Cell Culture Drug Resistance Testing (CCDRT) Cell Death Assays:
Misconceptions Versus Objective Data
-Chapter 11-
What the Critics Say: D. The Cortazar/Johnson Review (J Clin Oncol 17:1625-31,'99)
The Cortazar/Johnson review represents a substantial amount of work, and the authors took great pains to be comprehensive, accurate, and fair. The paper contains no factual inaccuracies, nor are there any important omissions of important studies of which I am aware. The authors have accurately described the substantial logistical barriers to completing studies such as this and offer helpful suggestions for future studies.
The take-home messages come through loud and clear. The studies analyzed suggest a response benefit, but do not confirm a survival benefit. The authors conclude that prospective clinical trials "have not yet demonstrated a clear benefit of chemotherapy using drug sensitivity testing." In 2 less comprehensive recent reviews, Markman recently made the same points, as discussed above (Markman, M. Chemosensitivity and chemoresistance assays: are they clinically relevant? J. Cancer Res. Clin. Oncol. 121, 441-442,'95; Brown, E. and Markman, M. Tumor chemosensitivity and chemoresistance assays. Cancer 77, 1020-1025,'96).
It is, however, extremely misleading to attempt a meta-analysis on the data. There are limitations to all studies in which one lumps together data from various studies and calculates overall means or medians. In this case, such lumping is particularly problematic.
The data in the Cortazar/Johnson review which attract the most attention are those data comparing survivorship with assay-directed versus empiric therapy. Indeed, it is likely that the take-home message for most readers will be that, in a fairly large total dataset of 13 prospective studies and 569 patients (actually only 5 studies and 92 patients, omitting one study which was inappropriately included, see below) receiving DST-directed therapy, the median survival of DST-directed therapy was 8.9 months, compared to 10.9 months for empiric therapy and that "only one non-randomized study showed patients treated with [DST-directed therapy] had a significantly longer survival than the group of patients treated with empiric chemotherapy." {n.b. the statistical power of these studies to show a difference, assuming that one existed, was very low}.
Even more simply and directly, the take-home messages of the above would appear to be clear:
1. There have been a lot of studies and a lot of patients, providing a reasonably fair test of the hypothesis that clinical chemotherapy directed by DST may improve clinical outcome.
2. The data strongly imply that there is no benefit to clinical chemotherapy directed by DST.
The above are outrageously misleading messages, unsupported by the studies and data included in this paper.
It is accurate to state that it has not been proven that the use of these assays improves the treatment of populations of patients in prospective, randomized trials (which have never been carried out and completed. It is not accurate to state nor helpful to imply that the hypothesis has been adequately tested and found not to be true. It is also unfair not to consider at the same time the considerable data which show that when patients are treated with drugs active in the assays that they have vastly superior reponse and survival rates than when they are treated with drugs which are not active in the assays (data reviewed earlier, in Part 1).
To begin with, in the Cortazar/Johnson review, it is not appropriate to include the study by Maenpaa, et al (authors' reference # 26). This was a study of the subrenal capsule assay, which is an in vivo assay which has never been utilized in this country or anywhere else in the non-investigational clinical setting. This assay was criticized in several publications by several different groups, who reported that the alleged tumor "growth" measured in the assay was mostly owing to host inflammatory response against the implanted tumor and was, thus, an artifact. To my knowledge, this assay has never been used by any of the private sector laboratories and has been abandoned as a research tool.
Remaining are 5 studies, 2 of which utilize the "human tumor colony assay" ("HTCA") and 3 of which utilized the "DiSC" assay. A total of 92 patients in these 5 studies actually received assay-directed therapy.
The HTCA and DiSC assay are completely different technologies.
The HTCA measures inhibition of cell proliferation. It utilizes very low drug concentrations. It is a relatively long-term assay. It suffers from a number of serious technical problems (which have been enumerated in a number of review papers, going back to the early 1980s). It has a very low evaluability rate. And it hasn't been used by any private sector clinical laboratory in at least the past 13 years, to my knowledge.
In contrast, the DiSC assay measures cell death (delayed loss of membrane integrity, which is what is measured by the DiSC assay, has been shown to correlate with apoptosis). It uses markedly higher drug concentrations than does the HTCA. It is a short-term assay. It poses entirely different technical challenges than does the HTCA. It has a very high evaluability rate, as discussed below. It has been used by private sector clinical laboratories since 1987 and it continues to be used by the three most prominent private sector laboratories which are providing cell culture drug resistance testing in this country today.
Basically, the authors lumped together 6 vastly differing studies, none of which had a control patient population which would be accepted in any journal publication comparing different forms of empiric therapy (i.e. the typical oncology journal chemotherapy paper), and quoted the following median survivals for patients receiving assay-directed therapy (in months): 6.2, 7.2, 8.6, 9.1, 24, and 38.5. They took the median of this series of 6 papers of different technologies and came up with a number of 8.9 (months) to represent the overall median result of assay-directed therapy upon meta-analysis. Then they took the following median survivals for patients receiving empiric therapy (who did not represent scientifically valid control groups): 4.2, 7.3, 10.6, 11.2, 19, and 28. The median of this series came out to be 10.9 and this was stated to represent the median survival for patients receiving empiric therapy.
Lumping together non-randomized data from widely varying studies of technologies which are not in any way comparable for meta-analysis to obtain parameters such as median survivals and then to make comparisons of these median survivals is not scientifically justifiable. Had the median survival with this sort of fractured analysis showed a "signficant" improvement, there is no way on earth the Journal's editor would ever have accepted this for publication. Only because the non-significance of the finding fit in with the Editor's pre-conceived bias was it published.
Since it was the authors' intention to evaluate the "efficacy" of DST-selected therapy, it would seem most appropriate to first evaluate the quality of the data which exist to make this determination. In order to be useful to the many hundreds of clinical oncologists who continue to use this DST in their clinical practices, it would also be helpful to note how the technologies evaluated in this review compare with the technologies which are currently being applied as a service to patients.
As the HTCA is not one of the technologies which has been used by the private sector laboratories, but as (technically-evolved) versions of the DiSC assay are used, it would appear that the only papers discussing survivorship which are relevant to present-day clinical practice are the three lung cancer studies from the NCI which ostensibly utilized the DiSC assay (authors' refs. 9, 10, 39, 11, 12). The problems at the core of these studies are described in the following section.
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