Chapter 7: Editorial Conclusions
The title of this review is current status of cell culture drug resistance testing. This review focused on a description of the technologies and a review of the clinical correlation data, because there are many misconceptions and much ignorance about both technology and data.
Several years ago, Cortazar and Johnson reviewed clinical trials of therapy ostensibly based on the results of cell culture assays . However, the Cortazar/Johnson review is not relevant to the technologies discussed here or to any technologies offered through clinical laboratories in the United States as a service to patients at any time within the past ten years. A critical discussion of this review is available on the Internet (http://weisenthal.org/cort_rev.htm).
One must recall the extraordinary difficulty in proving the efficacy of chemotherapy in general and of specific drug regimens in particular in studies of non-assay-directed chemotherapy. Only with extremely large studies (and sometimes only with meta-analyses of extremely large studies) has it been possible to document that chemotherapy of any type produces survival advantages compared to no chemotherapy at all, in many clinical situations. The quite impossible challenge of documenting the clinical standard of "efficacy" (as opposed to the heretofore traditional laboratory standard of "accuracy") with these non-proprietary, public domain technologies was, in fact, pointed out by Dr. Maurie Markman (a noted critic of Human Tumor Assays) who correctly wrote that "even if it were possible to establish the efficacy of [the assays] in a particular situation, this would do nothing at all to establish the efficacy of [the] assays in any other situation" .
The challenge of "validating" a single test for a single treatment in a single disease is challenging enough (e.g. estrogen receptor in breast cancer, which has still, after 30 years, only been shown to correlate with clinical outcome and has yet to be shown to improve clinical outcome). Now consider the challenge of "validating" a test for 40 different drugs which can be used in tens of thousands of combinations in hundreds of diseases. If documented clinical "efficacy" is the standard to be demanded of non-proprietary laboratory tests, then clinicians should abandon all tests currently used in their practices. It will be interesting to see which standard is applied in the future to other laboratory tests associated with the prediction of drug resistance, such as tests based on mechanisms of drug resistance (e.g. expression of thymidylate synthetase [146,150,151]) and Her2/neu expression [152-154].
While evaluating the data discussed here, please consider that it has taken 20 years to amass this body of evidence in an environment of continued hostility and non-support by the academic oncology community toward work in this area and consider also the little which has been achieved in the area of empiric methods of drug selection, despite billions of dollars spent on empiric clinical trials enthusiastically supported by this same academic oncology community.
If one critically evaluates the clinical trials data in ovarian cancer, for example, one finds that there is no advantage for platinum-based combination chemotherapy over single agent alkylator therapy and no advantage for platinum + paclitaxel over single agent cisplatin or carboplatin [155-157]. But this did not prevent platinum combination therapy from becoming "standard of care" before the introduction of paclitaxel and it did not prevent platinum/paclitaxel from becoming standard of care over single agent carboplatin or cisplatin. In point of fact, the only thing clearly established after 30 years of clinical trials is that carboplatin and cisplatin are therapeutically equivalent, albeit with different toxicity profiles. And there are absolutely no data to support any of the half dozen or so available drug choices for second and third line therapy over any other choice. So what is the "risk" in using currently available assays to help guide these choices?
Only when these assays are widely performed and used and routinely included as an integral part of clinical trials will these already promising technologies be improved and only then will their role in patient management become better defined. But this is true for all complex laboratory technologies (a good example being immunohistochemical staining for batteries of cell antigens).
Absent this testing, on what basis are drugs chosen today for use in the many clinical settings in which a single "best" empiric regimen has not been well-defined? An objective reviewer would admit that many oncology practices would base choice of drug regimen, at least in part, on the profit "spread" between the wholesale cost of the drug(s) and the reimbursement which the third party payers provide. This is a conflict of interest as well as a cost-ineffective method for selecting therapy; yet it is a method which the oncology and insurance communities support every single day in their treatment and coverage decisions. It is the loss of this "freedom to choose" and the overzealous dedication to a weak clinical trials paradigm (identification of the "best" treatment to give to the average patient) which is largely behind the reluctance to introduce these technologies as an important component of current clinical trials and as a part of the process of clinical drug selection in situations where clear empiric "best regimens" have not been well defined through prior clinical trials.
