Chemotalk Newsletter, Vol. 40: August 1, 2011
How sweet it is, to start off with good news!:
MEDICARE WILL CONTINUE TO COVER 2 EXPENSIVE CANCER DRUGS
By Andrew Pollack
Medicare confirmed that it would continue to pay for two expensive cancer drugs that had been at the center of debate -- Avastin from Genentech for BREAST CANCER and Provenge from Dendreon for PROSTATE CANCER.
A spokesman for the Centers for Medicare and Medicaid Services said the agency would continue to pay for Avastin for breast cancer, even if the Food and Drug Administration revoked the drug's approval as a treatment for that disease.
"The label change will not affect our coverage," the spokesman, Don McLeod, said.
An advisory committee to the F.D.A. voted unanimously in favor of rescinding the breast cancer approval, saying the latest evidence suggested the drug was not effective. The final decision will be made by the F.D.A. commissioner, Dr. Margaret A. Hamburg, after a public comment period ends on July 28 (2011).
Avastin would retain approval for other cancers so doctors could still use it off label for breast cancer. But some women fear that insurers will no longer pay for the drug, putting the medicine, which costs about $88,000 a year, out of reach for most women.
Mr. McLeod's statement could allay those concerns, at least for women covered by Medicare. He said that Medicare commonly paid for off-label use of cancer drugs. Still, Mr. McLeod said that while there were no plans for one right now, he could not totally rule out that Medicare might one day undertake a national coverage determination to decide whether to pay for Avastin. That process would take at least a year and involve public input.
Such a national coverage determination was undertaken for Provenge, which costs $93,000 for a complete course of treatment.
The final decision said the evidence was adequate to conclude that Provenge "improves health outcomes for Medicare beneficiaries" and was therefore "reasonable and necessary" for their treatment. The result confirmed a preliminary decision announced three months ago.
The decision applies to men who meet the criteria in the drug's label, meaning the cancer has spread beyond the prostate gland, it is no longer controlled by hormone therapy and the men have few or no symptoms.
The national coverage determination drew outcries from some men with prostate cancer, investors in Dendreon and critics of health care reform, who said the government was singling out the drug because of its cost and was on its way to rationing health care. Similar accusations about rationing greeted the F.D.A.'s proposal to remove the breast approval for Avastin.
Both Medicare and the F.D.A. said the costs of the drugs were not a factor in their deliberations.
Private insurance companies must also decide whether to continue paying for Avastin as a breast cancer treatment.
WellPoint said it would review the medical necessity after the F.D.A. makes its final determination.
Cigna and the Health Care Service Corporation, which operates Blue Cross and Blue Shield plans in Illinois, Texas, Oklahoma and New Mexico, both said they would evaluate their coverage positions after the F.D.A. made a final decision.
UnitedHealthcare said its CHEMOTHERAPY coverage decisions were based on a reference published by the National Comprehensive Cancer Network. That reference lists Avastin as a valid treatment for breast cancer.
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On the other side, this story is pretty frightening:
HOW BRIGHT PROMISE IN CANCER TESTING FELL APART
By Gina Kolata
When Juliet Jacobs found out she had LUNG CANCER, she was terrified, but realized that her hope lay in getting the best treatment medicine could offer. So she got a second opinion, then a third. In February of 2010, she ended up at Duke University, where she entered a research study whose promise seemed stunning.
Doctors would assess her tumor cells, looking for gene patterns that would determine which drugs would best attack her particular cancer. She would not waste precious time with ineffective drugs or trial-and-error treatment. The Duke program -- considered a breakthrough at the time -- was the first fruit of the new genomics, a way of letting a cancer cell's own genes reveal the cancer's weaknesses.
But the research at Duke turned out to be wrong. Its gene-based tests proved worthless, and the research behind them was discredited. Ms. Jacobs died a few months after treatment...
