1. According to a study published in Gynecologic Oncology, the most probable mechanism for the synergy between gemcitabine + platinum is gemcitabine inhibition of repair of platinum/DNA adducts. What this means is that platinum-resistant tumor cells "cut out" the damaged DNA (to which the platinum is attached) in the same way that the railroad company repairs damaged sections of rail track. Then the railroad company lays down new track. Platinum-resistant tumor cells do the same thing, and gemcitabine interferes with this process. (Belpomme, et al. Gynecol. Oncol. 91:32-38, 2003)

Thus, you want to administer first gemcitabine (to have gemcitabine on board to inhibit the repair process). Then, you want to administer platinum shortly thereafter. In addition, you don't want to give either gemcitabine or platinum by itself on any days of the cycle; this doesn't take advantage of the synergy between the drugs and, in many cases, will just increase toxicity.

It is possible that clinical investigators did not design their treatment schedule to take advantage of the gemcitabine + platinum synergy which exists when platinum is administered in the presence of gemcitabine. An example in the Belpomme, et al study: patients received a platin on Day 1 and gemcitabine on Days 1 (after a platin) and Day 8 (without the platin) of a 21 day treatment cycle. The results were about the same that would be expected with a single agent platinum alone. Overall response rate of 65% and median survival of 24 months.

So it may have been more a problem with synergistic scheduling of the drugs rather than the drugs themselves. It may be one example of how clinical oncologists may get it wrong.

Posted at 4:30PM on Jul 17th 2006 by Gregory D. Pawelski

2. In fact, the combination demonstrated a twofold increase in the complete response rate compared with carboplatin alone (14.6% versus 6.2%). The overall response rate for the Gemzar-Carboplatin combination was significantly higher than the overall response to Carboplatin -- 47% versus 31%.

Also, a major bendfit to longer progression-free survival is the potential for chemotherapy cycling. The extra 3 months break will allow one to cycle back to another agent if one is available and effective.

Posted at 7:43PM on Jul 17th 2006 by Michelle

3. Gregory -- Thank you for adding to the conversation a well-researched perspective into how the researchers might have come to the conclusions they did regarding these drugs. Dalene

Posted at 8:04PM on Jul 17th 2006 by Dalene

4. Mr. Pawelski's information comes from an author of potential questionable authority who may have a conflict of interest. The potential positive outcome from an altered dose schedule comes not from human study data, but from tissue assay. Larry M. Weisenthal

http://weisenthal.org/gem_cp.htm

continues to push for Medicare and private insurance reimbursement for his Cell Culture Drug Resistance Testing. Until we get sound scientific data, approval will not occur. As of April 2006, in vitro chemosensitivity assays, including but not limited to the histoculture drug response assay or a fluorescent cytoprint assay, are considered investigational.

http://www.regence.com/trgmedpol/lab/lab06.html

Therefore, the statement, "it may be one example of how clinical oncologists may get it wrong," needs further justification.

Clinical oncologists deliver Gemzar as prescribed by Eli Lilly:

http://pi.lilly.com/us/gemzar.pdf

Studies are ongoing to determine optimal dosage and combinations.

Posted at 10:08AM on Jul 18th 2006 by Michelle

5. Individualized testing (or as Michelle calls it - tissue assay) of the gemcitabine + platinum combination began in the mid-1990s by Dr. Robert Nagourney, Director of Rational Therapeutics, Inc. Many patients received treatment with this regimen because of individualized testing long before any clinical trials in their particular disease types had ever been published. The contribution of Dr. Nagourney in terms of recognizing the synergistic effects of this combination (and as Michelle states - altered dose schedule) had been very important in getting clinical trials with this regimen started in a broad spectrum of cancers.

ASCO assessments of cell culture assays completely excluded all studies describing test accuracy and only included studies purporting to relate to test efficacy. The only criteria ever before used to evaluate laboratory tests has been test accuracy. Can you imagine the Journal of Clinical Oncology accepting for publication a paper on the Estrogen Receptor or on Her2/neu (target for Herceptin) which excluded all publications relating to test accuracy?