The private sector laboratories offering CCDRT as a patient service (Table 2) have been able to make considerable progress in improving the assay technologies and in building databases which improve the interpretation of "raw" assay results. But this progress has only been possible because insurers and often patients have been willing to pay for the tests and because clinicians have wanted to have the information provided by the tests. The progress would have been much faster (and doubtless even more substantial) had the academic oncology community not done everything it could to oppose this work at every step of the way.
By raising the bar of acceptance to levels unprecedented for a laboratory test, in essence a tariff has been erected to protect the paradigm of the "best" empiric treatment for the average patient, as identified in appallingly non-productive clinical trials. This tariff also serves to protect the paradigm of drug selection with consideration of the spread between wholesale cost and reimbursement.
Finally, the tariff discourages discovery of new, effective drug regimens through the use of CCDRT to guide drug selection. Take, for example, the gemcitabine/cisplatin combination. Years before gemcitabine/cisplatin became a widely used drug regimen, CCDRT identified this as the most active regimen in a patient with pancreatic cancer metastatic to kidney, omentum, and liver, despite the poor activity of gemcitabine and cisplatin tested as single agents. This patient went on to achieve a complete remission with gemcitabine/cisplatin and remains alive with an excellent quality of life 5 1/2 years later [158,159]. A second such patient was an ovarian cancer patient with primary resistance to paclitaxel/carboplatin who then underwent tandem stem cell transplant/high dose chemotherapy regimens (at a cost of more than $250,000) without ever achieving a response. At a time when she had bulky, non-cytoreducible abdominal and pleural disease, CCDRT confirmed resistance to single agent cisplatin, carboplatin, and gemcitabine, but good activity for the gemcitabine/carboplatin combination. She subsequently received gemcitabine/carboplatin as an outpatient, achieved a durable complete response, and returned to work full time as an oncology nurse, where she remained well, for four years , until a recent relapse (she has recently been re-started on assay-directed chemotherapy). Indeed, early anecdotal results of this type occurring in diseases in which there was no existing clinical trials literature accelerated clinical trials of this regimen in diseases in which assay-directed responses had been observed .
With more widespread use of these assays in clinical oncology, it is very likely that the activity of new drugs and new regimens would be identified at a much earlier time than with the current system relying exclusively on usually-empiric, Phase II trials .
Why is it so necessary to protect the patient from the information provided by a perfectly rational laboratory test, supported by a wealth of entirely consistent, if understandably incomplete 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.
Think of all the objections to this testing. Now try to design all of the clinical trials which would be needed to meet all of these objections and think of how much money these would require and who is going to provide this money and how many years the studies would take and how many patients will continue to receive ineffective or suboptimum treatment in the interim. The body of information will never be sufficiently large and complete and definitive to encompass even a reasonable fraction of the situations where the information provided by the tests would be helpful. Now ask the questions: What is the potential risk? What are the potential benefits? What is the probability that these tests really do provide information which can improve the drug selection process in individual clinical situations? What is the potential cost? How does the benefit/risk ratio balance out? What is the (financial) cost as a percentage of total costs relating to management of patients on chemotherapy (including the costs of radiographic and laboratory studies performed only to determine if a given form of treatment is working or not)? What are the long term costs if drug selection always remains an empiric, one-size-fits-all, trial and error process? What would be the impact on improving existing technologies (through the attraction of more laboratory and clinical investigators into the field) and developing new technologies should these assays become more widely used?
If one wishes to see an example of an entirely rational technology advance, in a human disease crying out for precisely such a technology advance, supported by an entirely consistent (if understandably incomplete) body of data, where the advance continues to be held hostage to a high bar of extraordinarily difficult clinical trials which the critics have been entirely unwilling to support, in an area (laboratory testing) for which such trials would be entirely unprecedented, one need look no further.
Table 2 shows a partial listing of laboratories from which CCDRT as a clinical service is currently available. For specific information concerning the practical and technical aspects of these services, and for cost and reimbursement issues, the director of each laboratory should be contacted.
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