The episode is a stark illustration of serious problems in a field in which the medical community has placed great hope: using patterns fro large groups of genes or other molecules to improve the detection and treatment of cancer. Companies have been formed and products have been introduced that claim to use genetics in this way, but assertions have turned out to be unfounded. While researchers agree there is great promise in this science, it has yet to yield many reliable methods for diagnosing cancer or identifying the best treatment.
`Instead, as patients and their doctors try to make critical decisions about serious illnesses, they may be getting worthless information that is based on bad science. The scientific world is concerned enough that two prominent groups, the National Cancer Institute and the Institute of Medicine, have begun examining the Duke case; they hope to find new ways to evaluate claims based on emerging and complex analyses of patterns of genes and other molecules.
So far, the Food and Drug Administration "has generally not enforced" its regulation of tests created by individual labs because, until recently, such tests were relatively simple and relied heavily on the expertise of a particular doctor, said Erica Jefferson, a spokeswoman for the agency. But now, with labs offering more complex tests on a large scale, the F.D.A. is taking a new look at enforcement.
Dr. Scott Ramsey, director of cancer outcomes research at the Fred Hutchinson Cancer Center in Seattle, says there is already "a mini-gold rush" of companies trying to market tests based on the new techniques, at a time when good science has not caught up with the financial push. "That's the scariest part of all," Dr. Ramsey said.
Doctors say the heart of the problem is the intricacy of the analyses in this emerging field and the difficulty in finding errors. Even well-respected scientists often "oversee a machine they do not understand and cannot supervise directly" because each segment of the research requires different areas of expertise, said Dr. Lajos Pusztai, a BREAST CANCER researcher at M.D. Anderson Cancer Center at the University of Texas. As a senior scientist, he added, "It's true for me, too."
The Duke case came right after two other claims that gave medical researchers pause. Like the Duke case, they used complex analyses to detect patterns of genes or cell proteins. But these were tests that were supposed to find ovarian cancer in patients' blood. One, OvaSure, was developed by a Yale scientist. Dr. Gil G. Mor, licensed by the university and sold to patients before it was found to be useless.
The other, OvaCheck, was developed by a company, Correlogic, with contributions from scientists from the National Cancer Institute and the Food and Drug Administration. Major commercial labs licensed it and were about to start using it before two statisticians from M. D. Anderson discovered and publicized its faults.
The Duke saga began when a prestigious journal, Nature Medicine, published a paper on Nov. 6, 2006, by Dr. Anil Potti, a cancer researcher at Duke University Medical Center; Joseph R. Nevins, a senior scientist there; and their colleagues. They wrote about genomic tests they developed that looked at the molecular traits of a cancerous tumor and figured out which chemotherapy would work best.
Other groups of cancer researchers had been trying to do the same thing.
"Our group was despondent to get beaten out," said Dr. John Minna, a lung cancer researcher at the University of Teas Southwestern Medical Center. But Dr. Minna rallied; at the very least, he thought, he would make use of this incredible discovery to select drugs for lung cancer patients.
First, though, he asked two statisticians at M. D. Anderson, Keith Beggerly and Kevin Coombes, to check the work. Several other doctors approached them with the same request.
Dr. Baggerly and Dr. Coombes found errors almost immediately. Some seemed careless -- moving a row or a column over by one in a giant spreadsheet -- while others seemed inexplicable. The Duke team shrugged them off as "clerical errors."
And the Duke researchers continued to publish paper on their genomic signatures in prestigious journals. Meanwhile, they started three trials using the work to decide which drugs to give patients.
Dr. Baggerly and Dr. Coombes tried to sound an alarm. They got the attention of the National Cancer Institute, whose own investigators wanted to use the Duke system in a clinical trial but were dissuaded by the criticisms. Finally, they published their analyses in The Annals of Applied Statistics, a journal that medical scientists rarely read.
