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QUALITY: Is pre-chemo testing the future? by Harvey Frey MD

Careful readers of this blog will have noted that along with reporting about the change in reimbursement for cancer drugs (and to get the real scoop on that you should see JD Klienke’s excellent article in Health Affairs), there’s also been a trend generally in favor of chemo-sensitivity testing before chemotherapy–largely considered a fringe activity by mainstream oncologists. Then this week the NEJM had an article generally in favor of pre-chemo testing. Did the appearance of this article mean that oncologists were moving the way of the pre-chemo testing radicals or did I as the dumb layman misunderstand it? I asked Dr Harvey Frey, who has written for laymen on this subject for THCB before but has generally not been in favor of it, what he thought.

I think you’ve got it right.

Now oncologists guess at prognosis and probable effective treatment based on how a cancer looks under the microscope, how extensive it is when found, and some blood tests. But even within the groups they’ve determined that way, there are still huge variations in actual patient response and survival rates. Since they never know who needs the treatments for sure, many patients are treated who might not need the treatment, and some get ineffective treatments before finding an effective one, and since the treatments are not innocuous, that’s bad.

They first tried doing sensitivity testing by growing cancer cells with different chemotherapeutic agents. For a variety of reasons, that never was very helpful. For years they have thought that, if only they could determine the actual genes responsible for cancer, they could break down the large heterogeneous groups into smaller groups with better defined responses, and spare many patients any treatment at all.

This study is a start toward that end, but still a small step. The technique doesn’t require that they try to grow the cells, but can be done on regular biopsies as obtained now. But so far all it’s shown is a correlation between their test and survival. They haven’t yet shown that they can predict response to hormones or chemotherapy. But there’s every reason to hope that they will ultimately be able to make such predictions, at least with better accuracy than we can now.

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9 replies »

  1. where can a patient go to get the latest functional cell profiling or other useful markers… my wife is on her third chemo and each ct scan shows a new problem but some reduction in others.. don’t know what to do now… time is running out.. help please

  2. As the Google search engine still brings up this almost four-year-old posting, I am reminded of some of the ideas Dr. Harvey Frey still had of pre-chemo testing (cell culture assays).
    Most notably is the thought he has that sensitivity testing is done by growing cancer cells with different chemotherapeutic agents.
    In modern cell culture assays with Functional Tumor Cell Profiling, there is no growing of cells as in the old cell-growth assays.
    Cells are taken fresh “live” in their three dimensional, floating clusters. Cells are cultured in conical polypropylene microwells for 96 hours to increase the proportion of tumor cells, relative to normal cells.
    Functional Tumor Cell Profiling assays are the one test in oncology that can have the greatest immediate potential to improve therapy selection for “individual” cancer patients, not the “average population.”
    Data from studies demonstrate close correlation between prospective predictions of drug activity and patient chemotherapy response and overall survival.
    When individual patients are treated with drugs “active” in the assay, they have vastly superior response and survival rates than when they are treated with drugs which are “not active” in the assay.
    The “functional tumor cell profiling” method assesses the activity of a drug upon combined effect of all cellular processes, using combined metabolic and morphologic endpoints, at the cell “population” level (rather than at the single-cell level), measuring the interaction of the entire genome.

  3. Besides the existence of the Chemotherapy Concession (profit motive in drug selection) being one of the major factors working against the individualization of cancer chemotherapy based on testing the cancer biology, the NCI had made an attempt years ago, to study assay-directed therapy of lung cancer on its own.
    1. Their expertise was in establishing permanent cell lines and they only tested tumors after first culturing them to amplify their cell number (these were all passaged, grown up, multiplied, replated). The result was that their assay evaluability rate for primary lung cancers was only 11%.
    2. The second problem they had is that they were selecting subpopulations. Subsequent work showed that you get different results when you test passaged cells compared to primary, fresh tumors.
    3. The third problem is that the ability to get lung cancer to actually grow is an independent marker for virulent disease. It was actually the single greatest negative predictor for survival in one study.
    So the NCI concluded that it was too much trouble and not all that useful. If they couldn’t get it to work at the NCI, then of course no one can do it. That was the attitude thereafter.
    “If the NCI can’t do something, nobody can.” What a heck of a way to do science!
    This was all done with established cell lines, which have been conclusively proven to have no predictive value at all with respect to the clinical activity spectrum. The NCI spent 15 million dollars on a single cell suspension fresh tumor assay with cell proliferation (cell growth), rather than cell death as an endpoint. When that didn’t work, they folded their hand and specifically discouraged future applications of cell culture testing in their grant and contract guidelines, dating from the late 1980’s. They never supported any drug development work based on primary cultures of three dimensional cell clusters with cell death endpoints, which do very nicely recapitulate known disease specific activity endpoints.
    Above average in the “test tube” is a marker for above average in the patient, and vice versa. This has been confirmed (for both response and patient survival) in more than 40 peer-reviewed studies, involving more than 3,000 patients, with no controversy whatsoever. What is the problem with going with above-average choices of drugs, rather than below-average choices? In vitro apoptosis for choosing drugs is no different than a marker like estrogen receptor or CD20 or a gene expression pattern. They are all markers. One is a structural marker, the other is a functional marker. There is no conceptual difference.

