Two recent clinical trials showed that empiric combinations of bevacizumab and ant-EGFR antibodies, combined with chemotherapy, did not improve therapeutic outcomes in colorectal cancer – in fact, outcomes were inferior to single “targeted” therapy combined with chemotherapy.
Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009;27:672-680
Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563-572
In his video blog, Dr. Maurie Markman of MD Anderson editorializes that all new concepts must be proven in prospective, randomized clinical trials:
http://boards.medscape.com/forums/.29f0fd39 (may require free registration to view)
In the late 1980s, the NCI, aided and abetted by herd mentality study sections, effectively closed down research into fresh human tumor cell culture methods for testing and optimizing chemotherapy. The proof of this is the complete lack of NIH-funded studies relating to this topic appearing in PubMed for the last 15 years. Instead, we have put all of our clinical trials resources into trying to identify the best treatment for the average patient — in a disease notorious for heterogeneity. Drug screening (including therapy screening) belongs in the laboratory, not in the clinic. All of a sudden, there is a belated recognition that “personalized” therapy is worthy goal — yet 100% of the effort is going into static profiling of molecular markers, as opposed to dynamic, functional profiling of tumor response ex vivo. It’s crazy/nuts, and, down the road, tomorrow’s translational researchers will shake their heads and say “what on earth were they thinking?”
How to make progress in combined “targeted” therapy?
Here’s an example: http://tinyurl.com/weisenthal-breast-lapatinib But there’s absolutely no support for work such as this. And now there are efforts under way to make it impossible to do this work in grass roots, private sector laboratories, for example: http://www.cancertest.org/?cat=11
One relevant irony is that, in my opinion, few individuals have done more to extinguish support for the development of cell culture methodologies in clinical cancer testing than the afore-mentioned Dr. Markman.
I intend on discussing this further in the ongoing consideration of precisely what type of evidence should be required to “validate” a clinical cancer test.
- Larry Weisenthal/Huntington Beach, CA, USA
Tags: bevacizumab, cell culture assays, clinical trials, colorectal cancer, EGFR, Maurie Markman, randomized clinical trials, targeted therapy
I kind of remember doing some research on why there wasn’t support for these fresh human tumor cell culture methods over the last 20 years. It had to do with NCI’s failure at assay-directed therapy.
Good review papers existed on cell culture assays and were increasingly appreciated, understood and applied by the private sector and European clinicans and scientists.
The literature on these methods had not been understood by many NCI investigators and by NCI-funded university investigators, because their knowledge was almost always geared towards an assay technique (cell-growth) that hasnt’ been used in private labs for over fifteen years.
NCI studies never determined if “fresh” human tumor cell culture methods worked. All of the considerable literature which supported the use of these assays in patient management had been based on true “fresh” tumor (non-passaged) cell assays.
Some years back, NCI made an attempt to study assay-directed therapy of lung cancer. The study was a failure because it was done with established permanent cell lines (instead of fresh cells), which have been conclusively proven to have no predictive value at all with respect to the clinical activity spectrum. The result was a dismal 11% response.
NCI used “cell lines” because the major expertise of the investigators who carried out any study was in the creation of cancer cell lines, and they wanted to see if they could perform assays on these cell lines to use in patient therapy. The results showed they were able to test successfully only 22% of specimens received, including only 7% of primary lesions.
This contrasted with a 75% overall success rate reported by earlier investigators who used the same assay system in “fresh” tumor and a routinely obtained >95% success rate using improved (cell death) methods available today.
NCI spent $15 million 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.
NCI never supported any drug development work based on primary cultures of three dimensional cell clusters with cell death endpoints, which very nicely recapitulate known disease specific activity endpoints.
Then later, there were sophisticated programs to discover gene expression microarrays which predicted responsiveness to drug therapy. The NCI had a huge lab working on microarrays to look for patterns of mRNA and protein expression which are predictive of chemotherapy response. They spent 2 years trying to find patterns which correlated using the NCI’s various established ovarian “cell lines.”
They thought they had something, but when they started to apply them to “fresh” tumor specimens, none of the results in the “cell lines” was applicable to the “fresh” tumors. Everything they worked out in the “cell lines” was not worth anything and they had to start over from square one.
However, the limitations and non-applicability of the NCI efforts, failed to realize that the way to identify informative gene expression patterns is to have a “gold standard” and the (cell-death) cell culture assays are by far the most powerful, efficient, useful “gold standard” to have, adding the potential value of the assays to individualize cancer therapy.
It was routine for the NCI to append statements to grant and contract initiative announcements that applications relating to cell culture assays were strongly discouraged. Dr. Dan Von Hoff (after his failed attempt at the old technology cell-proliferation assays) published a paper in 1990 in which he stated that clinical trials of cell culture assays would never be supported. And the cooperative groups have utterly refused to do the studies.
There was an enormous amount of published, peer-reviewed research documenting the “accuracy” of cell culture assays. Scores of studies in thousands of patients. Based on both response and survival, but all of it excluded from the ASCO and insurance industry reviews some five years ago. And it’s the only evidence existing to validate any other medical test used as an aid in drug selection.
Disallow the introduction of published, peer-reviewed evidence documenting accuracy. While allowing the introduction of hearsay, unstated, undocumented, undescribed, unpublished, unpeer-reviewed non-evidence.
And the fact that “proving” efficacy in one situation would do nothing to prove efficacy in any other situation. This is why the FDA demands clinical trials data showing efficacy for each and every indication relating to drugs.
Let’s say a plan assay-directed clinical trial in relapsed NSCLC proves efficacy. All we prove is that it improves things for one small indication. Relapsed NSCLC, not ovarian cancer.
And it gets worse. The year after the close of the study, two new drugs become available and the assay-directed clinical study only proves efficacy with the old drugs. It doesn’t prove efficacy involving the new and improved drugs. A constantly moving target. So then you say, just go out and get a grant to do another one.
Sounds a little like the “twilight zone.”