federal charges ranging from conspiring to distribute a controlled substance to money laundering. The fourteenth physician, Gerald J. Klein, MD, was charged in a state court on August 18 with, among other things, first-degree murder in the death of a man who overdosed on a massive amount of hydromorphone and alprazolam that Dr. Klein had prescribed, according to authorities.
The 14 physicians worked in 4 pain management clinics that the federal indictment, which was made public August 23, depicts as set pieces in a gangster movie. Drug addicts and drug traffickers, most from out-of-state, packed the waiting rooms, and if they were not fighting each other, they were having drug-induced seizures. Security guards tried to maintain order. Opioid analgesics were dispensed and prescribed on an assembly line basis, and were paid for with cash and credit cards. Clinic employees hauled their money to the bank in large garbage bags. During a 2-year period, the clinics raked in more than $40 million from illegal drug sales, a federal grand jury stated.
The physicians prospered in the process, according to the indictment. The owners of the clinics paid most of them according to how many patients they saw, which ranged between 40 and 100 patients per day. The average physician earned more than $1 million a year this way.
The indictment states that the physicians prescribed opioid analgesics without a basis in medical necessity, but engaged in subterfuges to make it look otherwise. Before their visits, for example, patients were routinely directed to a mobile magnetic resonance imaging facility that operated 7 days a week past midnight in a strip club parking lot.
The clinic owners were careful to recruit physicians who supported their business plan, the indictment states. Applicants did not need any experience in pain management, only a willingness to write scripts every 10 minutes. During employment interviews, "the physicians were asked whether they would agree to prescribe large quantities of oxycodone, Xanax, and other controlled substances."
Once hired, physicians would receive instructions from the owners on the quantity of pain meds that a patient should receive. They agreed to not wean patients off high dosages or refer them to detoxification facilities or addiction experts. One unidentified physician told an investigator that the goal was to keep patients "happy."
Pain Clinic Owner a Convicted Felon
The criminal organization described in the federal indictment extended beyond the 4 pain clinics to encompass 2 drug stores, a pharmaceutical wholesaler that supplied clinic physicians with pain medications, the magnetic resonance imaging facility, illegal Internet sales of anabolic steroids, and a fraudulent time share business. Heading the enterprise, the indictment states, were 2 brothers, Jeffrey George and Christopher George, the second of whom has spent time in prison on drug charges. The George brothers also launched a pain clinic in Georgia and may have eyed expanding their operation to the Midwest, according to the indictment.
In the world of South Florida pain clinics, the George brothers played rough, the grand report alleges, directing coconspirators to vandalize competing facilities. The 2 brothers, along with 2 coconspirators, were charged with kidnapping and assaulting a suspected thief.
The federal government built its case against the George brothers and their accomplices in part by recording conversations with one of the physicians and tapping the cell phone of Christopher George.
"The significance of [the] takedown is that we have dismantled the nation's largest criminal organization involved in the illegal distribution of pain killers," said John Gillies, the bureau's special agent in charge of Miami.
Of the 32 defendants, only Christopher George and Steven Goodman, RPh, owner of the pharmaceutical wholesale company, have entered pleas as of today, according to federal court records. Both men have pleaded not guilty.
Criminal Expansion Into Pharmacies
In all, 32 individuals were indicted a federal district court in southern Florida as part of what authorities called Operation Oxy Alley. The US Department of Justice (DOJ) has recently prosecuted pill mills and their physician prescribers in other parts of the country, but the Florida bust ranks near the top in terms of size.
Gary Boggs, a supervisory special agent in the Office of Diversion Control in the US Drug Enforcement Agency, told Medscape Medical News that Florida is the epicenter of "rogue pain clinics."
One possible reason why Florida is such a magnet for pill mills is the state's high proportion of elderly citizens, said David Melenkevitz, a DOJ spokesperson.
"That population would bring about a large medical community — doctors, pharmacies, and hospitals," Melenkevitz told Medscape Medical News. "So there are a lot of medical professions for these drug dealers to corrupt."
The indictment notes that during the time frame of the alleged offenses (from 2006 to March 2010), Florida lacked a prescription drug monitoring program similar to the kind used in other states to detect drug abuse and diversion. Florida passed a law in 2009 authorizing such a program, but the DOJ states on its Web site that as of May 2011, the Florida program was not fully operational.
Another law enacted in 2010 prohibits felons from owning pain management clinics and limits clinics to dispending no more than a 72-hour supply of medications to a patient who pays in cash. The rationale here is that greenbacks are harder for law enforcement agencies to monitor than credit cards. Making it harder for Florida pill mills to dispense pain medications has caused their owners to open pharmacies, noted Gary Boggs.
The George brothers' enterprise included 2 pharmacies, according to the federal indictment.
The DOJ is cracking down on multibranched pill mill operations in other states. Four physicians, 1 psychologist, and 12 pharmacists working together with 26 pharmacies in Michigan were indicted earlier this month on Medicare and Medicaid fraud charges in connection with the illegal distribution of controlled substances.
Holding Physicians Responsible for Overdoses
The bust in South Florida further demonstrates a willingness of law enforcement authorities to hold physicians responsible for overdose deaths caused by their work in pill mills. Several weeks ago, 2 physicians who once practiced in Colorado were indicted in a federal district court of illegal prescribing that led to 4 deaths.
With the alleged pill mill operation in South Florida, a state grand jury went a step further and indicted Dr. Klein for first-degree murder on account of the overdose death of 30-year-old Joseph Bartolucci. Dr. Klein is accused of prescribing Bartolucci, a repeat patient, with 150 8-mg hydromorphone pills, 30 2-mg alprazolam pills, and 30 25-mg nortriptyline pills in 2009. Bartolucci filled the prescriptions for hydromorphone and alprazolam the same day and was found dead the following day, according to the indictment. An autopsy attributed the death to the 2 drugs.
The state grand jury charged Jeffrey George with second-degree felony murder in Bartolucci's death. George, Dr. Klein, and a third person who is also a defendant in the federal case face various drug-trafficking charges as well.
Federal and state authorities are aggressively prosecuting physicians said to be pawns of pill mill operators, but physicians who prescribe opioid analgesics in good faith to their patients have nothing to fear, said Melenkevitz.
"We're not targeting doctors who make a prescribing mistake on a bad day," he said. "We're targeting drug traffickers who are operating outside the scope of regular medicine."
"They're just drug dealers in white coats," added Boggs.

