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From: (RunnSwim)
Subject: Re: chemo failure
Date: 12 Sep 2000

O.K. I wasn't going to jump into this and I have not previously had any
postings to a general newsgroup such as this since I stopped participatating in
the CompuServe Cancer Forum over 5 years ago; but here goes:

I was innocently perusing the usenet search engine, looking up an
article I had previously posted on (my favorite sport and
pastime).  While looking under "Weisenthal," I came across this thread. At
first just sent a private e-mail to "Steph," as I did not read the complete
thread, and only one of his brief, initial messages on the "deja" retrieval:

I warn everyone, this is going to be a very long and detailed thread, if the
two good doctors involved to date are willing to stick it out, in terms of a
back and forth discussion of the issue and data, but I'm willing, if they

So here goes.  I think I'll just begin by reprinting my private e-mail to


Subj:	Cell Culture Drug Resistance Testing in Cancer
Date:	9/12/00
To:	Steph@vancouver.island

While "" searching newsgroups to find a lost posting of mine on, I was surprised to come across this thread.

>>Because of this and other reasons (including the different environment in
vitro from in vivo), in vitro testing has not proven of any real value.
It is true though, that tumours progressing on appropriate chemo are very
unlikely to respond well to another regime.<<

I'm sending this only to you (I presume you are a physician), because I
don't want to get involved with newsgroup cancer discussions where patients

You are regretably misinformed about the current status of cell culture drug
resistance testing, which is now officially covered as a medical service for
cancer patients by Medicare and by virtually all private insurance companies
in the USA.  This would not, I assure you, have happened in the absence of
a persuasive peer-reviewed, published literature.

You can find links to official US government transcripts of the Medicare
Coverage Advisory Committee deliberations (including two days of pro and
con testimony from laboratories, from the NCI, ASCO, and various other
organizations) on the Human Tumor Assay Journal website (

With regard to your statement above, there are so many cases where that
statement has been dramatically disproven...  a couple of e.g.s

39 y.o. oncology nurse with ovarian cancer. Failed first line
Taxol/carboplatin. Went to UCLA for TANDEM bone marrow transplants, with
ultrahigh dose chemotherapy.  In hospital for 6 weeks, at a cost of > $200,000
(US).  Terrible toxicity. No response.
Massive abdominal disease and bilaterally positive pleural effusions.
Non-resectable and not even debulkable.  Small biopsy taken for cell culture
assays, which identified a gentle, well-tolerated outpatient regimen which in
several months produced a complete clinical regression. Two years later the
patient remains in unmaintained complete clinical remission and has been
working for more than a year full time at her old job as an oncology nurse.

40 y.o. with pancreatic adenocarcinoma metastatic to liver and kidney. On
continuous parenteral narcotics for pain relief. Went to U of So California
(USC), UCLA, City of Hope Natl Med Ctr, and John Wayne Cancer Inst, all of whom
told him that only palliative treatment was available and median survival on
the order of 1-2 months. Went to local, private practice oncologist, who
arranged a laparscopic biopsy for cell culture.  An (at the time) novel
combination was identified (gemcitabine + cisplatin); he was treated with this
and has now been in complete remission nearly 4 years after his assay, with
negative PET scans, normal labs, no symptoms, leading a completely normal life.
 His case was described in Scientific American in an article which may be found
on a link on the above web site.

There are many, many more cases like this of patients who were treated with
novel therapies identified by individualized assays who derived unequivocal

While in agreement that prospective, randomized trials of assay directed vs
physician's choice therapy are desirable (and no one has worked harder than me
to get those trials launched and completed), the reality is that there are no
laboratory tests in all of medicine (including bacterial culture and
sensitivity tests) which have been shown to improve the results of treatment in
such prospective, randomized trials of treatment without tests versus treatment
with tests.  The accepted standard for judging laboratory tests has always been
predictive accuracy and not efficacy in prospective randomized trials.  And
there has been an appalling unwillingness of cooperative oncology groups to
agree to perform the necessary trials.

