Lung Cancer Therapy Could Be Guided By Pre-Treatment Blood Test
Main Category: Lung CancerArticle Date: 10 Jun 2007 - 17:00 PDT
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A multi-center team, led by Vanderbilt-Ingram Cancer Center investigators, has discovered a "signature" of proteins in the blood that predicts which non-small-cell lung cancer patients will live longer when they are treated with certain targeted cancer therapies.
The findings, published in the Journal of the National Cancer Institute, could one day help physicians decide which lung cancer patients to treat with drugs known collectively as EGF receptor tyrosine kinase inhibitors, a step forward in the era of personalized medicine.
"There's a real clinical need to identify which patients will benefit from targeted therapies," said David Carbone, M.D., Ph.D., Harold L. Moses Professor of Cancer Research at Vanderbilt-Ingram and the senior author of the study. "If our findings are confirmed, we will be able to use a simple and inexpensive blood test to select the most beneficial therapy for each patient."
Targeted cancer therapies are the newest generation of anti-cancer drugs. In contrast to traditional chemotherapy, targeted therapies affect proteins and signaling pathways that are selectively activated in certain malignant cells and not in normal cells. But this selectivity makes these therapies effective only for the subset of patients whose tumors are "driven" by the targeted pathways.
The drawbacks of treating every patient with a targeted therapy include the expense of these drugs, the delay - for those who do not respond - in initiation of effective therapy, and the possibility that some patients will be harmed by the targeted therapy.
In the case of the EGF receptor tyrosine kinase inhibitors (TKIs) gefitinib (Iressa) and erlotinib (Tarceva), studies have demonstrated a survival benefit for 30 to 40 percent of lung cancer patients, but there has been no method for identifying these patients prior to treatment, Carbone said.
Investigators at Vanderbilt-Ingram, the University of Colorado in Aurora, Colo., and Biodesix Inc. in Steamboat Springs, Colo., with worldwide collaborators providing patient samples, set out to determine if a protein profile in the peripheral blood could predict clinical benefit - measured in terms of patient survival - to EGF receptor TKIs.
Using mass spectrometry, the researchers analyzed pre-treatment blood samples from 139 patients who had been treated with gefitinib (three patient cohorts in Italy and Japan), identified a pattern of eight proteins that was correlated with survival, and developed a prediction algorithm.
They then tested the algorithm in two additional groups of patients - 67 gefitinib-treated patients in Italy and 96 erlotinib-treated patients in a U.S. Eastern Cooperative Oncology Group protocol. At the time of the mass spectrometry analysis and classification, the researchers were "blind" to the survival status of the patients.
"We classified the patients as being either likely to benefit ("good") or not likely to benefit ("poor") from the TKIs," Carbone said.
The method was highly successful in predicting a survival benefit. In the gefitinib-treated group, patients classified as "good" had a median survival of 207 days whereas those classified as "poor" had a median survival of 92 days. In the erlotinib-treated group, median survivals for "good" and "poor" groups were 306 and 107 days, respectively. The fact that the signature, which was developed from gefitinib-treated patients, also accurately predicted a survival benefit for erlotinib-treated patients buoys Carbone's confidence in the algorithm, he said, since these two drugs share a common mechanism of action.
The method was not prognostic - it did not predict a survival benefit in three different control groups of patients treated with either chemotherapy or surgery alone.
The investigators are currently working with the Eastern Cooperative Oncology Group to develop a prospective national phase III trial that will test the prediction method's clinical benefit in lung cancer patients who are just beginning treatment for advanced disease.
"This is a convincing set of data from multiple institutions and multiple cohorts of patients, and we're excited to test the prediction algorithm in a prospective way," Carbone said. "If it holds up, we will be able to separate patients into two groups - one that would benefit more from chemotherapy and the other from targeted TKIs - and treat them accordingly. The overall survival of the whole group of patients would be better by virtue of this biomarker-based test."
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The research was supported by the National Cancer Institute's Specialized Programs of Research Excellence (SPOREs) in Lung Cancer and cancer center core grants to Vanderbilt-Ingram and the University of Colorado.
Contact: Craig Boerner
Vanderbilt University Medical Center
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Targeted Cancer Therapy Improved With Ex-Vivo Chemosensitivity Analysis
posted by Gregory D. Pawelski on 16 Jul 2007 at 8:48 amResearchers at Rational Therapeutics and Todd Cancer Institute (Long Beach, Calif.) have reported clinical results obtained with a laboratory technique (Ex-Vivo Analysis of Programmed Cell Death - EVA-PCD(TM)) that accurately identifies patients who are candidates for targeted cancer therapy.