ANOTHER SECOND LINE CHEMOTHERAPY REGIMEN FOR SCLC

NEW YORK (Reuters Health) Aug 30 - The combination of epirubicin and ifosfamide is effective against relapsed or refractory small-cell lung cancer (SCLC), French researchers reported online August 9th in Lung Cancer.
Both drugs have clinical activity against SCLC, and the combination has been tolerated by patients with non-small cell lung cancer.
"This study validates in our opinion the use of this specific combination as it has a manageable toxicity and a good response profile," Dr. Jean-Louis Pujol from Montpellier Academic Hospital told Reuters Health in an email. "In addition, our results could be regarded as an additional clue in favor of anthracycline therapy in SCLC."
Dr. Pujol and colleagues tested the epirubicin/ ifosfamide combination in 70 patients (median age, 56 years) with SCLC after failure of a first-line regimen.
Fifteen patients (21.4%) had an objective response (including one complete response), and seven patients (10%) had stable disease.
Median overall survival was 3.9 months (which was lower than the 25 weeks reported in a recent study of topotecan monotherapy).
Most patients (71%) developed neutropenia. Thrombocytopenia and anemia were also common. There were three toxic deaths, two from neutropenic infection and one from cardiac failure.
High serum neuron-specific enolase (NSE) and brain metastases were the only independent negative prognostic variables.
"In our opinion, this combination could be proposed to patients with a good performance status, a good cardiac function, and who have had relapsed less than three months after end of first line chemotherapy (usually, Cis-etoposide or carbo-etoposide)," Dr. Pujol said. "This combination is also a good third line after failure of topotecan, a hydrosoluble analog of camptothecin that is active (and approved) in SCLC relapse."
"The first line of treatment in this setting depends upon the delay between the end of first line and time of recurrence," Dr. Pujol added. "When this duration is six months or more, the best is to reinduce the same chemo that had resulted in response induction as first line. Otherwise, our feeling is that in some cases, epirubicin-ifosfamide is the best choice (due to activity of anthracycline in SCLC)."