It's a case of what level of evidence you require:

Proof beyond reasonable doubt (does not exit for most cancer chemotherapy
treatments, much less the "efficacy" of virtually all laboratory tests)...this
is the "criminal justice" standard.

Preponderance of currently available evidence....this is the "civil justice"

Best wishes,

Larry M Weisenthal MD, PhD
Huntington Beach, CA

From: (RunnSwim)
Subject: Re: chemo failure
Date: 14 Sep 2000

>>Again the issue is whether patients should be paying for unproven
treatments or tests before proper evaluation confirms their validity.<<

This presumes that most cancer treatments have had their validity confirmed
through "proper evaluation."

What is proper evaluation for a treatment? For a test?

Let's consider the case of ovarian cancer, which I think is pretty
representative of what decades of clinical trials have produced (I'd be happy
to do the same sort of review, disease by disease, if this would be helpful).

For many years (from the early 60s to late 70s), the "standard" ovarian
cancer chemotherapy was single agent melphalan. This was an inexpensive
and usually well tolerated oral drug. In the late 70s, the NCI reported
the results of a randomized clinical trial in the New England Journal of
Medicine in which a complex and toxic combination ("HEXA-CAF")
ostensibly produced superior results, compared to single agent
melphalan. But this study was not confirmed. By the early 80s, some data
appeared to support the concept that cisplatin-based combinations might
produce superior outcomes. The new standard became cisplatin +
cyclophosphamide (CTX). Later on, carboplatin was introduced, and the
combination of carboplatin + CTX was found to produce results equivalent
to cisplatin + CTX, but the former combination was better tolerated.
This became the new standard. However, a landmark meta-analysis
published in the early 90s (Br Med J 303:884-93,'91), analyzing studies
including 8,000 patients
and 6,000 deaths to determine what had been learned about optimum first
line chemotherapy concluded that "no conclusions could be made." There
was a (non-significant) trend in favor of platinum-based regimens and
there was a (non-significant) trend in favor of combinations over single
agent melphalan. To be specific, there was a nonsignificant absolute 5-year
survival advandage for cisplatin-based combination chemotherapy compared to
non-platinum single-agent therapy of only 1% (95% confidence level = from -8%
worse to +10% better)!  Yet for a decade, 99% of ovarian cancer patients have
received platinum-based chemotherapy.

The above meta-analysis study authors concluded that previous studies
(often involving hundreds of patients) had been much too small to
provide statistical power, and the authors announced that their
cooperative group was initiating a prospective trial to compare single
agent carboplatin versus the combination of cisplatin + doxorubicin +
CTX which was to accrue 2,500 patients.

A re-analysis of the original meta-analysis (but leaving out - i.e. censoring -
about 25% of the patients in the original meta-analysis) finally did show a
very small advantage, 10 years out, for platinum-based therapy over
non-platinum therapy. But it took 20 years, scores of prospective,
randomized trials, and repeated meta-analyses (performed on a revised -
and reduced - database of prospective, randomized trials) to show a
minuscule advantage for platinum-based therapy over non-platinum-based

So, what about Taxol?

Midway into the above 2,500 patient study, the glamour drug of the
1990s, paclitaxel (Taxol), came along. A prospective, randomized trial
showed the superiority of cisplatin/Taxol over
carboplatin/cyclophosphamide, and the former combination quickly became
the new standard, which ostensibly made the ongoing, long-term,
expensive study of cisplatin + doxorubicin + CTX instantly irrelevant
and obsolete. The new cisplatin/Taxol combination is, parenthetically,
vastly more expensive and toxic than was the oral melphalan "standard"
of the 1970s (>$25,000 per patient, as opposed to <$1,000 per patient).
And does Taxol add anything to cisplatin (or carboplatin) alone? Of the
drugs introduced in the 1990s, probably no drug was more highly touted
than Taxol, and in no disease was it more highly touted than in ovarian
cancer. Indeed, it would be accurate to state that most clinical
oncologists probably feel that it would be tantamount to malpractice not
to use either Taxol/cisplatin or Taxol/carboplatin as first line therapy
in ovarian cancer. This point of view is, in fact, given the imprimatur
of the NCI's authoritative PDQ description of state of the art therapy.