A team led by Robert Nagourney, M.D., laboratory director of Rational Therapeutics and medical director of the Todd Cancer Institute at Long Beach Memorial Medical Center, report that ex-vivo laboratory analysis accurately identified non-small cell lung cancer (NSCLC) patients likely to benefit from the EGFr inhibitor, Erlotinib (Tarceva(TM)). The team's findings are published in the official proceedings of the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 1-5 in Chicago.
"While targeted EGFr-TKI therapy has proven effective in treating advanced non-small cell lung cancer, response rates remain low in randomly selected patients," said Dr. Nagourney. "We have found that the EVA platform can help doctors select those patients most likely to benefit from the new generation of targeted anticancer therapies."
The researchers used ex-vivo analysis (EVA) to examine tissue from NSCLC patients as part of an IRB-approved assay-directed clinical trial. Patients found sensitive to the EGFr inhibitors received oral Erlotinib at 150mg/day as first line therapy. All of the patients selected responded to this oral therapy, with several achieving long-term remissions. This outcome demonstrates that patients whose cancer cells undergo programmed cell death in the laboratory due to EGFr inhibitor exposure are those who respond to targeted Erlotinib (Tarceva(TM)) therapy. The research team's findings are summarized in an abstract titled, "Clinical Responses to EGFr-TKI's Characterized by Drug-Induced Cell Death in Human NSCLC Primary Cultures" (ASCO Abstract # 07-AB-34058-ASCO).
Traditional anticancer drugs are toxic to both cancerous and normal cells. In contrast, targeted anticancer drugs target cancer cells with specific mutations. While such drugs hold promise, their use requires new methods to enable doctors to accurately and consistently identify patients whose particular type of cancer expresses the drug's specific target.
Dr. Nagourney explains, "Efforts to administer targeted therapies in randomly selected patients often result in low response rates at significant toxicity and cost. While researchers continue to develop molecular probes to select candidates, the ex-vivo platform used in this study serves as a functional profile capable of examining the nuances of cellular response to drugs. To exploit the full potential of targeted anticancer therapies, physicians will need laboratory tests that match patients to specific drugs. We believe the EVA PCD platform is such a test."
The Todd Cancer Institute at Long Beach Memorial Medical Center is the first cancer program in the nation to apply assay-directed therapy as the first-line treatment for advanced solid tumors. The Center is currently hosting clinical trials for cancers of the lung, colon, stomach, pancreas and prostate.
One of those has been Phase II assay-directed therapy in previously untreated, measurable, Stage IV NSCLC. Patients who had high activity for erlotinib in vitro and received first line single agent erlotinib had a 100% response rate.
(Genetic Engineering and Biotechnology News, June 1, 2007).
Re: Targeted Cancer Therapy
posted by hchcec on 18 Jul 2007 at 4:43 pmIt's been almost 5 years since this EVA-PCD has been studied. This new study is not controlled and, thus, proves little at this time. Is it more beneficial than trying the targeted therapy , which insurance cos. pay for, or should you take the time to fly to CA, pay these researchers $3500+ for the test out of your pocket, which is unproven, and then try the covered targeted therapy anyway?
Why don't these researchers put the test to the test?
Almost 5 years and counting....
Re: Targeted Cancer Therapy
posted by Gregory D. Pawelski on 22 Jul 2007 at 8:22 pmDan Von Hoff was the most prominent member of the 2004 ASCO technology assessment panel on Cell Culture Assays. Before that time, he told people how the "old" clonogenic assay was the next great thing. However, if one thought he was trying to tell people that the "old" clonogenic assays should be studied in a research setting, is totally false. According to his mass mailings, he was trying to sell his assays outside the confines of a clinical trial.
He is one of the greatest organizers of clinical trials in the history of clinical oncology. Yet he virtually did not successfully organize and complete a single randomized trial to test "assay directed" versus "physician's choice" chemotherapy. Yet he sold his assays, not as a clinical trial, but as a service to patients. Then when his own pet technology was finally discredited, he spoke out against the use of cell culture assays in patient management. If he can't do it then no one else should be able to do it either. I'm glad no one took him up on it.
