June 12,  2007 Emerging data on a continuing problem: The corruption of medical oncology by a system which rewards doctors for being pharmacists: Choosing drugs for cancer patients based on profits to the oncologist.


Introduction:


1. The idea that we have been successful in identifying the best available treatments through "well designed, prospective, randomized trials" is a fiction. (e.g. breast cancer)


2. Faced with a large number of choices of otherwise equally acceptable therapies, owing to the situation described in #1, oncologists select the treatments which generate the most income for themselves (in the case of private practices) or which generate the least inconvenience for their clinical research clinics (in the case of academicians). (Click here to read further on this subject)


The latest developments in this saga are recent data chronicled in a two part New York Times series


Representative excerpt:

"Industry documents that have emerged in a federal civil lawsuit in Boston show that big pharmaceutical companies sometimes calculated to the penny the profits that doctors could make from their drugs. Sales representatives shared those profit estimates with doctors and their staffs, the documents show.

"In one PowerPoint presentation from 2000, a Bristol-Myers Squibb executive told employees that oncologists’ biggest concern was “Reimbursement Today, Reimbursement Tomorrow, Reimbursement!”

"Dr. Robert Geller, an oncologist who worked in private practice from 1996 to 2005 before leaving to join a biotechnology company, said that cancer doctors knew the profits they could make and in some cases would change treatment regimens or offer unnecessary care to make extra money.

“It’s clear that physicians stopped making decisions based on what made scientific or clinical sense in lieu of what made better business sense,” Dr. Geller said."


http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=45527


http://www.nytimes.com/2007/06/12/business/12cancerside.html?ref=business  (requires free registration)


http://www.nytimes.com/2007/06/12/business/12cancerpay.html?ref=health (requires free registration)


Why is the above relevant to the content of this website?  Simple; it explains why the American Society of Clinical Oncology has done everything in its power to discourage the utilization of well documented cell culture assay technologies for use in drug selection.  Absent the use of tests to characterize the drug resistance of individual tumors, clinical oncologists have freedom to choose the drug(s) which are most profitable to the oncologist.  And the above articles (and other data cited on this website) indicate that this is precisely how drugs are being selected in the real world of cancer medicine, as it exists today in the U.S.A.


May 19,  2007Functional profiling with cell culture-based assays for kinase inhibitors and anti-angiogenic agents. Presentation at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden April 18, 2007. (Literature citation: Eur J Clin Invest 37 (suppl. 1):60, 2007.)  PDF export (18 MB, if downloaded) of slide presentation.



March 31,  2007Functional profiling with cell culture assays for targeted drug therapy. Presentation at the American Society of Clinical Oncology (ASCO) GI cancer symposium (Orlando, FL, January 27, 2007). ASCO web site link (click on "Slides")  to slide presentation relating to  testing for antitumor and antiangiogenic activity of gefitinib, erlotinib, sunitinib, sorafenib, and bevacizumab in primary cultures of fresh human tumors.


Feb. 19,  2007Medicare coverage for cell culture drug resistance testing (CCDRT) officially effective February 19, 2007. Full Explanation of favorable coverage decision for cell culture drug resistance testing, encompassing both what were semantically referred to as "chemosensitivity" and "chemoresistance" testing (for PDF mirror of above website document, click here).



Jan 7,  2007Favorable local coverage decision regarding Medicare payment for cell culture drug resistance testing (CCDRT). (Details and Background.) The Medicare contractor responsible for California has completed an extensive review of all available information, including the recent ASCO reviews/position statements, and has finalized an official Local Coverage Decision (LCD) providing Medicare payment for "human tumor in vitro assays"  (CCDRT).

At the page below, click on FUTURE EFFECTIVE policies.

http://www.medicarenhic.com/cal_prov/policies.shtml

As part of this favorable coverage decision, the contractor (National Heritage Insurance Company) carefully documented the historical progression of Medicare policy dating from the "colony assays" of the 70's to the (noncoverage) National Coverage Decision regarding "stem cell" assays (1980), to the 1999 National Medicare Coverage Advisory Committee review (discussed and documented below on this website), to the initial coverage by National Heritage in late 2000 (in the absence of a formal LCD), to the present comprehensive review, culminating in this favorable Local Coverage Decision.


Jan 5,  2007Oncologist perspectives on pharmacologic intervention versus lifestyle intervention in breast cancer treatment (relevant to appropriate levels of evidence required to support tactics and interventions in cancer management)



Nov 25,  2006Plenary lecture on cell culture functional profiling in cancer treatment and research presented at the 5th International Symposium on Cancer Research and Treatment, presented in Tokyo, Japan November 25, 2006. PDF file containing the PowerPoint slides. Also, a 4 minute "tourist-travelogue" type video clip also shown at the meeting (requires Quicktime media player).