The situation finally grabbed the cancer world's attention last July, not because of the efforts of Dr. Baggerly an Dr. Coombes, but because a trade publication, The Cancer Letter, reported that the lead researcher, Dr. Potti, had falsified parts of his resume. He claimed, among other things, that he had been a Rhodes scholar.
"It took that to make people sit up and take notice," said Steven Goodman, professor of oncology, pediatrics, epidemiology and biostatistics at Johns Hopkins University.
In the end, four gene signature papers were retracted. Duke shut down three trials using the results. Dr. Potti resigned from Duke. He declined to be interviewed for this article. His collaborator and mentor, Dr. Nevins, no longer directs one of Duke's genomics centers.
The cancer world is reeling.
The Duke researchers had even set up a company -- now disbanded -- and planned to sell their test to determine cancer treatments. Duke cancer patients and their families, including Mr. Jacobs's husband, Walter Jacobs, say they feel angry and betrayed. And medical researchers see the story as a call to action. With such huge data sets and complicated analyses, researchers can no longer trust their hunches that a result does -- or does not -- make sense.
"Our intuition is pretty darn poor," Dr. Baggerly said.
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IMPLANTED NECK DEVICE MAY BE FUTURE TREATMENT FOR RHEUMATOID ARTHRITIS
Up to now, most arthritis treatments have involved pills, injections, or surgery. But the Academic Medical Centre in Amsterdam is studying a new approach for treating RHEUMATOID ARTHRITIS that would involve implanting a pacemaker-like chip in the neck of the patient. The implanted device would inhibit joint inflammation, based on the theory that rheumatoid arthritis symptoms are caused by interactions between the nervous system and immune system.
Ten study participants from several European countries will have the device implanted in their necks, to stimulate the vagus nerve (one of the cranial nerves). Vagus nerve stimulation has been used to treat epilepsy and depression. Researchers suggest that stimulating the nerve for one minute a day will inhibit inflammation and slow joint damage. The Dutch Arthritis Association is reportedly "cautiously optimistic" as they await results which the researchers hope to publish next year.
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There are no easy answers, and almost no home runs, when it comes to cancer treatment. As witnessed:
ADD PATIENCE TO A LEAP OF FAITH TO DISCOVER CANCER SIGNATURES
By Gina Kolata
Over the past several years, scientists have begun looking not just for individual genes linked to cancer, but for collections of genes and molecules, like proteins, that form telltale patterns, or signatures, that can be used to identify a cancer cell and reveal what drugs might kill it.
Signatures can be used to diagnose the disease, scientists hope, and to give a prognosis to patients who have CANCER. But there have been few successes in this brave new world of cancer research, and some notable failures.
Genetic tests devised at Duke University by researchers using the new methodology have turned out to be worthless, though they were once hailed as breakthroughs. Two new blood tests for OVARIAN CANCER have also been abandoned.
Despite the setbacks, researchers say they cannot give up on their quest for cancer signatures. Dr. Lajos Pusztai, a BREAST CANCER researcher at the University of Texas MD Anderson Cancer Center, is one of them.
How many new drugs, he asks, were approved for breast cancer treatment in the past decade? His answer: seven. None was much different from drugs already on the market.
Yet in the same decade, he said, there were 8,000 publications in medical and scientific journals on breast cancer and more than 3,000 clinical trials at a cost of over $1 billion. "What came out of this is seven 'me too' drugs," Dr. Pusztai said.
Yes, there have been studies showing single genes can go awry and fuel certain cancers, he and other scientists say. And yes, those studies have led to new drugs, so-called targeted therapies, that block the genes, extending the lives of some patients with some types of cancer.
But for a major advance in the way cancer is diagnosed and treated, Dr. Pusztai and other researchers believe that work must continue on genomic signatures. It's a very different sort of science, an elaborate enterprise that involves complicated analyses of patterns of genes or other components of cells.
The hunt for cancer signatures also is a type of work that requires a leap of faith. It is impossible for scientists to use their intuition to know whether a signature has any biological meaning -- it is just a pattern, and the meaning comes from its statistical association with a result.