A recent, large, multi-institutional trial (Gynecologic Oncology Group #
132) randomized ovarian cancer patients to (1) Taxol/cisplatin, (2)
Taxol alone, and (3) cisplatin alone. Patients could be crossed over to
the other drugs in the event of disease progression. The result? Taxol
alone was inferior to the other two regimens, while cisplatin alone was,
if anything, superior to the Taxol/cisplatin combination in complete
remission rate and duration of response and most certainly was no worse
than the combination. So what is the level of evidence supporting the
use of Taxol/cisplatin over cisplatin alone? And given that carboplatin
has been shown (in combination trials) to be therapeutically equivalent
to cisplatin, but less toxic, is it not reasonable to consider using
single agent carboplatin alone, as first line chemotherapy?

In a very recent editorial (JNCI 92:674-5,2000), Dr. William McGuire
succinctly summarized the status of clinical trials in ovarian cancer
and presented his own view of the future, stating "thus, even though
more than 5400 patients with advanced ovarian cancer have been accrued
to randomized trials in the last decade to "fine tune" the regimen with
the best therapeutic index, what is best is still unclear." McGuire
further maintained that randomized clinical trials must now be
international in scope, as single institutions do not have the
capability to carry out studies of sufficient statistical power, nor
even do individual cooperative groups, nor do intergroup studies
combining several cooperative groups; rather only a truly global effort
is up to the task of methodically testing all of the myriad potential
combinations to define the next 2 month improvement in median survival,
based on the paradigm of one size fits all chemotherapy.

By coincidence, in a perfect example of just such a global effort, the
results of a very important large international study were just
presented at the plenary session of the American Society of Clinical
Oncology annual meeting in New Orleans, May 20, 2000. The Third
International Collaborative Ovarian Neoplasm Study (ICON3) included 2074
patients from 132 hospitals in 8 countries. At the time of this second
planned analysis, median follow up was 29 months, 925 patients remained
alive without progressive disease and 1293 had either died or developed
progressive disease. Two year survival was 64% in the group treated with
carboplatin/Taxol (now considered "mandatory" standard therapy in the
USA) and an identical 64% in patients treated either with single agent
carboplatin or with the very old regimen cyclophosphamide + doxorubicin
+ cisplatin. Subgroup analysis revealed no group for which treatment
assignment caused significant differences in either progression-free
survival or overall survival. The study chairman reported that "even if
there is (ultimately) a difference in survival, it will probably be only
about 2%." Though there had been an initial suggestion (reported in the
printed abstract) that patients with bulky disease benefited more from
Taxol, this difference was not sustained in the longer-term data which
was reported at the meeting.


I doubt that objective reviewers outside of the academic clinical
oncology establishment would conclude that the paradigm of performing
huge randomized studies to identify the best treatment to give to the
average patient has done anything other than waste money and waste
patient clinical trials resources (i.e. patient lives), although it has
generously supported the careers of its proponents, who are the thought
leaders in clinical oncology today. At the end of the day, the only
clear conclusion possible after more than 20 years of these cooperative
group trials of empiric chemotherapy in ovarian cancer is that there is
no clear and meaningful advantage associated with any form of therapy
ever examined in these trials. This emperor truly has no clothes. Why is
it justifiable to defend (and even insist on) treating all patients with
Taxol combinations (which, for the average patient, probably cost
$15,000 more than non-Taxol combinations, such as single agent
carboplatin or cisplatin-doxorubicin-cyclophosphamide)?

What makes more sense?

1. Treat all patients with carboplatin/Taxol?
2. Choose between reasonable treatment regimens (e.g. single agent
carboplatin, carboplatin/Taxol, cisplatin/doxorubicin/cyclophosphamide,
gemcitabine/cisplatin, cisplatin/topotecan, cisplatin/vinorelbine,
cisplatin/Doxil, cisplatin/etoposide, etc.) with the assistance of
information from a well-validated Human Tumor Assay performed by an
experienced laboratory?