June 5, 2006Long term survival in relapsed non-small cell lung cancer (NSCLC) is predicted by (EGFR transduction inhibitor) gefitinib (Iressa) - induced cell death in (fresh human tumor) cell culture drug resistance testing (CCDRT). American Society of Clinical Oncology (ASCO) meeting abstracts, June, 2006 (American Society of Clinical Oncology (ASCO) meeting abstracts, June 2006.) All patients in the study had received prior chemotherapy with 1-3 different chemotherapy regimens. Gefitinib activity in the fresh tumor cell cultures correlated strikingly with the survival of the patients from whom the biopsies were obtained, as shown in representative examples for patients surviving 35 days, 131 days, 414 days, 616 days, and 864 days, respectively.

(New! July 19, 2006 Click here for news story).


May 19, 2006Medicare open meetings report. Open meetings regarding continued Medicare reimbursement for Cell Culture Drug Resistance Testing (CCDRT) were held April 17 and 19, 2006.  Consideration of the relevant issues is ongoing. At this point, I'm hopeful for a fair and well-reasoned outcome.  Full details will follow, once the issue has been settled.

Background and Details


Update January 7, 2007: FAVORABLE Local Coverage Decision announced.  Details above



March 31, 2006 Clinical oncology's failure: Why we need cancer cell profiling to match treatment to patient and why we are dropping the ball


1. The idea that we have been successful in identifying the best available treatments through "well designed, prospective, randomized trials" is a fiction (e.g. breast cancer)


2. Faced with a large number of choices of otherwise equally acceptable therapies, owing to the situation described in #1, oncologists select the treatments which generate the most income for themselves (in the case of private practices) or which generate the least inconvenience for their clinical research clinics (in the case of academicians). (Click here to read further on this subject)


3. For more than 2 decades, ASCO has been of the opinion (based only on preconceived bias and not on any actual data) that it is impossible to take freshly biopsied human tumors, place them in tissue culture, and obtain any useful information whatsoever concerning the likelihood of different drugs working against the very same tumor in the patient.  ASCO-affiliated investigators and reviewers have not only refused to support work in this field, but they have also done everything within their power to extinguish work in this field. (Extensively documented elsewhere on this website).


4. Most recently, ASCO has claimed to have reviewed the data pertaining to the application of "chemosensitivity and resistance testing" and concluded that tests should not be used in drug selection (See "ASCO controversy," Nov. 10, 2004, below). In their review, they specifically excluded from consideration all published studies (i.e. scores of studies, comparing assay results with treatment outcomes in literally thousands of patients) which documented "only" test accuracy, heretofore the only criterion used to validate any test ever used (and currently used) in all of cancer medicine.


5. Now, having (two decades ago) abandoned all interest in obtaining information from intact, functioning, cancer cells, the NCI and ASCO have embarked on a quest to characterize the forest by looking at the individual trees; in this case gene mutations (DNA structure) and/or gene expression (RNA content). 


To begin with, it must be realized that DNA structure is only important insofar as it predicts for RNA content, which is only important insofar as it predicts for protein content, which is only important insofar as it predicts for protein function, which is important only insofar as it predicts of cell response, which is only important insofar as it predicts for tumor response and function.


In 50 more years, cancer scientists will look back on us and wonder why on earth we totally abandoned studies on cell response for 20 years in the misguided quest to identify the best treatment for the average patient through spectacularly unproductive clinical trials of empiric therapies.  Then they will shake their heads and wonder why we decided to devote 99.9% of our resources to studies of the "trees" (DNA, RNA, and protein) and virtually nothing to the study of the forest (intact, living cancer cells).


It's one of the greatest lost opportunities in all of cancer medicine, and the efforts to extinguish work in this area continue unabated, because ASCO refuses even to look at data showing that patients are 7 times more likely to benefit from treatment with CCDRT active drugs than from treatment with CCDRT inactive drugs, in scores of studies, involving thousands of patients.


Click for continuation of this discussion


In the coming weeks, I'll take a closer look at "molecular" assays vis a vis cell culture assays.




Open letter to participants in NCI-Sponsored Ovarian Cancer State of the Science Meeting,Bethesda, MD September 16-17, 2005


At the afternoon session (Sept 16), the following question was asked: "Who needs Taxol?"


That's actually fairly easy to answer (click here).



August 11, 2005 Chemotherapy Response Rates and Survival in Metastatic Cancer: Implications of the Cree Study of Assay-Directed Chemotherapy

As discussed in the editorial referenced below, the clinical trial of Cree, Kurbacher and associates achieved exceptional chemotherapy response rates in platinum-resistant ovarian cancer, but with no clear improvements in overall patient survival.  This study, in the context of the existing clinical trials literature, points to the need for changes in our approach to the chemotherapy of the most common forms of adult cancers Continued, click here.