By looking for these signatures, scientists are looking for a sort of next generation of biomarkers, and biomarkers have a troubled history in cancer research.
About 15 years ago, when the world was simpler, the American Society for Clinical Oncology called together a group of experts and asked them to develop some guidelines. Which cancer biomarkers are useful for making clinical decisions?
Dr. Daniel Hayes, a breast cancer researcher at the University of Michigan, was part of the group.
"We all kind of sat around and looked at each other and said, 'We have no idea how to do this,'" Dr. Hayes recalled. The field of tumor biomarkers, he said, "had been so chaotic." All too often, researchers claimed to have discovered reliable ways to identify a particular cancer, but studies confirming they were valid had never been done.
The group ended up writing a paper with what they called a "level of evidence scale" outlining the results they needed before they would believe a claim. Only a handful of tumor biomarkers met their criteria.
Yet, Dr. Hayes said, "during that time there had been hundreds of putative markers reported for breast cancer alone, let alone other diseases."
With genomic signatures, the situation is more involved than it was 15 years ago, but many of the same problems remain, Dr. Hayes and others say.
Signatures can be used to identify cancer cells in the way a tartan can identify a Scottish clan, Dr. Hayes said. "Each tartan is composed of threads of several different colors, but when woven into a single cloth, resents a distinctive pattern or signature that distinguishes one clan from another," he said.
Yet the tools used to find signatures are so complex they can be misleading if the results are not tested properly. Investigators look for patterns in a huge arrays of genes or proteins or RNA molecules, and they constantly find spurious associations with cancer that look for all the world like true ones.
"The question is, what is noise and what is real" said Dr. Steven Goodman, a biostatistician at Johns Hopkins University. In these studies, he added, "you are guaranteed to find things," and almost always what is found is nonsense.
Gene or protein patterns, said Donald Berry, a statistician at MD Anderson Cancer Center, "are very difficult to get right." Finding them, he said, "is like looking for a needle in a haystack when you can't tell the needle from the hay."
Adding to the confusion is that the research requires a group of experts, each of whom has a different, highly technical skill. Each person on a team may be so specialized that no one is qualified to know exactly what his or her colleagues are doing.
Dr. Pusztai's team, for instance, includes pathologists, molecular biologists and biostatisticians. "No one person on the team sees all the pieces together," he said.
For example, he said, just analyzing cancer tissue for a genomics study involves 200 to 3,000 steps and takes several days to complete. "Any one of these steps can go wrong, and a good researcher should know what can influence the success of each step and control for the quality," he said.
What comes out of this analysis is "reams of numbers," Dr. Pusztai said. "If one were to print these out it would amount to thousands of pages. The interpretation of these numbers is purely statistical and mathematical."
Even when researchers find a real association, it may not be clinically useful. A genomic signature test that correctly identifies most tumors that will respond to a drug but incorrectly identifies others may not be of net benefit to patients.
What is needed, and what rarely has been done, is research to see if a test based on a new biomarker does more good than harm.
It's expensive and time-consuming, but it is the sort of evidence-gathering that is almost always done to see if a new drug is effective, Dr. Hayes noted. Yet there is little incentive to evaluate biomarkers, because the Food and Drug Administration does not require it and companies are not reimbursed as much for tests based on biomarkers as they are for new cancer drugs.
"There is a whole series of things in this cycle that need to be broken," Dr. Hayes said.
One step that could make a big difference, scientists said, would be for researchers who think they have found a new genome signature for cancer to publish enough of their data and analysis for others to verify their work. Surprisingly few have done so.
The only reason the Duke research was discovered to be flawed, in fact, was that it relied on publicly available data sets and algorithms. Even so, unraveling the details of the work was so complicated that it took Keith Baggerly and Kevin Coombes, two statisticians at MD Anderson, 2,000 hours to find all the errors.