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Subject: Re: chemo failure
Date: 18 Sep 2000

>>For a test, predictive accuracy (which appears to be good for some of
these assays); and for this type of test, survival impact.  That is the end
result of this test, after all:  is the survival outcome for the patient

Why should ovarian cancer patients receive Taxol when it hasn't been proven to
improve survival compared with either single agent cisplatin or single agent
carboplatin or even single agent oral melphalan?

Name a single laboratory test which has been proven to improve treatment
results in any disease (preferably survival in cancer - but I'll accept any
test in any disease).

There are vastly more data confirming that the tests are accurate in predicting
for both response and survival in cancer than there are for analogous tests in
infectious disease.

>>We may see something different as Taxol is nearly off its patent.
However we do not have comparable results yet for the survival impact of
in vitro assays so I think your conclusion is a little premature.  (It
would be ironic, wouldn't it, if the in vitro assay results routinely
suggest the very combinations you slam here.)<<

In point of fact, the tests show a great heterogeneity in drug resistance
between patients.  This reflects clinical results, where many patients fail to
benefit from first line therapy, only to respond to second line therapy.  These
patients should have received the best treatment the first time around.

You simply don't know the literature.  As I said, in the USA, insurance
companies, Medicare, HMOs etc. don't like paying for anything they don't have
to.  They wouldn't be paying for this in the absence of an extensive and
consistently positive peer-reviewed literature.

You keep making the point that cancer doctors shouldn't order tests (and
presumably offer treatments) without clearcut proof of survival benefit.  These
tests have vastly more documentation of strong predictive value for both
response and patient survival than exist in the case of most laboratory tests
used to aid in the management of cancer patients.  When Medicare convened an
expert panel of physicians to consider reimbursement for these tests, the
several pathologists on the panel made statements such as (and I am
paraphrasing from memory, but the verbatim transcripts are available in
official US govt links posted on the website for the Human Tumor Assay Journal
(URL posted previously on this thread)):

"there are few, if any, laboratory tests which have ever been shown to improve
the results of treatment"

"the documentation for these (cell culture drug resistance) tests exceeds that
of most of the tests used in cancer medicine"

"if we don't approve these tests, then perhaps we shouldn't approve bacterial
culture and sensitivity tests as well"

>> I'll restate it here:  what about
the survival impact factors for these assays?  How does predicting a
chemotherapy regimen based on this assay, contribute to overall patient
survival?  Not just single cases--but in controlled trials?  That J.
Clin. Oncology paper asks the same question, and I think it's one that a savvy
patient will want to ask too.  <<

I think that a "savvy patient" should ask the following question:

What are the data which prove that an empiric, "one size fits all" treatment
(in a disease - cancer - notorious for its heterogeneity) identified by the
clinical trials paradigm of randomized trials to identify the single best
treatment to give to the average patient is clearly the most promising
treatment to receive?

Let's take ovarian cancer:  There are at least a half dozen empiric regimens
that no honest clinical oncologist would say are not equally likely to work as
the others in an average patient.  Now let's say that we have a test which has
been shown, again and again and again, to be as accurate in predicting response
and survival to chemotherapy as is the case with bacterial culture and
sensitivity tests (which everyone uses without controversy). And the test shows
that 3 of those treatments look poor, one looks fair, and the last two look
good.  So the oncologist narrows his choices to the final two and then factors
in his/her clinical judgement in making the final choice.

What does the savvy patient decide to do?

I've got a solid track record dating back to 1984 of trying to get cooperative
groups to do just the sort of trials that you are suggesting are mandatory.
But they've always been vastly more interested in doing the logistically much
simpler trials of empiric, one size fits all therapy.  This is all they know.
It has generously supported their careers.  But it hasn't accomplished
anything.  Not anything of solid substance.