If a woman's tumor would be hormone receptor positive and Her2/neu positive, her oncologists would base their treatment on these test results. However, there has never been so much as a single clinical trial published to show that breast cancer patients who are managed on the basis of hormone receptor test results and Her2/neu test results do better than patients who are managed without benefit of the information provided by these tests. By the criteria demanded of cell culture assays by ASCO, there would be no justification for basing a woman's treatment on the basis of these "unproven" hormone receptor and Herceptin receptor test results.

The criteria always used to evaluate medical tests is the accuracy of the tests and not the efficacy of the tests. There is no single test (laboratory or radiographic) used in cancer which has been proven to be efficacious in prospective randomized trials, where patients are managed with and without the benefit of the information provided by the tests, and treatment outcomes compared. The only information which has ever been obtain is how accurate the tests are, and the accuracy of the a cell culture assay compares favorably with that of other similar tests used in cancer medicine.

Critics of the testing are demanding a standard of proof which is truly unprecedented, and which has not been met by all of the other tests used in cancer medicine. Most of the cancer treatments used have not met the standard of proof demanded of cell culture assays, which is a test and not a treatment. The degree to which "standard" cancer chemotherapy has been "proven" to be more efficacious than other forms of treatment has been overstated, overassumed, and over-sold.

Posted at 12:36PM on Jul 18th 2006 by Gregory D. Pawelski

6. You state, or I should say Mr. Wiesenthal states:
http://weisenthal.org/breast_ca_husband_letter.htm

"ASCO assessments of cell culture assays completely excluded all studies describing test accuracy and only included studies purporting to relate to test efficacy."

Yet the Working Group states:

"These studies should randomly assign patients to the regimens identified on the basis of in vitro testing (the "in vitro best regimen"), or to empiric therapy with the standard regimen based on clinical trial data. The end points in these clinical trials should include survival as the clinical measure of outcome."

http://jco.highwire.org/cgi/content/full/22/17/3631

A thorough examination of sound, scientific data has led to a policy statement, by one insurance co., Aetna. I encourage you, if interested to read the information under "Background" for an understanding of why the Working Group continues the policy of not recommending chemosensitivity testing at this time.

While the knowledge of drug resistance status may serve as a guide in planning treatment, it is incorrect to assume that this method will avoid ineffective treatment and related toxicities.

As is stated:

"Even the avoidance of potentially unnecessary toxicity is not a straightforward outcome. If one drug is eliminated from a regimen on the basis of chemoresistance, in most cases another drug with its associated toxicity will be substituted. As mentioned above, there is no guarantee that the toxicity of the new drug will be compensated by an improved outcome. Therefore, considering the above discussion, chemoresistance is intricately tied to chemosensitivity, and thus, improved patient survival becomes a relevant outcome."

I encourage your readers to read the ASCO statement before paying an enormous amount of money out-of pocket for an, as yet, unproven method. Perhaps, in time, one may see benefits to this method, but that time has not yet come. Large properly controlled studies are needed. This method has given us data that has added years to the lives of cancer patients. No longer do surgeons open up an abdomen, view the cancer, close up the abdomen and just send the patient home with no treatment. It is directly because of the scientific method and the courageous patients who have entered controlled clinical trials that we have made such tremendous strides.

Posted at 3:43PM on Jul 18th 2006 by Michelle

7. Yes. I have stated, ASCO assessments of cell culture assays completely excluded all studies describing test accuracy and only included studies purporting to relate to test efficacy. If Michelle wants to win arguments by debating issues, let's debate the issues, not by attacking the person making the arguments (or others), but I'm not sure exactly what was her point? What does wanting to improve the scheduling of an important drug combination (gemcitabine/platinum) have to do with assays and Medicare reimbursement?

http://www.jco.org/cgi/content/full/23/15/3640

http://www.jco.org/cgi/content/full/23/15/3643

http://www.jco.org/cgi/content/full/23/15/3645

http://www.pubmedcentral.org/articlerender.fcgi?artid=166157

I believe Dr. Weisenthal, as well as other individualized cancer treatment scientists, have been long time proponents of Medicare coverage. Why shouldn't there should be an expansion of Medicare and private insurance reimbursement to promote even greater utilization and development of laboratory-based mechanisms for improving the match between tumors and an ever-increasing number of partially effective and very expensive drug therapies?