Perhaps illustrating the perils of the needle-in-a-haystack approach, the only two genomic signatures for cancer that have been validated, used in the tests Oncotype DX and MammaPrint, were discovered in a very different ways.
In both cases, researchers started with hundreds of genes that they had some reason to believe were important. They winnowed the collection down to those that seemed to be clinically useful. The Oncotype DX assay relies on 21 genes, and MammaPrint on 70. Both companies then rigorously tested their signatures to be certain that they were accurate in women with breast caner. Oncotype DX showed its signature could predict prognosis and whether women would benefit from CHEMOTHERAPY.
Yet two signatures used to make these tests have just one gene in common.
"What it means, as I suppose everybody is beginning to know, is that cancer is a very complicated thing," Dr. Berry said.
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BIOGEN IDEC WINS EUROPEAN APPROVAL FOR MS DRUG
Biogen Idec received conditional regulatory approval in Europe to market its drug Fampyra, a treatment to improve walking in patients with MULTIPLE SCLEROSIS.
The European Commission approved the company¹s tablet based on studies showing it increased walking speed up to 25 percent in adults with multiple sclerosis. The approval is conditional and regulators are requiring the company to conduct a long-term, follow-up study of the drug¹s benefits. The approval will have to be renewed annually until full approval is granted.
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Ending this month with some positive news:
SYMPTOM IMPROVEMENT OBSERVED AFTER VENOPLASTY IN MS PATIENTS
Preliminary data from a series of MULTIPLE SCLEROSIS patients who underwent percutaneous transluminal venoplasty to treat chronic cerebrospinal venous insufficiency suggest that the treatment was safe and offered significant disease-specific and quality of life improvements.
The results of the controversial treatment on 125 patients in the series will need to be validated with future randomized, blinded, controlled trials that evaluate endovascular and surgical options, Dr. Manish Mehta said at the Vascular Annual Meeting.
The patient series follows Dr. Paolo Zamboni¹s identification in 2009 of stenoses in the internal jugular veins and azygous vein of patients with MS.
"Dr. Zamboni¹s theory has been that stasis of blood can cause reflux, and reflux can cause propagation and [can] break down the blood-brain barrier," Dr. Mehta said. The resulting microbleeds can allow red blood cells to escape into the brain matter, leading to hemosiderin deposits that can act as the inflammatory mediators of an autoimmune response, he said.
Although Dr. Zamboni, a vascular surgeon and professor of surgery at the University of Ferrara (Italy), observed a strong association between chronic cerebrospinal venous insufficiency (CCSVI) and MS, it is unclear if the relationship between CCSVI and MS is causative, or if CCSVI might play a role in the etiology of the disease.
In 2009, Dr. Zamboni also reported on a series of 65 patients who had significant improvements in functional composite scores and quality of life at 1 year.
The preliminary data that Dr. Mehta presented at the meeting came from the LIBERATION study, which is designed to assess the utility of percutaneous transluminal venoplasty for individuals with CCSVI and MS. It¹s a prospective, randomized, double-blind study that is currently enrolling 600 patients.
Because there is a learning curve involved with the assessment and technique, the researchers included a prospective longitudinal arm as part of the study. Dr. Mehta of the Albany (N.Y.) Medical College and the director of endovascular services for the Vascular Group PLLC, presented preliminary results on this group of patients.
In the study, investigators performed venograms to identify stenoses of 50% or greater in internal jugular and azygous veins in the patients, all of whom underwent venoplasty. Neurologists and other clinicians evaluated the patients at baseline, and then at 1 month, 3 months, and every 6 months thereafter.
The 125 patients included in the study had a mean age of 47 years, and 62% were female. Relapsing-remitting MS accounted for 54% of the patients, followed by secondary-progressive MS in 34% and primary-progressive MS in 12%.
