Hi Rich! Your suspicions were correct about the proper understanding of tumor sensitivity testing.
The cell-based assay judged by the infamous ASCO tech assessment in 2004 was a direct descendent of the old original Salmon/Von Hoff Human Tumor Stem Cell or Clonogenic assay of the late '70s/early '80s. Over twenty year old material that had been discredited twenty years ago. The so-called ASCO expert panel who did this tech assessment included only three investigators who had ever worked in the field of cell culture assay technology: Dan Von Hoff, Anne Hamburger and a German named Hanauske who worked with Von Hoff in San Antonio. All three were old-line "Human Tumor Stem Cell" (clonogenic) assay workers.
What ASCO said was cell culture assays should not be used outside the confines of a clinical trial setting. The same people who maintain that assay-directed therapy should not be used until proven in prospective randomized clinical trials, are the same people whose entire careers are utterly dependent upon mega-trials funded by pharmaceutical companies, that, plus fees from speeches they give for these companies, are the same people who control the clinical trials system, the grant review study sections, and the journal editorial boards. Why else would they want this techology tested under the clinical trial setting?
Opponents of cell culture assay testing can blow all the smoke screens they want, but the fact is that every single time advocates for cell culture assays have been given fair consideration by an impartial, non-ASCO adjudication, the decision has been made that this testing is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. It is only when ASCO or the insurance industry has been appointed itself as the judge/jury/prosecutor/defense rolled into one and not invited input from all "relevant" parties that the decisions have been unfavorable.
Opponents of cell culture assays are insesently confused with the old "clonogenic" chemosensitivity assays, the one that Dan Von Hoff had been discredited long ago. When most academic oncologists refer to "chemosensitivity testing," they are virtually always referring to and thinking about the "human tumor stem cell" assay or "clonogenic" assay. Yet this technology hasn't been used by any private sector laboratory, like Rational Therapeutics or Weisenthal Cancer Group) for more than twenty years. Nor has it ever been advocated the clonogenic assay as the best cell culture assay. But Von Hoff had tried to sell it, not within the confines of a clinical trial, but as a service to patients.
The previous CMS administrator for Medicare in Southern California (NHIC) spent almost the entire 2006 doing a extensive, transparent tech assessment of chemoresponse assays and made the decision that the assays were a perfectly appropriate medical service, worthy of coverage on a “non-investigational” basis. It was a local coverage decision (LCD) and not a national coverage decision (NCD) because Medicare has only about 20 doctors and 40 total clinicians working in its coverage office. Also, Medicare doesn't have a single oncologist on staff, yet since the year 2000, they issued 165 restrictions and directives on the use of cancer drugs and diagnostic tools.
Private insurers like NHIC, on the other hand, employ thousands of doctors and nurses to do this. Last year, an insurance company called Palmetto GBA was awarded the contract to administer Medicare services for California. Palmetto made an arbitrary decision to discontinue Medicare payment for chemoresponse assays in California, with doing any transparent tech assessment.
In regards to the discussion whether the in vivo response to a drug may be different in the body than in the petri dish. Rational Therapeutics and Weisenthal Cancer Group work with three-dimensional (3D) tumor cell clusters. Real life 3D analysis makes functional profiling indicative of what will happen in the body. It tests fresh "live" cells in their three dimensional (3D), floating clusters (in their natural state). Even researchers at Johns Hopkins and Washington University at St. Louis had recently found out, our body is 3D, not 2D in form, undoubtedly, making this novel step better replicate that of the human body.
Traditionally, in-vitro (in lab) cell-lines have been studied in 2 dimensions (2D) which has inherent limitations in applicability to real life 3D in-vivo (in body) states. Recently, other researchers have pointed to the limitations of 2D cell line study and chemotherapy to more correctly reflect the human body.
And other recent studies have shown that three-dimensional (3D) tissue culture models have an invaluable role in tumor biology today providing some very important insights into cancer biology. As well as increasing our understanding of homeostasis, cellular differentiation and tissue organization they provide a well defined environment for cancer research in contrast to the complex host environment of an in vivo model.
