Author:
Gregory D. Pawelski
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Date Posted: 21:09:56 06/18/06 Sun
In reply to:
Gregory D. Pawelski
's message, "Reimbursement for Assay Tests" on 21:07:32 06/18/06 Sun
The extreme drug resistance assays (EDR)cannot "accurately" predict for drug sensitivity. This kind of assay is specifically designed to identify "inactive" drugs and should not be used to identify "active" drugs. It has a very high specificity for drug resistance. However, many effective drugs do not test in the extreme drug resistance range. It has a relatively low sensitivity.
It must be realized that these assays are complex procedures, fraught with the potential for error and misinterpretation. The results are only meaningful to the extent that the laboratory in question is experienced and diligent in its quality assurance practices. A patient interested in this testing should not hesitate to ask specific questions and to require specific answers of the laboratories under consideration.
The EDR is a rather simple, straightforward test, requiring only about 5 minutes per assay of physician/lab work. DISC, MTT, and ATP assays are more geared to identifying active drugs (drugs which will work, as opposed to drugs which won't work), and are a whole lot more labor intensive, requiring an average of 3 hours of physician/lab work.
In order to have an assay done, tumor cells must be accessible through biopsy (needle biopsy is not enough). Tissue, blood, bone marrow, and ascites and pleural effusinos are possibilities, providing tumor cells are present, and only live cells can be used. At least one gram of fresh biopsy tissue is needed to perfom the tests, and a special kit must be gotten in advance from the lab. Arrangements have to be made with the surgeon and/or pathologist for preparation and sending of the specimen.
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, the lab test that pinpoints a germ so the right antibiotic can be prescribed.. Doctors cannot remember a time when they didn't have this technology. It is a 'gold' standard. Oncologists are even equating the new Oncotype DX molecular test for breast cancer, with that of Bacterial Culture and Sensitivity Testing.
Cell death assays are not intended to be scale models of chemotherapy in the patient, anymore than the barometric pressure is a scale model of the weather. But it's always more likely to rain when the barometer is falling than when it is rising, and chemotherapy is more likely to work in the patient when it kills the patient's cancer cells in the laboratory. It is no different than any other medical test in this regard.
Conventionally, oncologists make therapeutic decisions on an empirical basis rather than by thorough evaluation of pathological features and/or drug sensitivity tests. When tumors acquire multi-drug resistance, become refractory and cause relapse after first-line chemotherapy, their responses to routine drugs are greatly compromised.
Upgrading clinical therapy by using drug sensitivity assays can improve the conventional situation by allowing more drugs to be considered. Drug sensitivity tests support the idea that a marginal benefit in terms of overall survival is observed in cancer patients with normal prognoses, but there are marked survival benefits for cancer patients with poor prognoses.
The key to improving drug sensitivity tests is related to the number and types of drugs tested. The more anti-cancer drug types there are in the selective arsenal, the more likely the system is to prove beneficial. In order to acquire sufficient data, tumors should be tested with at least two assay endpoints, and most often three, for sensitivity tests in any one patient. On average, up to twenty drugs and combinations at two concentrations in three different assay systems, is an effective way to avoid false-positive or false-negative data. Careful choice of drug doses and administration intervals also improves outcomes.
Different methods of CCDRT results should be applied in choosing a particular drug regimen to be used in treating an individual patient's cancer. The different methods will sort the different reasonable treatment regimens into the different groups (above-average, average, below-average and very below-average), which would direct attention away from regimens "less" likely to provide benefit and toward regimens which are "more" likely to provide benefit.
Assays based on "cell-death" occur in the entire population of tumor cells, as opposed to only in a small fraction of the tumor cells occurring in "cell-growth." Cell-death assays (DISC, MTT, ATP and Fluorescein Deacetate) correlate very well with each other on direct comparisions of different methods.
Drug sensitivity assays do not harm patients in any way except in terms of cost. Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of drug sensitivity assays are being encouraged by growing patient demands, scientific advances and medical ethics. Drug sensitivity tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.
Having some foreknowledge of a given agent's expected result before its administration would benefit the individual patient.
The NCI had made a feeble 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!
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