New! August 7, 2005 Critical review of  (1) the  Cree, et al, prospective randomized trial of assay-directed therapy in platinum-resistant ovarian cancer and (2) the planned Gynecologic  Oncology Group prospective, randomized study in platinum-resistant ovarian cancer.

At the May, 2005 annual meetings of the American Society of Clinical Oncology (ASCO), Cree and associates presented their long-awaited findings from a study began in the late 1990s. 81 patients received chemotherapy selected by the results of a cell death assay (ATP endpoint) and 78 patients received "clinicians' choice" chemotherapy. Continued, click here



May 23, 2005 Prospective, randomized trial of "physician's choice" chemotherapy versus ATP assay-directed chemotherapy in non-surgically debulked, platinum-resistant ovarian cancer. Study by Cree, Kurbacher, and associates, presented at the May, 2005 ASCO meeting in Orlando.  Click here to view and listen to actual presentation (requires Windows Media Viewer and may not initialize properly with browsers other than late versions of Internet Explorer). I hope to post a critical analysis of this study within a day or two. - L. Weisenthal



April 21, 2005 Editorial: Lack of impact of prospective, randomized clinical trials on drug selection in metastatic breast cancer

In the pre-chemotherapy era of the 1960s, the median survival of patients with metastatic breast cancer was a little less than two years. Since then, the greatest cancer centers in the world have performed hundreds of prospective, randomized clinical trials, involving tens of thousands of patients, in an attempt to identify the best treatment to give to the average patient, to improve treatment outcome.  The results of these trials have been summarized by Dr. Lawrence Shulman, of Harvard's Dana Farber Cancer Center (click here , reference given here). In short, there has been not a hint of progress, with median survivals remaining exactly the same, just under two years... Continued: click here


December 8, 2004   Detailed letter from the husband of a patient with metastatic breast cancer, concerning questions which were raised in his mind by the recent Wall Street Journal series of articles on cancer sensitivity and resistance assays (cell culture drug resistance testing).


November 10, 2004   Introduction to American Society of Clinical Oncology (ASCO) controversy. (The material on this website relating to the ASCO/"CSRA"/CCDRT controversy has become unwieldy and confusing. The following is a brief introduction.)

The American Society of Clinical Oncology (ASCO) is a trade organization, representing the interests of its membership, who are largely medical oncologists in both academic and private practice. ASCO has recently drawn scrutiny and criticism (described below) for its attempts to maintain a reimbursement system in which oncologists derive most of their income not from being doctors but from running a retail pharmacy concession, which encourages the maximal use of chemotherapy (as opposed to other treatment modalities), which encourages infusion chemotherapy over oral dose chemotherapy, which encourages certain (more financially lucrative) forms of chemotherapy over other (less financially lucrative) forms of chemotherapy, and which discourages the individualization of drug selection through the use of cell culture drug resistance testing (CCDRT).  ASCO has never supported either the study or use of CCDRT, because of short-sightedness and unwarranted dedication to a failed clinical research paradigm (the identification of the "best" treatment to give to the average cancer patient, through endless generations of prospective, randomized clinical trials pitting one form of empiric therapy against another form of empiric therapy).  The failings of this paradigm were recently exposed, in an investigative report (PDF file) in the March 22, 2004 issue of Fortune Magazine, written by the Executive Editor of Fortune, himself a cancer survivor.

In the September 1, 2004 issue of the Journal of Clinical Oncology (the official organ of ASCO), there were two (hopelessly inept and misleading) "technology reviews" published on CCDRT (referred to in the articles as "chemosensitivity and resistance assays" or CSRAs).  Appearing below on this website are various discussions and writings relating to ASCO's position on CCDRT/CSRAs, based on the controversial September 1, 2004 Journal of Clinical Oncology papers.

Starting with the section below (dated November 9, 2004), it is easy to see that the concepts of information control and censorship are much in evidence at the Journal of Clinical Oncology, official organ of the American Society of Clinical Oncology (ASCO).

November 9, 2004   Weisenthal's correspondence to the Journal of Clinical Oncology concerning the September 1, 2004 JCO reviews relating to "chemotherapy sensitivity and resistance assays" (also known as Cell Culture Drug Resistance Testing, or CCDRT).  

  1. (1)Weisenthal's cover letter, which accompanied manuscript submission

  2. (2)Manuscript submitted to the Journal of Clinical Oncology)

  3. (3)Decision of Dr. Daniel Haller, Editor in Chief, regarding publication of the submitted manuscript.


