PHARMA/QUALITY: More in chemo sensitivity testing, by Larry Weisenthal

As I mentioned the other day, I have another article on oncology in the queue which got pressed for space as the election heated up. Larry Weisenthal, MD, is a board certified medical oncologist with a 25 year history of full time work in the field of cell culture drug resistance testing (otherwise known as “chemosensitivity testing”). More about Larry may be found by looking at his CV. He writes:

The issues and data relating to chemosensitivity testing defy concise summary and can be reviewed on my website. For the moment, I just want to make a brief response to the comments of Harvey Fry (on THCB a couple of months back). Harvey had written about chemosensitivity testing:

I fought for chemo-sensitivity testing of cancers over 20 years ago, and finally lost because of the problems with the tests. First, it’s often hard to get a representative sample of tumor cells by biopsy. Then it’s hard to get them to grow. Then you’re not sure whether the cells that grew out are the tumor cells, or normal matrix, like fibroblasts. Then there’s the delay in starting treatment while waiting for the cells to grow out. Then there’s the question of whether cells in metastases have the same response as those in the primary. But the killer was that the clinical response was not that well predicted by the cell survival tests in the lab. And of course, there was the expense.

Unless there has been some major advance in the intervening years, I can understand the reluctance of some oncologists to go back to it. Alternatives to growing the cells and seeing what kills them may now exist, but they are only surrogates for the real end-point of interest.

Firstly, Dr Fry obviously has no understanding whatsoever of the current technologies, which are based on cell death and not cell growth. To put things into historical perspective, interest in “culture and sensitivity testing” for cancer received a tremendous boost with the publication of a preliminary paper describing a cell growth assay in the New England Journal of Medicine in 1978. When the NEJM talks, people listen. Within a year, hundreds of laboratories were working with this particular cell growth assay, and it did, indeed, pose the problems cited above by Dr. Fry. These problems were exposed in a devastating, negative editorial, published in the NEJM in 1983. The NEJM giveth; the NEJM taketh away. All the laboratories shut down; research in the field virtually ceased, and the take home message in the minds of most clinicians was that the assays had been discredited. Dr. Fry’s comments reflect this thinking.

In 1983, other publications introduced assays based not on cell growth, but on cell death. This was a good 5 years before dissemination of understanding of the concept of apoptosis (a genetically programmed cell death pathway which exists in all cells, which is supposed to cause them to commit suicide if they become functionally deranged, but which doesn’t function properly in cancer cells, allowing them to grow abnormally without committing suicide, but which can be triggered to occur by effective anti-cancer drugs). Because clinical oncologists did not understand about apoptosis, these pioneering publications with cell death (instead of cell growth) endpoints were ignored, and neither clinical trials nor the application of cell death drug resistance assays were supported by academic and private practice clinical oncologists.

Despite the theoretical concerns expressed by Dr. Fry, the clinical utility and clinical accuracy of cell culture drug resistance testing with cell death endpoints has now been proven beyond doubt. These data may be reviewed on-line at: http://weisenthal.org/oncol_t.htm. The issues and data are also available in a 27 minute video excerpt of my testimony before an official Medicare technology assessment committee meeting in Baltimore.

Regarding the “expense” part of it. The tests cost in the neighborhood of $2,000, so it’s a legitimate consideration, but expense has to be put in context. A couple of quick examples:

1) A 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. The cost of ineffective therapy for this one patient alone would have paid for 125 assays.

2) One of our most “loyal” referring oncologists is financially independent and therefore he is free to manage his patients without any conflicts of interest relating to the fact that prescribing chemotherapy instead of counseling against it has financial repercussions to the oncologist and prescribing certain forms of chemotherapy over certain others likewise has financial repercussions. In the absence of information that some drugs are more likely than others to work, it is “ethical” to choose more remunerative forms of chemotherapy. The assay presents great problems for non-independently wealthy oncologists, because they take away their freedom to choose. The above oncologist recently told me of an interesting anecdote. He had a patient scheduled to come to his office on a recent Wednesday for chemotherapy. This treatment would have earned the oncologist $6,000 for a single patient, for a single afternoon’s worth of treatment. But the patient missed the appointment. The next day was the beginning of the oncologist’s vacation. So he had to arrange for the patient to be treated at the nearby, world famous, NCI-designated comprehensive cancer institute, which billed $28,000 for the treatment and which received 75% of this total (the oncologist knows this, because it had happened before).

The cost of drugs is enormous. And this is only part of it. Patients are “followed” with serial CT scans, MRIs, and even PET scans, just to ascertain if the tumor is growing or shrinking. And the hospitalizations for toxicity, etc. The point is that the cost of ineffective therapy is truly enormous, and the assays are particularly good at identifying ineffective therapy.