Why are 80% of academic oncologists and 35% of private practice oncologists ordering a $3,600 test (OncotypeDX) at a time when it had only been shown to be accurate (and not efficacious) and only in a retrospective study in which all assays were done not under real world conditions but by a single lab team in the space of two weeks? All studies being be planned are studies to confirm the predictive accuracy prospectively.

Why is it appropriate to specifically exclude test accuracy as a factor to evaluate cell culture assays when test accuracy is the only factor used to evaluate every single other type of medical test?

Since 1981, the National Medicare policy on chemosensitivity assays (specifically described but not limited to Human Tumor Stem Cell Assay and Fluorescent Cytoprint Assay) are considered investigational. However, as anyone researching would have found, neither of those assays has been used in the clinical management of patients in a non-investigational setting for more than 15 years.

National Medicare currently has no national coverage policy relating to the technologies that are in current use, leaving it to local coverage decisions.

http://www.rationaltherapeutics.com/experiences/pred_acc_gyn_tum.htm

http://www.regence.com/trgmedpol/lab/lab06.html

http://www.rational-t.com/

Posted at 5:14PM on Jul 18th 2006 by Gregory D. Pawelski

8. Medicare coverage for the Oncotype test has begun because the Oncotype test gives one a recurrence score. It "accurately" predicts who will get a recurrence. And, it is "effective" in that it produces or is capable of producing an intended result. This is much different from chemoresistance assays which have not yet been scientifically proven in large controlled studies to produce the intended result of a desired clinical outcome. Oncotype DX is not a test of direct chemoresitance as are the tests performed by all those quoted in your linked URLs. By looking at genes researchers can predict chance of recurrence and thus a decision can be made as to whether one may benefit from tamoxifen.

Oncotype DX is validated for use in breast cancer patients whose disease is:

Newly diagnosed
Stage I or II
Node-negative
Estrogen receptor-positive

and who will be treated with tamoxifen.

This is much different from testing individual chemotherapeutic agents, though Oncotype may do that. The goal is to determine who will benefit from a this SERM.

As far as this study goes http://www.pubmedcentral.org/articlerender.fcgi?artid=166157, as you link to:

The objective response rate was 40.5% for the assay-directed group vs 31.5% for the physician's choice of treatment. Progression-free survival (intention-to-treat analysis) was 104 days in the assay-directed vs 93 days in the physician's choice groups. In addition, there was no difference in overall survival between the strategies. This study provides support for the conclusion that the ATP-based tumor chemosensitivity assay is not superior to physician's choice in the selection of chemotherapy in women with platinum-resistant ovarian cancer.

We need larger prospective studies before these tests should be covered.

--------

"Although numerous attempts have been made to analyze the effects of drugs on cell metabolism, cell morphology, radionuclide incorporation, and various aspects of cell membrane integrity, there is no consensus that these [chemorestistance] assays can be utilized routinely in the clinical setting. Major questions remain unanswered, such as how best to select patients who benefit from these tests and whether patients receiving assay-selected chemotherapy show better response than those receiving best current therapy."

http://www.aetna.com/cpb/data/CPBA0245.html

As far as you suggestion of an ad hominem attack from me, I'd simply ask where I have made such astatement and I shall correct that fallacious argument.

Appeals to emotion are real red herrings and I certainly understand that they do not belong in this type of discussion. We're all here becuase we care about cancer research.

Posted at 7:17PM on Jul 18th 2006 by Michelle

9. None of the available laboratory tests used in the selection of treatments for cancer patients have ever been tested for efficacy. This includes estrogen receptor, progesterone receptor, Her2/neu, immunohistochemical staining for tumor classification, bacterial culture and sensitivity testing, CT, MRI and Pet Scans to measure tumor response to treatment, and yes, cell culture assays. The only data supporting any of them relate to test accuracy, and there is a total lack of information regarding test efficacy (randomized trials with outcome measurements for diagnostic tests).

Also, no one is seriously proposing that any of the molecular tests now available (Oncotype DX, EGFR amplification/mutation) should have to be proven efficacious, as opposed to merely accurate, before they are used in clinical decisions regarding treatment selection.