CHEK2 MUTATION AND BREAST CANCER RISK

NEW YORK (Reuters Health) Aug 30 - Screening for mutations in a gene known as CHEK2 may help determine a woman's odds of breast cancer if the disease runs in her family, Polish scientists suggested Monday.
A woman harboring a CHEK2 mutation, for instance, would have a 34% risk of developing breast cancer if her mother or sister had the disease, they estimate.
But U.S. experts said the test isn't ready for prime time yet, and emphasized that Polish women might be different from Americans.
"It would be premature to tell women that you should all go out and get CHEK2 screening," said Dr. James P. Evans, editor-in-chief of the American College of Medical Genetics' journal Genetics in Medicine.
Still, he called the study "a nice start."
Women with a suspicious pattern of breast or ovarian cancer in the family are already encouraged to get screened for mutations in the BRCA 1 and 2 genes that warn of a heightened tumor risk.
But if those tests come up empty, doctors don't have much to offer, Dr. Diana Petitti, of the Arizona State University in Phoenix, told Reuters Health.
"This does represent an important breakthrough," she said of the new findings. "But this is a field where replication is critical."
The Polish researchers tested the genes of nearly 7,500 women with breast cancer who didn't have BRCA 1 mutations.
They found that three percent had a certain type of mutation in the CHEK2 gene. Among women without breast cancer, less than one percent harbored mutations.
Although CHEK2 has been tied to cancer before, it wasn't clear what role cancer in the family played. When the team asked the women whether they had any affected relatives, those whose mother or sister had had breast cancer were at highest risk.
About one in eight American women -- or some 12% -- will get breast cancer at some point in their lives.
In Poland, that figure is only 6%, Dr. Cezary Cybulski of the Pomeranian Medical University in Szczecin and colleagues write in their report, published online August 29 in the Journal of Clinical Oncology.
From their findings, they estimate that a woman with a CHEK2 mutation has a risk of 20%. If she also has a mother or sister with breast cancer, her risk jumps to 34%, and to 44% if a second-degree relative is also sick.
"CHEK2 mutation screening detects a clinically meaningful risk of breast cancer and should be considered in all women with a family history of breast cancer," the researchers say.
According to Dr. Evans of the American College of Medical Genetics, such tests are already available, likely for less than $100. While that may sound cheap, it adds up quickly, he added.
"If we give this test to all women who have a close relative with breast cancer, you are now talking about a huge expenditure," Dr. Evans told Reuters Health.
At this point, he said, women with a family history of breast cancer would be better off talking to their doctor, or a genetic counselor, to find out what options they have.
Those who have BRCA 1/2 mutations, for instance, may consider having their breasts and ovaries removed, or taking certain medications, to stave off tumors.
Dr. Petitti also struck a cautious note about the new test.
"We are just not there yet," she said. "It's a matter of research at this point."
SOURCE: http://bit.ly/r57Y51
Journal of Clinical Oncology 2011.