October 4, 2004  Public Interest Watch Calls for Government Investigation of  American Society of Clinical Oncologists (ASCO)


As described elsewhere on this website, ASCO has worked shamelessly to preserve a system which presents an impossible conflict of interest for both cancer centers and treating oncologists.  This is a system in which there is a financial incentive to choose certain forms of chemotherapy over certain others and to administer infusion chemotherapy as opposed to providing other forms of patient care   Full Report


September 27, 2004  Developments in ASCO versus COFIT Controversy:

American Society of Clinical Oncology ("ASCO") Responds to Criticisms by the Clinical Oncologists for Individualized Therapy ("COFIT")


September 21, 2004  Follow-up:  Health Mailbox section of Wall Street Journal, Sept. 21st edition, page D4.

Wall Street Journal health columnist Tara Parker-Pope answers a reader's question: "I was very interested in your article about chemosensitivity and resistance assays, and would appreciate [knowing more] about having the test done."  Ms. Pope provided detailed and helpful information in two paragraphs and then concluded as follows:  "To get started, patients should discuss [cell culture] testing with their doctors. Several patients wrote to say their doctors initially resisted the idea, but the patient insisted or found a different doctor."  The columnist went on to quote me: "The most important thing is to have both surgeon and pathologist on board in advance." She concluded by noting that "a list of labs that do the tests can be found on weisenthal.org under frequently asked questions."

September 14, 2004  Wall Street Journal article (full article available/clickable only to WSJ subscribers after Sept. 21) on cell culture drug resistance testing .
*************************************
From the Wall Street Journal
Health Journal   September 14, 2004; Page D1

  1. By TARA PARKER-POPE

  2. Tests Hold Promise for Tailoring Drugs to Cancer Patients, But Some See Risk "A lab test that may help predict which chemotherapy drugs will work best in a patient has sparked controversy after a leading cancer panel ruled the tests aren't ready for routine use.
    "The tests, known as chemo sensitivity and resistance assays, or CSRAs, have the potential to revolutionize cancer treatment by testing different chemotherapy drugs directly against a sample of the tumor to identify which is the most effective.
    "Right now, chemo drugs are prescribed based on their overall performance in past clinical trials. But even the best drugs may fail to help between 30% and 60% of patients, depending on the disease. It's impossible to predict the outcome of a particular cancer treatment for any individual because every cancer is different." Article summary and discussion


    September 4, 2004: 27 minute explanation of technology and data behind cell culture drug resistance testing ("chemosensitivity testing").  Streaming video in WMV (Windows Media Viewer) format. Note: works well in Explorer 6 browser. Viewer may not initialize properly in Mozilla or Netscape. Presentation by Larry Weisenthal.



  3. September 1, 2004 Press Release:  Chemotherapy Experts Refute ASCO Recommendations on Use of Drug Sensitivity and Resistance Assays

    Flawed Analytic Methods and Conflicts of Interest Cited as Factors Behind ASCO Panel Findings
    Long Beach, Calif. -- August __, 2004 – A group of leading chemotherapy experts assembled as the Clinical Oncologists for Individualized Therapy (COFIT) refute the findings of the American Society of Clinical Oncology (ASCO) technology assessment panel regarding the use of chemotherapy sensitivity and resistance assays (CSRA).
     

  4. The investigators, led by Robert Nagourney, M.D., Larry Weisenthal, M.D., Ph.D., Robert Hoffman, Ph.D. and William Grace, M.D.,  promote research and application of a specific class of CSRAs that measure drug-induced cell death. These assays have been clinically validated for the selection of optimal chemotherapy regimens for individual patients. (Full Press Release)

     
    August 20, 2004 Bad link repaired. It was just brought to my attention that one of the links on this website wasn't working. This is the link summarizing results of assay-directed chemotherapy in ovarian cancer. This link has now been repaired.


    August 16, 2004  Journal of Clinical Oncology reviews on Cell Culture Drug Resistance Testing

    The September 1, 2004 edition of the Journal of Clinical Oncology will contain two reviews relating to cell culture drug resistance testing (CCDRT). Electronic versions of these reviews are available (to JCO subscribers) on the website for the Journal of Clinical Oncology. Links to the abstracts are provided. I have read the full text versions of each, but copyright restrictions prevent me from posting the full text versions of the two papers. However, these papers are potentially important, and I would like to discuss them (Discussion and Abstracts).


    August 16, 2004 Cell Culture Drug Resistance Testing (CCDRT) is the "Rosetta Stone" for relating microarray gene expression patterns to clinical drug resistance
    The August 5, 2004 edition of the New England Journal of Medicine contains a truly seminal article (New Engl J Med 351:533-542, 2004), relating microarray gene expression patterns to clinical drug resistance.  The investigators used a 96 hour suspension culture drug resistance assay with a cell death (MTT) endpoint  to define cut-offs for "sensitivity" and "resistance."  They then used these data to define gene expression patterns associated with sensitivity and resistance to each of 4 drugs commonly used in the treatment of childhood leukemia.  They were then able to show that these gene expression definitions of sensitivity and resistance were significantly and independently associated with treatment outcome on multivariate analysis.