In summary:

There have been over 40 publications in the peer-reviewed medical literature showing correlations between cell death assay results and the results of clinical hemotherapy in more than 2,000 patients. In every single study, patients treated with drugs active in the assays had a higher response rate than the entire group of patients as a whole. In every single study, patients treated with drugs inactive in the assays had lower response rates than the entire group of patients. In every single study, patients treated with active drugs were much more likely to respond than patients treated with inactive drugs, with assay-active drugs being 7-9 fold more likely to work than assay-inactive drugs. A large number of peer-review publications also reported strong correlations between the assay results and the survival of cancer patients. These data are completely non-controversial and have
never been challenged or refuted. Thus Dr. Fry’s comment that “the killer was that the clinical response was not that well predicted by the cell survival tests in the lab” is absolutely incorrect.

The material on my website is very complicated (it is targeted to health professionals more than to laypersons). For a short overview of the most important issues, I’d recommend the Frequently Asked Questions section, which was also quoted by Wall Street Journal Health columnist Tara Parker-Pope in her weekly question and answer column appearing in the September 21, 2004 issue of the WSJ.

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  1. Medicare Coverage for Cell Culture Assays
    Favorable local coverage decision (LCD) regarding Medicare payment for Cell Culture Assay Test
    Cell culture assay technology has been clinically validated for the selection of optimal chemotherapy regimens for individual patients. It is a laboratory analysis based on tumor tissue profiling that uses fresh human tumor biopsy or surgical specimen to determine which drugs or combinations of chemotherapeutic agents have the highest likelihood of response for individual cancer patients.
    Individualized assay-directed therapy is based on the premise that each patient’s cancer cells are unique and therefore will respond differently to a given treatment. This is in stark contrast to standard or empiric therapy, which chemotherapy for a specific patient is based on average population studies from prior clinical trials.
    ASCO’s 2004 position paper focused on an older cell-growth assay method and not on a newer cell-death method, which is the most relevant biological measure. Their panel made no attempt to distinguish cell-death from cell-growth techniques. Their conclusions simply did not apply to cell-death assays. In fact, cell-death assay results have consistently correlated with response, time to progression, and overall survival.
    The ASCO paper focused solely on a lack of prospective, randomized clinical trials proving superior outcomes with assay-directed therapy, a standard not met by ER/PR testing, HER2 protein or gene analysis, or any other clinical test in cancer medicine, and has seldom been met by even the eimpiric chemotherapy treatments supported by ASCO. Were they to apply the standard measure of predictive test accuracy, the results of their analysis would have been much different and in favor of the use of cell-death assays in clinical practice.
    This omission was so significant that Medicare contractor, National Heritage Insurance Company which spent six months reviewing everything about the cell culture assay, including all of the ASCO arguments, and upon reviewing all available information, approved Medicare coverage for the tests as Oncologic in Vitro Chemoresponse Assays. They made the courageous decision to reverse trend and noted that the ASCO paper had failed the consider any of the many studies which support the predictive accuracy of cell death-based in vitro chemosensitivity testing.
    The decision had been made that the assay is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. What is of particular significance is that they are finally abandoning the artificial distinction between “resistance” testing and “sensitivity” testing and are providing coverage for the whole FDA-approved kit.
    Cell cuture assay tests based on cell-death have proven very effective in identifying novel treatment combinations for a variety of cancers. It is unfortunate that ASCO had not carried out studies to assess the value of cell-death assays, because they can and do accurately predict clinical outcomes and define novel chemotherapeutic synergies. In many cases, these same tests have induced highly durable remissions in patients whom current medical literature have deemed otherwise hopeless.
    Medicare coverage has been available for Chemosensitivity (Resistance) Testing for a tumor specimen from a Medicare patient obtained anywhere within the United States, but submitted for testing by one of the approved laboratories located within California.
    Source: http://www.medicarenhic.com/cal_prov/policies.shtml
    Reference: Various Bio-Assay Laboratories

  2. I am a 57 yo orthopeadic surgeon diagnosed with stage 4 thymic carcinoma after presenting with SVCS in 9/03. I’ve had radiation to the tumor mass in the chest with no local recurrance. CAPP X6 cycles produced perceived total remission by PET/CT after the 3rd cycle. All disease came back in 2 months.
    Since then I have failed 3 months of Iressa, 3 months of xeloda and now 2 months of Gemzar. Dr. Pat Leohrer wants me to enroll in his Alimta study while we wait for his Taxol/Gleevec study to be approved by his hospital’s IRB.
    My “problem” is that my liver mets have increased 30-50% in 2 months and now occupy about 40% of my liver. By my calculations, I’ve got about 2-3 months until I have 70% involvement with liver failure, coma and death.
    Neither my local oncologist nor Pat believe in cancer cell assays to determine which combination of drugs will be more likely to work than others. I don’t have time to “experiment.” Can you help me? I will travel as needed.
    JR (Jonathan Rogers, MD}

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