If the so-called respectible Journals (the ones that fail to adhere to guidelines on conflict of interest) won't publish articles because they have a lock-up on information, don't lay blame on me. If trials show that an assay-directed group actually did better than a physician's choice group, but because these are small and non-randomized studies, it is concluded that efficacy hasn't been proven.
No one has ever said or represented that cell culture assays have been proven to be efficacious in randomized trials, just that the tests are accurate and that accuracy has always been the standard used to evaluate tests. But, just because trials may have never been done, this should not be the reason for an medical oncologist to refuse to have the tests performed.
The current clinical trial of the EDR assay should not be designed as a self-fulfilling prophecy (to disprove the merits of this approach) but should legitimately seek an answer to the questions regarding the role of assays. They should be simple head to head comparisons between different assay endpoints in a real world, cooperative group setting, to determine whether the assays are of value. Then you can actually design a trial which has the best possibility of actually improving treatment results.
Thank goodness for America's private laboratories.
Re:Pawelski
posted by hchcec on 23 Jul 2007 at 5:23 pm"No one has ever said or represented that cell culture assays have been proven to be efficacious in randomized trials, just that the tests are accurate and that accuracy has always been the standard used to evaluate tests."
This is false. Pawelski believes tests are approved based on accuracy and not efficacy. This is not true. And, bte, who wants to pay $3500 for a test that has never been proven to be effective?
"But, just because trials may have never been done, this should not be the reason for an medical oncologist to refuse to have the tests performed. "
Huh? Design the test. Bring it on. You could say the same thing about homeopathy. I guess you want docs to advise patients to use homeopathic "remedies", too.
"Thank goodness for America's private laboratories."
Nice statement. But it's meaningless and their anecdotes are meaningless if they are hyping unproven tests as they regularly do.
(Sorry, my name is not Michele.)
Re: Charlatans Like Michelle H. (hchcec)
posted by Gregory D. Pawelski on 24 Jul 2007 at 9:03 amThe issue isn't about the "accuracy" of cell culture assay tests, they have been "proven" accurate. The issue is about what criteria should be used to judge the tests. The tests themselves are a direct threat to the income of private practice oncologists and they are a threat to the research protocols of academic oncologists. So these groups want to see an unprecendented evaluation of "efficacy" as they do for newly "patented" cancer drugs.
A California Medicare contractor spent a whole year studying the issue of these tests. They got lots of negative feedback from lots of academic and private practice people. They also got positive feedback. Most importantly, they evaluated the tests by the criteria used to evaluate all other tests and concluded that the tests should be covered. So now virtually all Medicare patients, anywhere in the country, can have these tests and Medicare will pay for them.
Likewise, California Blue Shield has had two separate, extensive technology reviews, where all points of view and all data were considered. On both occasions, the impartial board of expert physicians voted unanimously in favor of reimbursement, despite active opposition from certain oncologists and oncology organizations.
It is totally wrong to portray this as being something where there is unanimity of opinion. In point of fact, in every situation where a neutral panel of adjudicators had the opportunity to hear both sides of the story, the decision came down in favor of coverage of these tests as a reasonable and scientifically supportable medical service.
So, it is by no means arguing in favor of snake oil and on the side of charlatans, as Michelle H. (hchcec) wants to portray this.
Re Pawelski
posted by hchcec on 25 Jul 2007 at 8:53 pm"The tests themselves are a direct threat to the income of private practice oncologists and they are a threat to the research protocols of academic oncologists."
Ah, conspiracy. (I should stop right here as anything that follows in his post is, well, biased.) Of course, oncologists and researchers are only in it for the money and, yet, the assay sellers are not. Sure.
This is an example of a Placing Blame Elsewhere Logical Fallacy. You have no evidence for your statement, so you blame the those who examine the evidence; they're greedy evildoers. Also known as the exaggeration fallacy, it is committed when an argument tries to include additional causal influences which are ultimately irrelevant to the matter at hand. We can say that committing a fallacy of exaggeration is a consequence of failing to heed Ockam's Razor, which states that we should prefer the simpler explanation and refrain from adding "entities" (causes, factors) which are not specifically necessary.
Cell Culture Testing, which is not empirically validated in relation to clinical response is not covered by the vast majority of large insurers. A novel testing technique is not automatically assumed to correlate with clinical performance simply because it measures cell survival or death in vitro.