    Note that this work could not have been done without the prior work in more than a thousand CCDRT assays from children with leukemia to define sensitivity and resistance cuf-offs for each of the four drugs.  The cell culture assays, therefore, are the "Rosetta Stone" which allows for identification of clinically relevant gene expression patterns which correlate with clinical drug resistance for different drugs in specific diseases.  This further shows how short-sighted it has been for the academic and clinical oncology community not to support the development and clinical application of CCDRT ( Additional Details ).

    June 1, 2004  First prospective, randomized trial to assess the impact of cell culture drug resistance testing (CCDRT, "chemosensitivity testing") is currently in progress. The first prospective, randomized trial of cell culture drug resistance testing (CCDRT) is currently taking place in the United Kingdom (UK). It is part of a large trial in which 750 newly-diagnosed patients are being enrolled. It should be noted that, if successful, this will be the first prospective, randomized clinical trial to document that performing ANY type of laboratory or radiographic test in ANY form of cancer makes a difference with respect to treatment outcome. Thus, this clinical trial is truly unprecedented.   (Details).

  5. March 29, 2004 Drug treatment of cancer: No progress in three decades. The March 22, 2004 issue of Fortune has an excellent article which shows that there has been no real progress in the treatment of the most common forms of cancer.  Entitled "War on Cancer: Why the New Drugs Disappoint,"the article cites NCI data showing that US cancer mortality rates have increased and age-adjusted cancer mortality rates in response to treatment have not improved in several decades, despite the introduction of many new drugs.     (Additional Comments)
    March 1, 2004- "Feedback" letter and reply relating to criteria for FDA approval of new anticancer drugs (Click here)


  6. Feb. 23, 2004-Updated! Does cell culture drug resistance testing (“cancer chemosensitivity testing”) make a difference with respect to the outcome of cancer chemotherapy? (Click here)

  7. Dec. 15, 2003 New Medicare law provides partial correction to a conflict-of-interest for oncologists providing cancer chemotherapy, which relates also to cell culture drug resistance testing ("cancer chemosensitivity testing")(Click here)  Updated Jan. 31, 2004



  1. Dec. 8 , 2003 Peer-reviewed original research paper: Platinum resistance determined by cell culture drug resistance testing (CCDRT) predicts for patient survival in ovarian cancer.  Dec. 10 , 2003-New! Revised PDF file  with improved graphics resolution(Includes highly-detailed description of  CCDRT technical methodology, to allow for independent confirmation of reported findings). (Click here)

  2. Oct. 17, 2003- Clinical oncologists continue to use sub-optimal dosing schedules for the most important solid tumor drug combination introduced during the past 15 years (Click here)

  3. Oct. 22, 2003- Explanation of Cell Culture Drug Resistance Testing (CCDRT) Reports Click here. June 14, 2003-Synergy analysis of "classic" and newer drug combinations. (Click here)

  4. April 19,  2003-Cell culture drug resistance testing (CCDRT) improves patient survival in chemotherapy of ovarian cancer. Introduction
    30 years' worth of prospective, randomized clinical trials based on attempting to identify "best" one-size-fits-all treatment regimens have produced no important progress in the chemotherapy of advanced (Stage III, IV, and recurrent/refractory) ovarian cancer.

  5.    Continuation of this introduction


  6. Summary of data indicating that CCDRT improves clinical outcomes in ovarian cancer
    In the case of ovarian cancer, there have been over 600 published correlations between assay results and clinical response. Overall, patients treated with drugs having good activity in the assays had a 77% response rate, while those treated with drugs having poor activity in the assays had a response rate of 11%, in a population of patients who overall had a 51% response rate. Also reported were highly positive associations between assay results and patient survival. (Click here for summarized data correlating CCDRT results with patient survival in ovarian cancer)


  7. Three different groups have reported clinical outcomes of ovarian cancer patients treated on the basis of the results of cell culture drug resistance testing (CCDRT or "chemosensitivity testing").  (Click here for summarized data reporting clinical outcomes of patients treated with the knowledge of results from CCDRT)


  1. March 25,  2003-Cell culture drug resistance testing predicts for patient survival in ovarian cancer.  There have now been 5 different studies of the relationship between the results of cell culture drug resistance testing (CCDRT)  and patient survival in ovarian cancer, and all 5 studies show significant correlations between CCDRT and patient survival. To review summaries of these studies, click here.