A PARADIGM SHIFT IN LUNG ADENOCARCINOMA TREATMENT

September 1, 2011 — The US Food and Drug Administration (FDA) recently granted accelerated approval to crizotinib (Xalkori, Pfizer) for the treatment of patients with advanced-stage nonsmall-cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive.
A companion diagnostic test — the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc.) — was approved concurrently. It is designed to detect rearrangements of the ALK gene, which are found in about 4% to 5% of patients with NSCLC.
This is the first targeted agent to be developed with an accompanying diagnostic test, said Mace Rothenberg, MD, senior vice president of Pfizer's Oncology Business Unit.
The first target discovered was the epidermal growth-factor receptor (EGFR), but at the time the technology wasn't available to test which patients would benefit most from anti-EGRF therapies, he explained during an expert panel discussion sponsored by Pfizer.
Paradigm Shift
Paul Bunn, MD, professor of medicine and James Dudley Chair in Cancer Research at the University of Colorado School of Medicine, in Aurora, who was on the panel, noted that the approval of crizotinib is part of a paradigm shift in the care and management of lung cancer.
"It used to be that everyone with lung cancer was treated the same, but then about 30 years ago, it was discovered that some patients with small-cell lung cancer could be cured with chemotherapy and radiation therapy," said Dr. Bunn. "So lung cancers were then divided into small cell and nonsmall cell."
"More recently, it has been appreciated that lung cancer is a group of heterogeneous diseases with different molecular origins," he explained. "It was then recognized the some lung cancers were driven by EGFR mutations — about 10% to 15% in Western countries. But then in 2007, it was recognized that some lung cancers are driven by the ALK oncogene, which is activated not by a mutation but by a breakage in chromosome 2 and a refusion of the 2 genes in the opposite direction."
The current paradigm is that the molecular features of a tumor have to be considered, not just histology, to select patients for the appropriate treatment, Dr. Bunn emphasized.
There are now 2 molecular subsets of lung cancer patients with specific therapies, namely those with EGFR and ALK mutations.
Research coming out of the Lung Cancer Mutation Consortium has shown that almost 60% of patients with adenocarcinoma have 1 of 10 genomic abnormalities for which there is a drug. "We have 2 drugs approved now for 2 molecular abnormalities. The question is, will we go 10 for 10?" he asked.
There is also the question of being able to test patients for all 10 molecular abnormalities, but Dr. Bunn pointed out that technology is now moving as fast as drug development. "It is possible now to test for all 10 at a cost that is cheaper than it used to cost for testing for 1 in the past," he said.
Fantastic Development
Mark G. Kris, MD, chief of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center in New York City, noted that this is a "fantastic development."
"I see this as a delivery on the promise of personalized medicine and genomic medicine," he said during the panel discussion. "Clinical trials have shown that virtually every patient with an ALK fusion who received crizotinib has had some benefit. It is very effective."
By testing for the ALK fusion gene, it is almost guaranteed that there will be some benefit, although the degree of benefit can vary, he noted. Conversely, if a patient lacks the ALK fusion gene, then crizotinib is not likely to demonstrate any efficacy. "This will be sparing individuals side effects, as well as not wasting time and resources for taking a drug that is not going to help them," he said.
Dr. Kris pointed out that there has been a lot of attention focused on the fact that only a small percentage of patients have the ALK fusion gene. "But in terms of lung cancer, even though the percentage is small, the numbers are quite large," Dr. Kris explained. "It is estimated that in United States alone, there are somewhere between 6,000 and 11,000 new patients each year who have an ALK fusion gene. To put that into perspective, that's more people than would have Hodgkin's disease, more patients than would have testicular cancer, and more patients than would have chronic myelogenous leukemia — all serious diseases where we have made important inroads."
Safety and Efficacy Established
The safety and efficacy of crizotinib were established in 2 multicenter, single-group studies that enrolled 255 patients with locally advanced or metastatic ALK-positive NSCLC: a phase 2 study (PROFILE 1005) and a part 2 expansion cohort of a phase 1 study (Study 1001).
In PROFILE 1005 (n = 136), the objective response rate (ORR) was 50%, and that included 1 complete response and 67 partial responses. The median duration of treatment was 22 weeks, and 79% of objective tumor responses were achieved during the first 8 weeks of treatment.
In Study 1001 (n = 119), the ORR was 61%, and that included 2 complete responses and 69 partial responses. The median duration of treatment was 32 weeks, and 55% of objective tumor responses were achieved during the first 8 weeks of treatment.
Expensive But...
Like many targeted therapies, crizotinib comes with a hefty price tag. According to Geno Germano, president and general manager of specialty care and oncology at Pfizer, the drug will cost $9,600 per month, or $115,000 per year.
But Mr. Germano pointed out that with the approval of crizotinib, treatment will be improved. "We are going to be treating patients more effectively and avoiding treatments that don't work," he said.
He also noted that Pfizer has devised a number of programs to help with the cost. "We realize that we have to be attentive to the individual needs of each patient," he said.
Pfizer's initiatives would cut some patients' share of that cost significantly. The company is offering copay assistance of up to $24,000 per year with a program that would have privately insured patients pay only $100 per prescription. For example, if a patient has a 20% copay, that would cover a full year of treatment.
Pfizer has said it will also help patients who are uninsured or insured by Medicaid or Medicare figure out how to cover the cost of crizotinib. However, the assistance programs do not help payers cover their costs.
ALK Gene Test
The companion diagnostic test approved along with crizotinib uses Abbott's fluorescence in situ hybridization (FISH) technology to detect rearrangements of the ALK gene on the 2p23 chromosome.
It offers clinicians a standardized, clinically validated method of identifying the patients most likely to benefit from the therapy. Experts have predicted that the simultaneous FDA approvals will change clinical practice for the diagnosis and treatment of patients with NSCLC.
"The Abbott ALK FISH test was developed in conjunction with Pfizer and the clinical trials for crizotinib," said Kathryn B. Becker, PhD, director of Abbott Molecular Oncology. "It was configured to work specifically in NSCLC patients, and we have ensured that it is a very high-quality product that is reproducible."
The cost of the test is in line with other clinically validated assays of this type, and will be less than $250 per patient. "We believe that the test brings an extremely high value to this patient population and the outcome of the therapeutics," Dr. Becker said.
Dr. Becker also feels that this test will eventually be widely used. "In the clinic today, a number of biomarkers are commonly being tested for," she said. "We believe that the Abbott ALK FISH test will become a standard part of testing for nonsmall-cell lung cancer patients, along with EGFR mutations and KRAS status."
Both the diagnostic test and crizotinib were accelerated approvals. "The fact that Pfizer and Abbott were able to work together, in concert with the FDA, to bring both the therapeutic and the diagnostic to approval so early is a testament to the way that Pfizer and Abbott have communicated and collaborated throughout this whole process," she added. "It has been a great pleasure working with Pfizer. We had a really interactive collaboration; without that, we may not have been that successful."