Let's say we'd never done a single randomized clinical trial comparing one form
of chemotherapy with another in lung cancer or breast cancer or ovarian cancer
or melanoma or colorectal cancer?  Would things be any worse than they are now?
 Tell me what you think are the great lessons from these trials...any lessons
from these clinical trials regarding drug selection (regimen A vs regimen B)?
What have we learned that has really made a big difference for patients with
these diseases?

The time to do a randomized trial is when you have a disease like testicular
cancer, when you start getting a lot of durable complete remissions.  Then it's
worthwhile asking questions such as "is carboplatin as good as cisplatin?"
Until then, you are doing individual patients a disservice and you are doing
science a disservice by insisting that patients receive treatments which have
been studied but which have not been validated as offering a clear cut

If the cooperative groups had been willing to study these tests during the past
15 years, we'd by now have a tremendously valuable tool for both clinical
treatment and clinical research.  It could have happened, but it didn't.

So the savvy patient is left with the following dilema:

1. Do you receive only treatments or tests which have been proven beyond
reasonable doubt to improve the survival of the average patient, as documented
by prospective, randomized trials?  If so, you will have few if any treatment
or testing options open to you.

2.  Do you consider receiving treatments and tests which have the support of a
preponderance of a large amount of evidence, if less than proof beyond
reasonable doubt?

I think that a savvy patient should ask his doctor to show the patient the
survival curves for a given recommended form of treatment, including the
survival of patients treated on phase II and phase I trials which the doctor
may recommend.  The patient could also ask the laboratory for the survival
curves of patients for whom laboratory tests have been ordered.  In the absence
of survival data directly pertaining to the recommended treatment or test, the
patient could then listen to explanations of why such data are not available.

And then decide as to the best course of action.

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Subject: Re: chemo failure
Date: 19 Sep 2000

>>But despite your handwaving, and a few
impressive testimonials, you still have not addressed the key issue:
what survival impact do these tests have? <<

What survival impact does a CA-125 have? What survival impact does a 2nd look
laparotomy have? What survival impact does a CT scan or MRI scan have? Do you
think that patients live longer when you "follow" results of chemotherapy with
serial CT scans, as compared to just doing a physical exam, simple lab tests,
weighing patients, and asking them how they feel?  What survival impact does
performing a Her2/neu by fluorescence in situ hybridization assay have? What
survival impact does 2nd line and 3rd line and 4th line chemotherapy have?
And, again, what survival impact does Taxol have?

I can prove to you that patients who are treated with in vitro active drugs
have a seven to nine fold response advantage and a significant survival
advantage over patients treated with in vitro inactive drugs. These are not
randomized studies, but, again, I am still waiting for an example of a single
laboratory test which has been shown to improve treatment results in studies
where patients are randomized to treatment with and without test results.

In the absence of test results, what factors go into selection of treatment

Well, if you are treated at an NCI designated cancer center or a typical
University, you will be steered into a treatment protocol comparing Pepsi Cola
versus Coca Cola (in the words of one sage commentator at a previous ASCO
Plenary Session), where the purported differences between Pepsi and Coke are
usually insignificant and even less often consistently confirmed in follow-up
trials, and where the magnitude of difference, even if significant, is
virtually always trivial, and where the contribution to true progress in
scientific knowledge is non-existent.

But the contribution of the clinical trials capitation fees to the balance
sheet of the University and to the curriculum vitaes of the professors is
considerable.  Why should the professors do something logistically difficult
(trials of assay directed therapy) and non-remunerative (e.g. I'm a single
practitioner and not a corporation and I can't pay them thousands of dollars
per patient; I can only offer to do the tests without charge; but I'm also a U
of Michigan and National Cancer Institute trained MD/PhD who is an
internationally recognized expert in these technologies and who has been
performing and improving them on a full time basis for the past 20 years).  But
it's tough luck; come back and talk to us when you can pay us the same thing as
an Eli Lilly gemcitabine empiric trial which is much less bother to do.