Cell culture assays have been well proven to have predictive accuracy with that of estrogen receptor, progesterone receptor, Her2/neu and the newer molecular tests. There is nothing wrong about the Oncotype DX. The data for predictive accuracy of cell culture assays is the same data that exists to validate the Oncotype DX test, which wasn't a prospective study and certainly wasn't a real world study.

The study you referred to, the results from the very first prospective, randomized clinical trial of physician's choice versus ATP assay-directed chemotherapy by Cree, Kurbacher and associates achieved exceptional chemotherapy response rates, and a trend toward improvements in overall patient survival. ATP-TCA-directed therapy resulted in a total clinical benefit of 65% compared with 51% for patients who received chemotherapy based on physician choice, and a slight improvement in progression-free survival.

The results were highly suggestive of an effect due to the assay, and the most successful drug regimens used were nearly all developed using the assay. UK results in cancer are always lower than in the U.S. for a variety of reasons. Part of this is probably lead time bias and the amount of surgical debulking. Patients in the U.S. get a whole lot more surgery along the way than in Europe. However, we are discussing accuracy as opposed to efficacy.

It is within each practitioner's prerogative to order cell culture assays, if test results are used to assist in the selection of a regimen chosen from a series of otherwise reasonable alternatives, then patients will never be harmed by using the test result, and best available evidence strongly indicates that they will often be helped.

I agree, appeals to emotion are real red herrings and accusations of noted scientists having questionable authority (potential or ortherwise) do not belong in this type of discussion. We are here because of the concern about cancer research.

Posted at 10:34PM on Jul 18th 2006 by Gregory D. Pawelski

10. The results of the UK study were compelling, however have yet to be dupliacted in a large well-controlled study. As the Working Group indicates:

"The Loizzi et al study was designed to compare response rates to chemotherapy for recurrent ovarian cancer among patients receiving either assay-guided therapy or empiric treatment. This was a prospective, but not randomized, clinical trial including 100 consecutive patients (50 treated by assay-guided regimen; 50 empirically). A subset analysis looking at secondary end points among the platinum-sensitive group revealed a survival difference; no survival difference was seen in the platinum-resistant group. Because standard treatment for recurrent ovarian cancer includes platinum therapy, and owing to the lack of a randomized design and the small number of patients, this study has not made an impact on current treatment recommendations. In addition, the chemotherapy regimens selected under assay-guidance are nearly identical to those selected by empiric treatment. This makes it hard to understand the dramatic difference in survival. It is a provocative finding, which may justify large, randomized, prospective clinical trials with similar treatment elements."

I direct readers to this section of this page. It's written for the layman:

Summary of Literature and Recommendations for Practice--> http://jco.highwire.org/cgi/content/full/22/17/3631

I also direct readers to this compelling summary of why HER2 "accuracy" should now be used clinically. You will notice that extensive research, including large, long term, controlled studies have been completed.

http://jncicancerspectrum.oxfordjournals.org/cgi/content/full/jnci;91/2/110

There is simply no substitute for well-designed, large studies. Dr. Wiesenthal should put one together.

Posted at 10:57AM on Jul 19th 2006 by Michelle

11. I'll remind readers that there are "sound scientific data," but all of it was excluded from analysis by ASCO assessment. In the ASCO (and insurance industry) reviews, all papers dealing with accuracy were specifically excluded from review. Only papers relating to efficacy were included.

If the same criteria were applied to evaluate every single other test used as an aid in selecting treatments, exactly ZERO tests would be available.

Furthermore, accuracy is not being applied to a single test currently under development for use as an aid in selecting treatment. This criterion wasn't applied by the FDA, which regulates test kits for cell culture assays, while not regulating the tests themselves. The FDA applied the same criterion it applies to every single other of the hundreds of test kits (maybe thousands) that they do approve (Accuracy).

Look at the difference between drugs and treatment devices on one hand and the kit used for cell culture assays on the other hand. Drugs and treatment devices are proprietary, patented products which are typically sold for multiples of production costs which commonly run in the range of 100 to 1000 to 1. In other words, drugs are protected by patents and sold for 100 times production costs to 1000 times production costs.

The cell culture assay kit is non-proprietary, public domain. Profit margin is on the order of 1.5 times production costs and 1.15 times total costs, including facilities, billing, insurance, utilities, etc.