 

DEPAKINE USE MAY INCREASE SURVIVAL IN GLIOBLASTOMA

September 1, 2011 — A new study suggests that use of the antiepileptic drug (AED) valproic acid may improve survival among patients with newly diagnosed glioblastoma receiving temozolomide radiochemotherapy vs other such drugs or no treatment.
Retrospective analysis of the pivotal European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) clinical trial showed those receiving valproic acid with temozolomide radiochemotherapy survived an average of 3 months longer than those taking other enzyme-inducing AEDs or receiving no AED treatment.
This effect wasn’t seen among patients who received radiotherapy alone. Those receiving valproic acid, though, had higher rates of thrombocytopenia, leukopenia, and neutropenia than those taking other or no AEDs.
"Despite the limitations of this retrospective analysis, these results suggest that the choice of AED in patients with brain tumors should be carefully considered because it may affect survival," the authors, led by Michael Weller, MD, from the University Hospital Zurich, Switzerland, conclude.
This observation also further supports a recent trend to favor a non-enzyme-inducing AED for patients with a malignancy to allow administration of modern chemotherapy and targeted agents that often show increased hepatic metabolism if patients are given an enzyme-inducing agent, they add.
The study was published online August 31 in Neurology.
"Thoughtful" Use of Antiepileptic Drugs
Seizures occur in up to 50% of patients with glioblastomas, the researchers report. There are many considerations to the "thoughtful" use of AEDs in these patients, they note, including the resistance of the seizure disorder, drug-to-drug interactions and side effects.
Rash, drowsiness, or other cognitive alterations may affect the patients’ quality of life, they point out, and drug interactions with chemotherapy are a concern because of overlapping hematologic toxicity or hepatic enzyme induction or inhibition.
"Notably, the older AEDs such as phenytoin, phenobarbital, or carbamazepine will induce a number of coenzymes of the cyto-chrome P450 system and may thus enhance the metabolism of many commonly administered chemotherapy agents as well as corticosteroids," the authors write. "Conversely, the enzyme-inhibiting effect of valproic acid appears clinically of lesser importance although increased myelosuppression may develop in patients receiving nitrosoureas or cisplatinum-based chemotherapy concomitantly."
Intrinsic antitumor activity of certain AEDs and synergy with chemotherapy or radiotherapy has been suggested in some, but not all, studies, they point out. For instance, phenytoin has been attributed antimitotic and anti-invasive properties, and valproic acid has been suggested to induce cell differentiation, growth arrest, and apoptosis mediated by its histone deacetylase–inhibiting properties.
A recent retrospective analysis of 3 trials performed by the North Central Cancer Treatment Group and published in 2009 suggested a possible association of enzyme-inducing AED use with a favorable outcome in patients with glioblastoma, Dr. Weller and coauthors write. "This observation prompted us to assess a potential predictive value on outcome of the AED used within the pivotal trial of concomitant and adjuvant temozolomide and radiotherapy, the current standard of care."
The EORTC/NCIC clinical trial database of radiotherapy with or without temozolomide for newly diagnosed glioblastoma was examined to look for the effect of any interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors.
When treatment began, they write, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED, and 135 (23.4%) were taking any non-enzyme-inducing AED.
Patients receiving valproic acid only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an enzyme-inducing AED only, they report.
The overall survival of patients who were receiving an AED at baseline vs those not receiving any AED was similar, the authors note. However, patients receiving valproic acid alone appeared to derive more survival benefit from temozolomide radiochemotherapy than patients receiving only an enzyme-inducing AED, or those not receiving any AED.
Survival With Temozolomide Radiochemotherapy by AED Treatment