Now you go to the private practice medical oncology situation.  How are
treatment regimens selected there?  In an era when most Internal Medicine
subspecialists are badly "hurting" (in a financial sense), many medical
oncologists are doing pretty well...not for reimbursement for cognitive
services, but for, in effect, running a retail pharmacy for antineoplastic
drugs.  The reimbursement for these drugs is based on some index of average
wholesale cost.  A savvy retail pharmacist will shop around for the lowest cost
(always under the "average" wholesale cost), as will a savvy oncologist who is,
in effect, running a retail pharmacy.  Thus, the profits will bear a direct
relationship between the "spread" between average wholesale cost (on which
reimbursement is based) and the actual reimbursement.  This will differ for
different drugs.

Given that we have a situation, in virtually all types of cancer, where there
is a legitimate choice between perhaps a half dozen or more equivalent
therapies (precisely because of the lack of meaningful difference between Pepsi
Cola and Coca Cola), one could justify selecting a treatment regimen literally
by flipping a coin, particularly in the second, third, fourth line treatment
situation (where survival advantages for such treatment have never been

You don't think that possibly the "spread" between cost of the drugs and
reimbursement for the drugs and cost of administration versus cost of
reimbursement enters into the picture?  Viewed in these terms, the many medical
oncologists who currently do use these tests deserve some
ordering the tests, they run the "risk" that the best treatment might actually
turn out to be something which loses them money (particularly if the best
treatment is an off label situation, which does happen not infrequently).

Now, let's say that we hadn't put anyone on empiric therapy trials of Pepsi
Cola versus Coca Cola and instead had been treating hundreds of thousands of
patients with the assistance of in vitro testing.  Besides me and a small
handful of Southern California labs (where Southern California is truly the
Silicone Valley of this technology), you'd have scores of really major players,
with really major resources, and lots of really smart people.  Can you imagine
the progress which could have been made in technology?  We'd by now have superb
technology which would be used to move drug development research out of the
dark ages of animal models and immortal cell lines into the modern era, with
preclinical studies in real human cancer, just as drug discovery in bacterial,
fungal, and viral disease is done using real bacteria, fungi, and virions.

This is the greatest lost opportunity in all of clinical cancer research.  The
longer that well-intentioned but misinformed critics hold this technology
hostage to a bar of unprecedented height in an environment where the cancer
research establishment refuses to lift a finger to help, the longer it will
take to bring about the paradigm shift which has been so badly and obviously
needed for at least a quarter century.

But informed patients can do a lot and, with the help of the internet, maybe
they will.

Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Subject: Re: chemo failure, Part 1
Date: 19 Sep 2000

Continuing my reply (sorry for the inadvertent premature posting of just a
re-play of Dr. Laing's prior message...prematurely and inadvertently hit the
"send" button):

Subject: Re: chemo failure From: T D Laing  Date: 9/18/00 10:07 PM PDT
Message-id: <>

>>Is it wise to discard an imperfect mode of treating
patients in the absence of information validating a new

In a situation where randomized trials have failed to
indentify an advantageous treatment and where multiple,
equally effective treatments exist one is hardly
"discarding" anything.  One is simply selecting one of
many treatments which might have been selected instead
with a coin flip.  But the selection is based on tests
which have been shown to correlate strongly with
clinical outcomes.

>>The myriad of tests that distinguish between
methicillin-resistant and methicillin-sensitive strains
of Staph aureus?<<

I last reviewed the bacterial C&S literature (with
respect to comparability with human tumor assays) about
5 years ago.  At that time, I was unable to find the
results of a clinical trial in which patients were
randomized to antimicrobial drug selection with and
without test information.  Are there clinical trials in
which patients with staph infections were randomized to
receive treatment with antibiotics with and without
drug sensitivity testing?  Or just clinical trials
showing that the tests have a reasonable accuracy in
detecting drug resistance?