Due to their enormous potential 3D tumor cultures are currently being exploited by many branches of biomedical science with therapeutically orientated studies becoming the major focus of research. Recent advances in 3D culture and tissue engineering techniques have enabled the development of more complex heterologous 3D tumor models.
Blood assays ususally proliferate (grow) cancer cells from a small sample and subject those cells to chemo. Cells 'grown' in the lab will not behave the same way as the actual cancer cells do in your body's own environment. Because they test on subcultured cells (as opposed to fresh tumor cultures) and test the cells in monolayers (as opposed to three dimensional cell clusters), the cell grown in the lab will not behave the same way as the actual cancer cells do in your body's own environment.
Older technology assay tests failed because scientists looked to see which drugs inhibited the cancer cells' growth (cell-growth endpoint), not which chemotherapies actively killed the tumor cells (cell-death endpoint). Cancer wasn't growing faster than other cells, it's just dying slower. The newer assay testing technology connects drugs to patients by what 'kills' their cells, not by what 'slows' them down.
All of the work in the past twenty years in the cell culture field has been carried out largely on three dimensional clusters of cells (not monolayers). Work is done exclusively with three dimensional, floating, tumor spheroids. When you test the cells as three dimensional spheroids, they are many-fold resistant in vitro, just as they are in vivo (multicellular resistance).
What is not ready for prime-time is molecular profiling in light of the recent findings about the limitation of genetic testing, gene-guided chemotherapy research being questioned, and gene-expression signatures not ready for prime-time. Examining a patient's DNA can give physicians a lot of information, but as the NCI has concluded (J Natl Cancer Inst. March 16, 2010), it cannot determine treatment plans for patients. For truly personalized cancer care, patients can only rely on functional profiling assays.
http://her2support.org/vbulletin/showthread.php?t=46200
The labs vary considerably with regard to technologies, approach to testing, what they try to achieve with the testing, and cost. Some labs have been offering these assays as a non-investigational, paid service to cancer patients, in a situation where up to 30 different drugs and combinations are tested, at two drug concentrations in three different assay systems.
The labs will provide you and your physician with in depth information and research on the testing they provide. Absent the assays, the oncologist will perform "trial-and-error" treatment until he/she finds the right chemotherapy regimen. You should have the right chemo in the first-line of treatment.
By investing a little time on the phone speaking with the lab directors, you should have enough knowledge to present the concept to your physician At that point, the best thing is to ask the physician, as a courtesy to the patient, to speak on the phone with the director of the laboratory in which you are interested, so that everyone (patient, your, physician, and laboratory director) understand what is being considered, what is the rationale, and what are the data which support what is being considered.
Some molecular tests (like the AZ lab) do utilize living cells, but generally of individual cancer cells in suspension, sometimes derived from tumors and sometimes derived from circulating tumor cells. This was tried with the human clonogenic assay, which had been discredited long ago. Again, traditionally, in-vitro (in lab) "cell-lines" have been studied in 2 dimensions (2D) which has inherent limitations iin applicability to real life 3D in-vivo (in body) states.
The cell-block technique (which is used for genetic testing) is useful for special stains and immunohistochemistry (IHC) and can give morphological (structural) details by preserving (in paraffin wax) the architectural patterns. However, investigators can only measure those analytes (substance or chemical constituent) in paraffin wax that they know to measure. If you are not aware of and capable of measuring a biologically relevant event, you cannot seek to detect it.
Cell-blocks are paraffin-embedded, and parffin-embedded tissue can change over time. These proliferating populations of cells are biologically distinct in their behavior from "fresh" live cells that comprise human tumors. Established cell-line is not reflective of the behavior of "fresh" live tumor cells in primary culture in the lab, much less in the patient. You get different results when you test passaged cell-lines compared to primary, fresh tumors. You can't use cell-blocks at a later date.
Greg