  4. Besides the existence of the Chemotherapy Concession (profit motive in drug selection) being one of the major factors working against the individualization of cancer chemotherapy based on testing the cancer biology, the NCI had made an attempt years ago, to study assay-directed therapy of lung cancer on its own.
    1. Their expertise was in establishing permanent cell lines and they only tested tumors after first culturing them to amplify their cell number (these were all passaged, grown up, multiplied, replated). The result was that their assay evaluability rate for primary lung cancers was only 11%.
    2. The second problem they had is that they were selecting subpopulations. Subsequent work showed that you get different results when you test passaged cells compared to primary, fresh tumors.
    3. The third problem is that the ability to get lung cancer to actually grow is an independent marker for virulent disease. It was actually the single greatest negative predictor for survival in one study.
    So the NCI concluded that it was too much trouble and not all that useful. If they couldn’t get it to work at the NCI, then of course no one can do it. That was the attitude thereafter.
    “If the NCI can’t do something, nobody can.” What a heck of a way to do science!
    This was all done with established cell lines, which have been conclusively proven to have no predictive value at all with respect to the clinical activity spectrum. The NCI spent 15 million dollars on a single cell suspension fresh tumor assay with cell proliferation (cell growth), rather than cell death as an endpoint. When that didn’t work, they folded their hand and specifically discouraged future applications of cell culture testing in their grant and contract guidelines, dating from the late 1980’s. They never supported any drug development work based on primary cultures of three dimensional cell clusters with cell death endpoints, which do very nicely recapitulate known disease specific activity endpoints.
    Above average in the “test tube” is a marker for above average in the patient, and vice versa. This has been confirmed (for both response and patient survival) in more than 40 peer-reviewed studies, involving more than 3,000 patients, with no controversy whatsoever. What is the problem with going with above-average choices of drugs, rather than below-average choices? In vitro apoptosis for choosing drugs is no different than a marker like estrogen receptor or CD20 or a gene expression pattern. They are all markers. One is a structural marker, the other is a functional marker. There is no conceptual difference.

  5. Providing us a lots of inrank, isn’t it our duty to spreading that vital purpose to all over proples unaware from health care ?

  6. They tell you that a given form of treatment has an above average probability of being associated with a clinical response and/or with being associated with above average survival.

  7. Dr Ian Cree, Director, Translational Oncology Research Centre, Queen Alexandra Hospital, Portsmouth UK performed the very first prospective, randomized clinical trial of physician’s choice chemotherapy versus ATP assay-directed chemotherapy in non-surgically debulked, platinum-resistant ovarian cancer and presented it at the May, 2005 American Society of Clinical Oncologists (ASCO) meeting in Orlando, Florida.
    The results were highly suggestive of an effect due to the assay, and the most successful drug regimens used were nearly all developed using the assay. UK results in cancer are always lower than in the US for a variety of reasons. Part of this is probably lead time bias, but data on surgical debulking may be part of the explanation. Patients in the US get a whole lot more surgery along the way than in Europe.
    As a result of this, the Gynecologic Oncology Group (GOG) has decided to move forward with a study in platinum-resistant ovarian cancer, utilizing a different assay called EDR, to direct chemotherapy. However, this assay is specifically designed to identify ‘inactive’ rather than ‘active’ drugs. In this light, the EDR assay has the advantage of telling you who will ‘not respond’ but cannot in any way change the negative outcome by selecting an ‘active’ alternative. At least it’s a start!
    There are other medical oncologists in the US, headed up by Drs Larry Weisenthal and Robert Nagourney, that are making proposals for a separate study, a front-line randomized trial with head to head comparison of several assays (EDR, ATP, DISC, MTT, as well as Caspase 3/7). These assays correlate very well with each other on direct comparisons of different methods. Different methods of assay results should be applied in choosing a particular drug regimen to be used in treating an individual patient’s cancer.
    My question: Why did it have to take so long? Perhaps asking Schrag, Burstein, Von Hoff and the rest of ASCO, why they have single-handedly done more over the past 20 years to keep assay-testing technology under a bushel basket and out of the light until now? It has ultimately hurt literally hundreds of thousands of patients. We’d be much further along and technology would have improved, even more accurate. New treatments would have been discovered and targeted immediately to the people who could most benefit from them. This has been one great lost of opportunity in clinical cancer research, and that’s what it is.

  8. Assay-testing is based on a biological principle that when a drug is effective, it will induce cell-death (apoptosis) in the cancer cell (this is the new technology). If the cancer cell is resistant to a drug, apoptosis will not occur. Assay-testing for apoptosis will determine whether a drug kills the tumor. Chemosensitivity testing (assay-testing) can take the guesswork out of cancer treatment. Currently, physicians select a drug and must wait about six months to see whether it is effective on a particular patient.
    Conventionally, oncologists rely on clinical trials in choosing chemotherapy regimens. But the statistical results of these population-based studies might not apply to an individual. For many cancers, especially after a relapse or when a particular treatment is ineffective, more than one standard treatment exists.
    These cell-culture assay-tests provide much more powerful prognostic information. They tell you that a given form of treatment has an above average probability of being associated with a clinical response and/or with being associated with above average survival. Likewise, they indicate that given treatment is associated with a below average probability of response and/or survival.
    Why is it so necessary to protect the patient from information provided by a perfectly rational laboratory test, supported by a wealth of entirely consistent data? If used to assist in the selection of a regimen chosen from a series of otherwise reasonable alternatives, then patients will never be harmed and best available evidence strongly indicates that they will often be helped.
    The fact that most doctors don’t agree isn’t stopping many cancer patients from taking this matter into their own hands, and sending their live path specimens off to private labs for assay-testing to be done. There has been much discussion about whether assay (in vitro) tests are of any use, as the in vivo response to a drug may very well be different in the body than in the petri dish. But, they said the same for Bacterial Culture and Sensitivity Testing. Doctors cannot remember a time when they didn’t have this technology. It is a “gold” standard. So will pre-chemo testing.

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