    "Standard" (One-Size-Fits-All) Chemotherapy in Metastatic Breast Cancer: A Zero Sum Game? Revised   18-March-2003 "We relentlessly combined chemotherapy agents in various regimens, with ever-increasing dose intensity...as seen in this compilation of data, the survival for patients participating in these studies is exactly the same, less than 2 years. These four studies are a snapshot of hundreds of studies done throughout the world, spanning 30 years, utilizing innumerable combinations of standard dose chemotherapy without a hint of significantly improved survival."
    -- Lawrence N. Shulman, M.D., Vice Chair for Clinical Services/Adult Oncology, Dana-Farber Cancer Institute (Harvard Medical School), Boston.
    His commentary is remarkable in that it pulls no punches in describing the lack of any progress whatsoever in the chemotherapeutic treatment of metastatic breast cancer since 1970. He also raises the question of whether "standard" (i.e. empiric) chemotherapy of metastatic breast cancer is, in fact, a zero sum game.


    DISC assay and biologic response modifiers; See "Feedback" (click here ) 9/2/2002 
    Editorial: Proposed clinical trials of biologic response modifiers in ovarian and breast cancers (click here)


  1. 8/26/2002European collaborative research challenges superiority of Platinum/Taxol as first line chemotherapy for ovarian cancer


Progress in improving chemotherapy treatment regimens in ovarian cancer has been more a matter of illusion than fact. For example, it has not been proven that platinum-based combinations are superior to the single agent alkylators used since the 1960s, and it has not been proven that platinum/Taxol combinations are superior to single agent cisplatin or single agent carboplatin. The only clear conclusion is that there are no meaningful differences between cisplatin and carboplatin, except for carboplatin being generally more tolerable. We are left with a multitude of drugs and combinations with clear-cut activity in ovarian cancer, with clear-cut therapeutic outcome differences at the level of the individual patient, but with no proven best "one size fits all" chemotherapy. During this period, there has been virtually no attention paid to the potential of cell culture drug resistance testing (CCDRT, using apoptotic, cell death endpoints), world-wide, and absolutely no attention paid within the USA. In point of fact, the major opinion leaders have objectively done nearly everything possible to bury this path of inquiry, ignoring what is now a large and unrefuted body of data pointing to the clear utility of CCDRT identifying the most clinically-promising therapies in a wide range of neoplasms, including ovarian cancer, and not cooperating with attempts to prove this utility in the US taxpayer-funded clinical trials system. Appearing on this website are abstracts , data reviews , editorials , and news articles (see below) relevant to the above issues.


For the point of view of a clinical investigator who still favors platinum/Taxol as "standard" therapy, in the face of  the lack of convincing data from controlled trials, please review the following lecture http://www.medscape.com/viewarticle/416489_1 .  In reviewing this lecture, two points are striking: firstly, how the author flat-out states that platinum-based first line therapy has been proven to be superior to single agent alkylator therapy,  in the face of the very data cited by the author, which show no such thing, and, secondly, how platinum/Taxol should still be considered "standard" therapy in the face of two large, unrefuted studies (GOG-132 and ICON-3) which showed that single agent cisplatin and single agent carboplatin were at least as good and in some respects better. Click below for an excellent streaming audio summary of the ICON-3 study, by the principal investigator, Dr. Peter Harper, from Guy's Hospital, in London: http://www.audiomedica.com/oncology/ajo105.htm. (nb: once on the website, click on the "listen" icon just beneath the "ICON-3" headline in the interviews section).



  1. 3-Way Correlation Between DISC, MTT, and ATP Assays  8/16/2002   (Justification for meta-analysis of assays with different cell death endpoints.)


Invited review prepared for publication in the journal ONCOLOGY 7/19/2002
Current Status of Cell Culture Drug Resistance Testing (CCDRT)

Click here for optimally-readable text
Click here for printer-friendly PDF file
History behind the above paper: Editorial Review vs. Censorship?

      1. 1. Invitation from journal ONCOLOGY to write the above paper

      2. 2. Brief letter to author , 4 months following manuscript submission, informing author that paper would not be published.

      3. 3. Letter to ONCOLOGY from author , protesting decision not to publish.

      4. 4. Letter to author , affirming decision not to publish.

      5. 5. Anonymous written review provided by ONCOLOGY: " The Article Reviewed "

      6. 6. Author's rebuttal of annonymous review

      7. 7. Letter to author , again affirming decision not to publish

      8. 8. Letter to the Editor , from author, ultimately published in the July, 2002 issue of ONCOLOGY .


  1. Invitation to Authors The Human Tumor Assay Journal is soliciting contributions of original research, reviews, and editorials. The Editor will provide a private review and suggestions within one week of submission, but the final decision on whether to publish and what to publish will rest with the submitting author. All scholarly papers submitted will be published within 10 days of submission. Readers are invited to submit uncensored reviews and these will be published as received, linked to the original paper.