And this comment from a leader in the field:
"In response to the statement, 'The extreme drug
resistance assay accurately identifies ineffective chemotherapy and helps the oncologist avoid unnecessary treatments and toxicity', Markman wrote, 'It is unquestionable that oncologists use these assays to assist in the positive selection of chemotherapeutic agents. Therefore, it is highly relevant to ask if the use of such an assay improves quality of life, reduces toxicity, improves
survival, or reduces cost. In the absence of actual data .it is INAPPROPRIATE to make claims .'"
Indeed. And the claims Pawelski makes are false. And the Medicare decision was a small local one, not national, as suggested.
PLUS,
One standard for Medicare coverage decisions is general acceptance in the medical community, while acceptance by individual health care providers, or even a limited group of health care providers fails to meet this standard (PIM Chapter 13.7.1). One laboratory under NHIC jurisdiction had hundreds of referring Medicare providers in 2005, requesting over 2,000 assays for ovariancancer alone (the incidence in the Medicare population is circa 10,000). NHIC must view these referrals as showing a tenable standard of practice and not an individual provider or small group However, to NHIC s knowledge there has never been anational organization s guideline that sensitivity testing is required for chemotherapy decisions, and this LCD shall in NO WAY be construed as making any such suggestion."
http://www.weisenthal.org/medicare_lcd_final.pdf
Hey, I hurt my back. I rest for 1 week, do some light exercise, and recover a another week later.
OR
I go to a chiropractor and feel better in 14 days. Medicare covers chiropractic. So what?
There is NO proof that these very expensive assay tests are beneficial.
Who's this Michele H?
Private Researchers Have Put Chemosensitivity Analysis To The Test!
posted by Gregory D. Pawelski on 25 Jul 2007 at 10:57 pmFor over ten years, GOG, CCG, SWOG, ECOG, NSABP, and CALGB have never accepted the challenge to compare their results with Ex-Vivo Chemosensitivity Analysis. More important, the concept of testing a test needs to be in the context of other tests like ER/PR, CT or PET scans.
PET scans were not approved because they saved lives in a controlled clinical trial that compared the outcome of patients who received care with or without the benefit of a PET scan. They were approved because their performance characteristics (sensitivity/specificity) are reporducible, favorable and provide useful information to treating physicians.
Chemosensitivity analyses have performance characteristics that are reproducible, favorable and provide useful information to treating physicians. What's more, the information is the result of a clinical trial in which NSCLC patients underwent an assay as part of a Phase II assay-directed trial (IRB-approved). It so happens that these patients were found more sensitive to Tarceva than to other forms of chemotherapy, all of which were tested for the same $3,500 price.
If costs well in excess of $1,000 to do EGFR mutation and FISH for amplification. All of which tells you whether or not to give Tarceva (one drug). Chemosensitivity analyses more often find MSCLC patients sensitive to other compounds and combinations and can recommend these all from one assay. It costs a lot more to give a single cycle of chemotherapy than it does to test all of the possible options.
The evidence supporting a doctor's use of therapy may be far less solid than the evidence supporting chemosensitivity analysis. If a physician uses chemotherapy for NSCLC, does he/she give second-line chemotherapy to patients with good performance status who fail first-line therapy? If so, there is only one study to support it, Docetaxel. There is also one non-inferiority trial for Alimta. If the physician does anything other, he/she is not adhering to the evidence. I'm sure there are dozens of practices that fail to meet these lofty evidence standards.
Michelle H. (hchcec), you haven't the foggiest idea! It is entirely inappropriate to regard the randomized clinical trial as being the "gold standard" for judging whether a treatment does more good than harm. After thirty-six years of holding back the "war on cancer," it is time to move on to a better, more efficient paradigms of cancer treatment.
Re Pawelski
posted by hchcec on 26 Jul 2007 at 3:12 pmNo studies were identified that provided direct evidence comparing outcomes for patients treated either by assay-guided therapy or contemporaneous empiric therapy in the previous post.
Why?
There are none. (This is why national Medicare policy and all major health ins. cos do not cover this experimental, unproven test and have not for many, many years. This is becoming quite troubling as the assay salesmen are forced to blame the insurers.)
Let's see the evidence. Instead of attacking oncologists and researchers. Let's see the evidence from the assay salesmen. If they want the taxpayer to pay $3500 for the test, should we see some, any, evidence of benefit?
Science cares not about anecdotes from web sites and assay bloggers. it's scientifically meaningless.
Where's the data?
Where?
( BTW, that name thing? it's getting a little disturbing...)