AED	Survival, n (%)	Hazard Ratio (95% CI)
Valproic acid	97 (16.9)	0.39 (0.24 - 0.63)
Enzyme-inducing AED	252 (44)	0.69 (0.53 – 0.90)
No AED	–	0.67 (0.49 - 0.93)

CI = confidence interval
Valproic acid may be preferred over an enzyme-inducing AED in patients with glioblastoma who require an AED during temozolomide-based chemoradiotherapy, they conclude. "Future studies are needed to determine whether [valproic acid] increases [temozolomide] bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo."
Jury Still Out?
In an editorial accompanying the paper, Patrick Y. Wen, MD, from the Department of Neurology at Brigham and Women’s Hospital and Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts, and David Schiff, MD, from the University of Virginia Medical Center in Charlottesville, write that although the results are "intriguing," they should still be interpreted with caution until further information becomes available.
First, they point out, as the researchers also do, that the results are from an unplanned retrospective analysis and that the study was underpowered and not randomized.
The finding that median overall survival in the radiation-alone group was worse in patients receiving valproic acid, at 10.1 months, than in those receiving enzyme-inducing AEDs (12.5 months) and those without an AED (12.0 months), they write, "is surprising and raises the possibility that the apparent benefit of [valproic acid] with radiation and temozolomide occurred by chance."
In addition, they note, valproic acid was associated with a higher rate of hematologic toxicity during adjuvant temozolomide therapy and almost twice as many patients required delays in their treatment cycles.
"Fortunately, additional data addressing this issue may be forthcoming from analysis of the recently completed Radiation Therapy Oncology Group phase 3 trial (RTOG 0525) comparing standard adjuvant temozolomide vs a dose-dense regimen, as well as phase 2 trials of [valproic acid]…and the HDAC [histone deacetylase] inhibitor vorinostat…with radiation therapy and temozolomide for newly diagnosed glioblastoma," Dr. Wen and Dr. Schiff conclude.
"Until data from these studies become available, it is unclear whether the potential survival benefit of [valproic acid] outweighs the definite increase in hematologic toxicity."
The study was supported by the National Cancer Institute in the United States and a grant from the Swiss Cancer League to the European Organisation for Research and Treatment of Cancer Charitable Trust in Switzerland. Dr. Weller serves on scientific advisory boards for Roche, Merck Serono, Merck & Co., Inc., OncoMethylome Sciences, Exelixis Inc., and Bristol-Myers Squibb; received funding for travel or speaker honoraria from Roche, Merck Serono, Schering Plough Corp., and Merck & Co., Inc.; serves as European Editor for the Journal of Neuro-Oncology and on the editorial boards of Glia, Journal of Neuro-Oncology, Journal of Neurochemistry, and Cellular Physiology & Biochemistry; and receives research support from Roche, Merck Serono, Schering Plough Corp., and Merck & Co., Inc. Disclosures for other coauthors appear in the article.