    Legal Case Against Wellpoint Blue Cross of California for Non-Payment of Services Related to Cell Culture Drug Resistance Testing 6/18/2002
    Introduction: Blue Cross of California was previously a non-profit corporation and approved payment for Cell Culture Drug Resistance Testing (CCDRT) as stipulated in an "internal directive" dated December, 1993. However, this company later became a wholly-owed, for-profit subsidiary of Wellpoint, Inc., and then denied coverage for CCDRT, on the grounds that the service did not meet Wellpoint's medical necessity guidelines. Greater than 10 court cases were brought against Wellpoint Blue Cross in California by patients seeking payment for CCDRT by Wellpoint Blue Cross. In each and every case, Wellpoint Blue Cross was found by the court to be in the wrong, and was ordered to provide full payment of services as originally billed, plus court costs. In a small claims court case argued and adjudicated in January, 2002, Wellpoint Blue Cross appealed the judgment to the Superior Court of California, County of San Diego. Oral arguments were heard April 12, 2002, with follow-up written arguments filed on behalf of both plaintiff (April 25, 2002) and defendant (May 9, 2002). The State of California Superior Court Judgment was rendered June 3, 2002.
    Presented on this website are:

    1. Brief introduction to the case

    2. Plaintiff's arguments (in favor of compelling Blue Cross reimbursement)

    3. Defendant's arguments (against compelling Blue Cross reimbursement)

    4. Superior Court Judgment (6/3/02)

    5. Additional relevant letters sent by Larry Weisenthal:

    6. Letter to National BlueCross/Blue Shield Technology Eval Ctr (5/4/02)

    7. Follow-up letter to Wellpoint Blue Cross (6/18/02)



  2. ***Medicare Coverage for Drug Resistance Testing Announced ***(December 1, 2000) Effective immediately, Medicare will provide payment for "cell culture tumor resistance" assays, while continuing to withhold payment for "human tumor cell sensitivity" assays.


    Editorial Regarding Ovarian Cancer Assays Showing Results Which Do Not Support Treatment with "Standard" Taxol/Platinum as First Line Therapy (click here for full text of editorial) June 11, 2002
    History of Randomized Clinical Trials in Ovarian Cancer: Pre-Taxol Era
    For many years (from the early 60s to late 70s), the "standard" ovarian cancer chemotherapy was single agent melphalan....
    Taxol Bursts Upon the Ovarian Cancer Scene
    Midway into the above 2,500 patient study, the glamour drug of the 1990s, paclitaxel (Taxol), came along. A prospective, randomized trial ....



    News and official government transcripts pertaining to national Medicare coverage for Human Tumor Assays


    Status of Medicare review of Human Tumor Assays March 15, 2000
    Brief history and current status of Medicare review of Human Tumor Assays.

  3. Selected quotations from each of the MEdicare Coverage Avisory Committee members, capturing the "take home message" conclusions of each of the committee members, after hearing detailed pro and con presentations from both proponents and critics of Medicare coverage for Human Tumor Assays. January 19, 2000


    Medicare Coverage Advisory Committee Meeting on Human Tumor Assays - Baltimore, MD. November 15/16, 1999
    Announcement: At the just concluded 2 day national Medicare Coverage Advisory Committee meeting in Baltimore to consider human tumor assay systems (following in depth pro and con presentations by me and by other proponents, by the NCI, FDA, HCFA, ASCO, and by outside consultants), the eleven voting members of the expert panel clearly expressed support of cell culture drug resistance testing as a covered service for Medicare beneficiaries. [November 17, 1999]
    News Story : Medicare Advisory Panel Concludes Chemo Lab Test Offer “Clinical Utility”  Meeting of MCAC panel highlights new era, process for seeking Medicare coverage. HCFA's new FDA-like "applications process" for national Medicare coverage decisions got a full workout on medical device issues November 15-16. After listening to detailed clinical evidence, a subcommittee of HCFA's Medicare Coverage Advisory Committee (MCAC) concluded that a group of lab tests known as human tumor assay systems (HTAS) can aid physicians in deciding which chemotherapies work best in battling an individual patient's form of cancer. HCFA will now take the panel's recommendations into account in developing national coverage policies for the tests, which are currently not covered by Medicare. [ November 22, 1999]
    Verbatim Transcript of Medicare Coverage Advisory Committee (MCAC) Meeting November 15,16, 1999 at which time pro and con testimony relevant to Human Tumor Assays (HTAs) was considered and voted upon.