Michelle H. (hchcec)
posted by Gregory D. Pawelski on 26 Jul 2007 at 11:13 pmMichelle H. (hchcec) is condemning "personalized" cancer medicine. Wonder what Andrew C. von Eschenbach thinks about that? He has made it his career ambition to bring "personalized" cancer medicine to the forefront.
At the FDA, he is presiding over a transformation in medicine as scientists come to understand diseases in a more detailed way that could improve doctors' ability to treat patients. Much of what has been done previously has been based on the antiquated model of empiricism (the so-called evidence-based medicine).
He wants to see that doctors will be able to intervene with medical treatments more effectively to a specific patient's illness. Doctors treated illnesses based on how well "average" people have responded to a given treatment. Now they can develop a tailored (personalized) response built around understandings of the patient, the treatment and the disease.
I am enamoured by his belief that much of what has been done has been based on a model of empiricism, but now, doctors should be able to intervene with medical treatments more effectively matched to a specific patient's illness (individualized treatment). The era of empiric treatment should come to an end. We should put much more emphasis on matching the treatment to patient, through the use individualized testing.
Medicare coverage is available for Chemosensitivity (Resistance) Testing for a tumor specimen from a Medicare patient obtained anywhere within the United States, but submitted for testing by one of the approved laboratories located within California. Medicare bills for this testing are billed through NHIC because the test is conducted by one of the approved laboratories in California.
The same tortured syntax was evident when Michelle H. (hchcec) stopped using the name Michelle and started using hchcec on the same repeated blogs sometime in the fall of last year (like a blog groupie). Everybody caught on. Perhaps she should take the paper bag off her head and let everybody else on this blog know who she is, instead of hiding behind a symbol. Condemning the messenger instead of having any rational thought on the message does drift too far from reality.
Re Pawelski
posted by hchcec on 27 Jul 2007 at 5:12 pmIn fact, I do not condemn the science. I do condemn the internet blogger who pushes unproven therapies.
I do not condemn (never have) individualized testing that shows benefit , e.g. Oncotype Dx. What MUST be condemned is these chemotherapy assay bloggers who take advantage of the vulnerable, who tell them their oncologist is living in the past, who claim they care nothing about anything except $$, and who keep therapies off the market so money is kept in their pockets.
Ridiculous, unsubstantiated, fear mongering of the worst kind.
The non-scientist assay blogger wants cancer patients to spend $3500, often travel to CA, and hope a test can help them when there's not one study (and you'll notice Pawelski presents none - never has) to show any benefit whatsoever. But, perhaps the assay bloggers pocket the cash and hope they are of help. Are they? No one knows. Why? They despise the scientific method. Why? Because, so far, those studies have not shown any benefit. Therefore, just attack the scientific method. Very convenient. Oh, yes. And put a few anecdotal stories on your web site to entice. No research. Just anecdotes.
Sort of like those Mexican clinics who offer "hope."
(Why haven't I ever given my real name? Truthfully, I do all the time, but not in response to Mr. Pawelski. An internet search will find thousands upon thousands of entries by this individual on cancer support sites, telling patients that they, in his words, may end up "in a mortuary" earlier than need be if chemotherapy assay testing is not performed. This has been going on for years. Finally, last year, his claims had to be answered. But, it had to be done anonymously (with good data, of course) as I found the sheer volume of posts disturbing.
Chemotherapy assay testing holds promise, but is unproven. The are not covered by Medicare nationally (one small local area does) and NO major health insurance co. covers the test.
Isn't it time to chill out?
"Although the concept behind CSRAs (chemotherapy sensitivity and resistance assay is compelling, unfortunately, there does not appear to be a single assay that is ready for routine use in a clinical setting. This is likely due to problems in the technical success and yield of the assays, the lack of adequate prospective evaluation of CSRAs in clinical trials, and the tendency of CSRAs to "recommend" treatments that would have been given based on the results of research published from clinical trials.
Decisions about which chemotherapy regimen you receive should be based on discussions with your oncologist about how the results of clinical trials pertain to your situation. At this time, CSRAs should not be used to select the choice of chemotherapy. Because the concept of customizing chemotherapy is important, participation in research studies that evaluate the accuracy of laboratory testing of tumor specimens to predict chemotherapy response is encouraged."
http://www.plwc.org/portal/site/PLWC/menuitem.169f5d85214941ccfd748f68ee37a01d/?vgnextoid=8ef241eca8daa010VgnVCM100000ed730ad1RCRD
(Mr. Pawelski will now attack ASCO in his next post, but not his own lack of data.)
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