Dr. Wen serves on scientific advisory boards for Merck, Genzyme Corp., Eli Lilly and Co., and Novartis; received funding for travel or speaker honoraria from Merck; serves as an Associate Editor for the Journal of Neuro-Oncology; and receives research support from Merck, Genentech, Inc., AstraZeneca, Medimmune, Amgen, VBL Therapeutics, and Novartis. Dr. Schiff served on a scientific advisory boards for Genentech, Inc., VBL Therapeutics, and Merck; serves on the editorial board of Neurology; receives publishing royalties from UpToDate; and serves as a consultant for Tau Therapeutics.
Neurology. 2011;77:1156-1164. Abstract

ZOLEDRONIC ACID KIDNEY RISK WARNING

September 1, 2011 — Zoledronic acid (Reclast, Novartis Pharmaceuticals), an injectable bisphosphonate used to prevent and treat osteoporosis, is now contraindicated for patients with creatinine clearance below 35 mL/min or evidence of acute renal impairment, according to a label change announced today by the US Food and Drug Administration (FDA).
The revision, which also includes an updated warning on kidney impairment, comes in the wake of continued cases of fatal acute renal failure associated with the drug.
Novartis Pharmaceuticals also sells zoledronic acid under the brand name Zometa as a treatment of cancer-related indications, but the labeling changes unveiled today apply only to Reclast. The label for Zometa already contains a warning about renal toxicity.
Patients who take zoledronic acid and have underlying moderate to severe renal impairment are at risk for renal failure — a rare adverse event — and this risk increases with age, according to the agency. Other risk factors for renal failure are severe hydration occurring before or after infusion with zoledronic acid and concurrent use of kidney-damaging or diuretic medications.
In 2009, an FDA postmarket safety review identified 5 patients who died of acute renal failure after being treated with zoledronic acid. The FDA revised the drug’s label that year to include reports of renal impairment from clinical studies, and a recommendation to monitor serum creatinine before each infusion of the drug.
Another agency review earlier this year identified 11 more fatal cases of acute renal failure after zoledronic-acid infusion, as well as 9 cases of renal injury that required dialysis.
The FDA is advising clinicians to continue to screen patients prior to each dose of zoledronic acid to spot those with underlying acute or chronic renal impairment, or dehydration, and to pay attention to their age.