    1. Volume 1 of 3: Introductions by HCFA and by the FDA and also including presentations of data by proponents of Medicare coverage of HTAs. At the end of the volume are comments by a regional Medicare contract insurance company and by ASCO. (nb. There is a major error in this volume of the transcript. On page 137 line 15: "18 percent" should read "80 percent.") Backup link for volume 1 of 3

    2. Volume 2 of 3: Presentations by critics, including the NCI, two outside consultants, and the HCFA staff. Backup link for volume 2 of 3

    3. Volume 3 of 3: Deliberations by the Medicare Coverage Advisory Committee, including individually stated opinions by each of the 13 panel members, and votes on a number of specific issues. The committee was not allowed to make a straight up or down vote on Medicare coverage, but the strong support of the committee for Medicare coverage is quite evident in the deliberations. Backup link for volume 3 of 3


  4. Reviews, Editorials, News Stories on Human Tumor Assays
    January 29, 2003Reuters news story on cell culture drug resistance testing (http://www.cancersourcern.com/tools/print/print.cfm?ContentID=26539)


    News Flash! DNA Microarray most powerful prognostic marker for breast cancer survival yet reported. December 17, 2002
    In the December 19, 2002 issue of the New England Journal of Medicine1, there appears perhaps the most remarkable clinical oncology paper I have ever read. A team of scientists from the Netherlands Cancer Institute reported absolutely astonishing correlations between long term survival of early breast cancer patients (Stages I and II, small tumors, age less than 55 years) and the results of a DNA microarray test which measured the patterns of expression of a set of 70 different genes. The correlations reported were vastly superior to those obtained with standard prognostic marker studies. These results have enormous implications for the short-term future of cancer research in general, and, if confirmed, will be one of the truly great cancer breakthroughs of our time. This DNA microarray work will, I predict, prove to be highly complementary to what I anticipate will shortly be parallel breakthrough efforts in targeted therapy through cell culture drug resistance testing (CCDRT). Stay tuned.
    1ref: van de Vuver, MJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999-2009, 2002


    Cell Culture Drug Resistance Testing (CCDRT) Cell Death Assays: Misconceptions Versus Objective Data Cell culture drug resistance testing (CCDRT) refers to obtaining fresh biopsy specimens of human neoplasms, isolating tumor cells from these specimens, exposing the tumor cells to drugs during short-term (3 - 7 days) culture, and assessing drug effects by measuring either cell proliferation or cell death.[August 31, 1999]
    Research Summaries:
    Milestone Publications Relating to DISC and MTT Cell Death (Apoptotic) Assays
    Cell Culture Drug Resistance Testing (CCDRT) refers to testing a patient's own cancer cells in the laboratory to drugs that may be used to treat the patient's cancer. The idea is to identify which drugs are more likely to work and which drugs are less likely to work. By avoiding the latter and choosing from among the former, the patient's probability of benefiting from the chemotherapy may be improved. [ September 15, 1996]
    Physician's Weekly : Should chemotherapy protocols be individualized by drug-resistance testing? Point/Counterpoint - Two sides of the issue discussed by Larry Weisenthal, M.D. Hematologist, Oncologist, Medical Director, The Weisenthal Cancer Group; Associate Clinical Professor of Medicine, UC Irvine and William P. McGuire III, M.D. Section Chief, Chemotherapeutics and Research, Gynecologic Oncology Center, Mercy Medical Center, Baltimore [September 23, 1999]
    Response to Issues Raised in Physicians Weekly Debate on Human Tumor Assays. [September 23, 1999 ]
    Scientific American Article: Pretesting Tumors - Long derided, test-tube screening for cancer-drug sensitivity slowly gains acceptance . (Scientific American, February 1999 )


    Featured Studies:
    August 14, 2002   Bosanquet and colleagues report that (1) fludarabine resistance in the DiSC assay correlates with patient survival in CLL; (2) apoptosis-related Bax and Bcl-2 expression do not correlate with patient survival; (3) reduced Bax expression correlates with resistance to alkylators, doxorubicin, and vincristine, but not with resistance to fludarabine or glucocorticoids; (4) Bcl-2 expression does not correlate with resistance to any drug. They conclude that apoptosis-activation pathways are different in the case of fludarabine and glucocorticoids than in the cases alkylators, doxorubicin, and vincristine. The abstract and literature reference for the study may be found here .
    March 8, 2000   Dr. Peter Staib and colleagues from the Universities of Cologne and Munich reported at the American Society of Hematology annual meetings on Dec. 4, 1999 in New Orleans that DISC assay results (in 122 patients) provided the strongest independent prognostic factor for survival in adult acute non-lymphocytic leukemia. The abstract describing the study may be found here or at the ASH Annual meeting web site.

Feedback ( 3/24/2004) - A compilation of messages, case summaries, reviews, and critiques submitted by readers (professionals, patients, family members, or other interested readers)