The patients had a total of 230 lesions altogether, 90% of which involved the internal jugular veins; the majority of these were at the origin. The remaining 10% of patients had stenoses in their azygous veins.
The mean degree of occlusion was about 80%, with approximately 1.8 lesions per patient. Immediate success (defined as less than 20% residual stenosis) occurred in 82%. The remaining patients underwent a second venoplasty without stenting. In all, 79 patients were available for follow-up at a mean of 4.5 years. Restenosis of 50% occurred in eight of these patients, occlusions occurred in two patients, and one patient had new-onset atrial fibrillation.
The investigators reassessed 48 patients with the EDSS (Extended Disability Status Scale) following initial baseline testing. From before to after the procedure, "there was a statistical improvement. Improvements occurred in each of the MS types, except in primary progressive MS," Dr. Mehta said.
Re-evaluations of 79 patients who performed a timed 25-foot walk at baseline showed a significant improvement in walking speed. In terms of MS quality of life, from before to after the procedure "there were significant improvements in physical and mental ability. There clearly seems to be a trend. In the modified fatigue impact score, there also seems to be a clear improvement," he said.
Dr. Mehta also said that there was a trend toward improvement in balance, lower-extremity weakness, incontinence, coordination, and vertigo in more than 80% of patients.
Dr. Mehta and his colleagues reported that they each had several significant financial relationships with device manufacturers.
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MAJOR INTERNATIONAL STEM CELL TRIALS FOR MULTIPLE SCLEROSIS GET FUNDING
UK scientists getting ready to work on major international trials to investigate the safety and effectiveness of stem cells in slowing, stopping or reversing brain and spinal cord damage in people with MULTIPLE SCLEROSIS have received £1 million in funds from the MS Society and the UK Stem Cell Foundation (UKCSF). Many scientists believe this unique international collaboration will significantly reduce the timescales for finding out if stem cells are safe and effective in treating MS.
The MS Society said in a statement that the funding is for three UK studies within the international trials. One of these will investigate the use of autologous mesenchymal stem cells as a form of immunotherapy to prevent and potentially reverse neurological deterioration in RELAPSING-REMITTING MS. The trial, a collaborative phase II study, will involve 150 to 200 MS patients from across the world, including UK, Italy, the US and Canada.
In the UK, the trial will be sited in London and Edinburgh, with Dr Paolo Muraro from Imperial College London as study leader. Muraro and colleagues will collect bone marrow stem cells from 13 MS patients, grow them in the lab, then re-inject them back into the same patients, such that each patient receives a large boost of his or her own stem cells. The hope is that the stem cells will travel to the brain and start to repair the damage caused by MS, including that currently in progress in "active lesions".
Another project, led by Professor David Baker of Queen Mary University of London, will evaluate the use of transplanting neural stem cells as a therapy for optic neuritis, a symptom of MS that impairs sight because the optic nerve in the eye becomes inflamed.
And in a third project, study leader Professor Cris Constantinescu of Queen's Medical Centre (QMC) Nottingham, and colleagues, will be finding out more about mesenchymal stem cells, which influence the immune system and have potential to protect and repair brain cells and nerves. They will be using ultra-high field imaging and looking in particular at mesenchymal stem cells' phenotypic characteristics and immune interactions, so we know more about these types of cells for future trials.
In the UK, MS affects about 1 in every 650 people. Having parents or siblings with MS increases a person's risk of developing the disease to about 1 in 100.
MS is caused by the body's own immune system attacking and damaging the protective myelin sheath that stops nerve fibers short-circuiting in the brain and spinal cord. The damage stops messages travelling to and from the brain and the body, so that patients eventually become sight-impaired, get stiff muscles, become disabled and lose control of their bladder and bowels. Although more and more drugs are becoming available that treat some aspects of MS, none as yet can reverse the damage or limit the progression of the disease.
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Enjoy your summer!
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And if you have any thoughts of how this newsletter could be improved, please email me directly, at email@example.com