SOME PATIENTS WITH ER+ CAN FORGO ADJUVANT TREATMENT

August 31, 2011 — Some older women with hormone-responsive breast cancer can forgo adjuvant endocrine and chemotherapy and not be at increased risk for mortality, according to a Danish study published online today in the Journal of the National Cancer Institute.
In the study, the investigators analyzed 3197 systemically untreated early breast cancer patients of all ages who had hormone-responsive node-negative disease and tumors of 20 mm or less.
The national guidelines of the Danish Breast Cancer Cooperative Group dictate that such patients not be treated with systemic adjuvant therapy.
The investigators found that women in this group who were 60 years or older with grade 1 tumors measuring up to 10 mm (n = 458) were not at increased risk for mortality, compared with women in this age group in the general population in Denmark (adjusted relative risk, 1.02; 95% confidence interval [CI], 0.89 to 1.16).
Thus, there was a "small subgroup" of women in the study "who experience a prognosis similar to the background population of women even without systemic adjuvant therapy," write the authors, led by Peer Christiansen, MD, from the Aarhus University Hospital in Denmark.
In an accompanying editorial, 2 American experts emphasize that such women are a minority of breast cancer patients.
The women who "do not stand to gain any survival benefit from systemic adjuvant therapy" represent a "very small fraction" of the women in the study, say Jennifer Griggs, MD, and Daniel Hayes, MD, from the University of Michigan Cancer Center in Ann Arbor. Furthermore, they are "an even smaller proportion of the overall population of women diagnosed with breast cancer," they write.
Lead author Dr. Christiansen echoed those comments: "In Denmark, 85% of all patients with breast cancer have hormone-receptor-positive tumors. The low-risk group of patients, which we identified in our study, makes up less than 10% of the total population of breast cancer patients," he told Medscape Medical News.
Challenge to Prevailing Opinion
Small numbers aside, the findings represent a challenge to prevailing opinion in breast cancer, suggest the study authors.
"The Panel at the 2009 St. Gallen International Breast Cancer Conference [in Switzerland] recommended adjuvant endocrine treatment in almost all patients whose tumors show evidence of endocrine responsiveness," they observe. "The present results indicate that there is a small subgroup of node-negative patients who might not benefit from such an approach."
At the same time, the study suggests that adjuvant systemic therapy is potentially life-saving treatment in many women with early breast cancer.
In the study, younger women and those with larger tumors had increased mortality rates.
Compared with the general population of age-matched women, the mortality rate was associated with larger tumor size (11–20 mm vs 1–10 mm; standard mortality rate [SMR], 1.42) and with age (35 to 59 years; SMR > 1).
Overall, women with breast cancer had higher mortality rates than the general population, the investigators found. In the study population, there were 970 deaths; the expected number of deaths was 737, which is an excess mortality of 233 deaths (SMR, 1.32; 95% confidence interval [CI], 1.24 to 1.40). Mortality rates were 2356 per 100,000 person-years in the study population and 1790 per 100,000 person-years in the general population of women.
The median follow-up after surgery was 14.8 years. The breast cancers were diagnosed between 1989 and 2001 and were tracked in the Danish Breast Cancer Cooperative Group database.
Not Unprecedented
Other research has found that adjuvant endocrine therapy does not reduce the risk for mortality in patients with very small node-negative hormone-receptor-positive breast cancer, observe Drs. Griggs and Dr. Hayes in their editorial. The reason for that is "because the risk of mortality is already extremely low," they note.
They cite an example of the mixed results that endocrine therapy has in women with low-risk tumors.
A study from the National Surgical Adjuvant Breast and Bowel Project (NSABP B-21) was designed to identify the role of tamoxifen and breast radiation on risk for recurrence in women with breast cancers measuring 10 mm or more in greatest dimension. "Radiation therapy and tamoxifen were effective in reducing the risk of ipsilateral recurrence, and tamoxifen was effective in reducing the risk of contralateral breast events. Tamoxifen was not associated, however, with a reduction in the risk of distant metastases," they summarize.
They note that this study and others beg the question: Whom should be treated with systemic therapy?
"The stakes in these clinical decisions are high," the editorialists say, because "omitting adjuvant therapy might allow an otherwise preventable recurrence and therefore loss of curative potential."
This study helps identify patients who might forgo systemic adjuvant treatment, say both the study authors and the editorialists. Both also say that the study is limited by the lack of immunohistochemical tumor characteristics and gene profiling.
"Data on HER2, topoisomerase (DNA) II alpha (TOP2A), and Ki67 expression would have allowed us to make a more exact evaluation of the data and to perform a more precise definition of a group of patients completely matching the current low-risk criteria," say the study authors.
Research into which patients can forgo chemotherapy, which is more toxic than endocrine therapy, has included studies that look at single-gene proliferative markers, such as Ki67 and multiparameter assays (e.g., the 21-gene recurrence score), "which can quantify the risk of distant recurrences in patients who take adjuvant tamoxifen," write Drs. Griggs and Hayes. "Such tumor attributes have the potential to identify node-negative hormone-receptor-positive patients with such a favorable prognosis that they should be treated with endocrine treatment only and simply do not require chemotherapy," they write.
The Danish study shows that some women with "very low-risk invasive cancers" are "exceedingly unlikely" to "reap a survival benefit" from either form of systemic treatment, the editorialists write. Still, they emphasize that patients and their preferences play a "critical role in decision-making" with regard to possibly forgoing endocrine therapy.
The editorial writers were supported in part by grants from the National Cancer Institute and the Fashion Footwear Charitable Foundation of New York.
J Natl Cancer Inst. Published online August 31, 2011. Abstract, Editorial