And the fact is 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 that a planned clinical trial in relapsed NSCLC proves efficacy. All that is proved is that it improves things for one small indication. Relapsed NSCLC; not ovarian cancer. And it's worse than that. The year after the study would close, two new drugs could become available and the test only proves efficacy with the old drugs. It doesn't prove efficacy involving the new, improved drugs. It's a constantly moving target.

NCI made an attempt years ago to study assay-directed therapy of lung cancer on its own.

Their expertise was in establishing permanent cell lines and they only tested tumors after first culturing them to amplify their cell number (these were all passaged, grown up, multiplied, replated). The result was that their assay evaluability rate for primary lung cancers was only 11% (a very dismal result).

The second problem they had is that they were selecting subpopulations. Subsequent work showed that you get different results when you test passaged cells compared to primary, fresh tumors.

The third problem is that the ability to get lung cancer to actually grow is an independent marker for virulent disease. It was actually the single greatest negative predictor for survival in one study.

So, the NCI concluded that it was too much trouble and not all that useful. That was the attitude thereafter. If the NCI can't do it, nobody can (if Mikey doesn't like it.....). That's not the way to do science!

Posted at 3:14PM on Jul 19th 2006 by Gregory D. Pawelski

12. Partially on the basis of the recent article by Loizzi et al demonstrating a significant survival advantage for ovarian cancer patients who were treated with assay assisted therapy, (this is highly debatable as 'lack of a randomized design and the small number of patients, this study has not made an impact on current treatment recommendations') the Gynecological Oncology Group has approved the concept of performing a trial to assess assay directed therapy for patients with platinum resistant epithelial ovarian carcinoma. We await the results of this and other "assay directed" trials with the hope that the time for successful tailored therapeutics has finally come.

And, I await. Then, a sound decision will be made.
As Bush says, "Bring it on."
http://www.jco.org/cgi/content/full/23/15/3641

Posted at 5:30PM on Jul 19th 2006 by Michelle

13. I heard about that last year. Thanks for the information. The GOG had decided to move forward with a study in platinum-resistant ovarian cancer, utilizing the EDR-only assay to direct chemotherapy. I have to go along with you on this one, the design is one that is bound to fail (about as successful as the "Bring it on.").

This assay is specifically designed to identify "inactive" drugs and reports on this assay even state that the assay results should "not" be used to identify "active" drugs. The EDR assay can only identify a small percentage of patients who will "not respond" but then when the results were used to select an non-EDR alternative, it did not provide responses. In this light, the EDR assay has the advantage of telling you who will "not respond" but cannot in any way change the negative outcome by selecting an "active" alternative.

A pilot study, in which two GOG investigators used the EDR assay to identify the "best" treatment regimens for platinum-resistant ovarian cancer was negative, with both assay-directed and non-assay-directed patients having the same median survival.

I believe that a separate study, a front-line randomized trial with the primary endpoint being "time to disease progression," secondary endpoint being "overall, long-term survival," and third endpoint being "correlation between assay-directed and physician's choice therapy, would be more in keeping with positive results.

Assays based on "cell-death" occur in the entire population of tumor cells, as opposed to only in a small fraction of the tumor cells occurring in "cell-growth." Cell-death assays like DISC, MTT, ATP and fluorescein diacetate assay, correlate very well with each other on direct comparisons of different methods.

Different methods of assay results should be applied in choosing a particular drug regimen to be used in treating an individual patient's cancer. They will sort the different reasonable treatment regimens into the different groups (above-average, average, below-average, and very below-average), which would direct attention away from regimens "less" likely to provide benefit and toward regimens which are "more" likely to provide benefit. I am increasingly convinced, along with many others, that the best trial is a first-line study, no prior therapy, assay versus a control.

Posted at 3:14AM on Jul 20th 2006 by Gregory D. Pawelski

14. Ovarian Cancer Drug Combination Identified at Rational Therapeutics Receives FDA Approval

http://biz.yahoo.com/bw/060728/20060728005151.html?.v=1

Posted at 4:57PM on Aug 1st 2006 by Gregory D. Pawelski

15. 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

http://www.anticancer.com/News%20ASCO%20Sept.2004.html

Posted at 1:37AM on Sep 12th 2006 by Gregory D. Pawelski