>>Then perhaps you can point me in the direction of
some proof of this point--that there are more studies
supporting your tests than for analogous tests for
infectious disease.  Or if this is simply your opinion,
please state it as such.<<

Again, when I last reviewed the infectious disease in
vitro testing literature, there were few studies
correlating in vitro results with clinical outcomes.
There are, however, myriad studies correlating one form
of in vitro antibacterial drug test with another test.
The quoted web site contains a review of the clinical
trials of the human tumor assays.  In aggregate, there
are now close to 2,000 published correlations between
assay results and treatment outcome for the type of
technologies now in widest use.  These include more
than 30 individual studies, with every single study
showing that patients treated with assay "postive"
drugs were more likely to benefit from chemotherapy
than patients treated with assay "negative" drugs.

>>Please do not assume what I do and do not know.<<

Please accept my apology.  I should have said "your
statements indicate to me that you do not have a
complete understanding of the literature."

>>My cynical take on this is that US health insurance
is interested primarily in lowest cost--not necessarily
what is most effective.<<

And I agree with you...which is why it is noteworthy
that the insurance companies and HMOs do pay in most
cases most of the extra costs associated with this

>> You keep making the point that cancer doctors
shouldn't order tests (and > presumably offer
treatments) without clearcut proof of survival
benefit.  These > tests have vastly more documentation
of strong predictive value for both > response and
patient survival than exist in the case of most
laboratory tests > used to aid in the management of
cancer patients.

>>How does that reconcile with the Journal of Clinical
Oncology's assessment re information of patient
survival impact factors?  A paper that is quoted on the
Rational Therapeutics website?<<

I'll discuss the J Clin Oncol paper in a later posting.

>>Your paraphrases certainly make for nice soundbites.
I checked your summary of the Medicare meetings on your
site, and to me they appear far more reserved than what
you make them to be.  And why did you omit a
substantial portion of Dr. Klee's assessment on your
site?  Telling us he was "misled" means nothing without
a description of his opinion--and that doesn't look
very good.<<

The website has links to the official US government
verbatim transcripts of the entire two day meeting.
Here's the full text of the deliberations relating to
Dr. Klee's motion:

 4              DR. KLEE:  Number five.  I guess I will
 5    just have to take it the way it's written here
 6    and make a motion, in that:
 7              I move that the advisory committee
 8    recommend that there is not sufficient scientific
 9    evidence to demonstrate the clinical utility of
10    HTASs in selecting appropriate cancer
11    chemotherapy.
12              DR. FERGUSON:  Okay.  Is there a second
13    to that?
14              DR. MURRAY:  Second.
15              DR. FERGUSON:  All right.  It has been
16    moved and seconded that there is not sufficient
17    evidence for these tests.  Is there some
18    discussion on that point?
19              DR. SUNDWALL:  I'm surprised.  I
20    thought that the discussion so far would indicate
21    there is sufficient scientific evidence to
22    demonstrate clinical utility in the selection of
23    an appropriate chemotherapeutic agent, and
24    inserting not in there surprises me.
25              DR. KLEE:  The reason I was putting it
 1    that way is that this is a very comprehensive
 2    statement and if we look at it in all disease
 3    states, we haven't seen data, so there isn't
 4    sufficient information in that.  If we target it
 5    to one specific one, we have already said that up
 6    in the earlier ones, where we looked at CLL.  So
 7    I think as it's stated, I don't think there is
 8    sufficient scientific evidence to recommend this
 9    across the board.
10              DR. FERGUSON:  So you're in effect
11    saying it's a bit too broad.  Yes, Dr. Kass?
12              DR. KASS:  My problem with the motion
13    as stated is that if I'm being confused by it
14    after sitting here for a day and a half and
15    listening to all the discussions, I'm afraid that
16    when the Medicare coverage policy is written that
17    it's going to be confusing to the people in HCFA
18    as to what our intention was.  I would like to
19    see a motion that clarified exactly the point
20    that you're trying to make.
21              DR. HAUSNER:  I would like to have a
22    crack at just that.  To, if you would consider
23    this as I don't know, an amendment or a revision,
24    adding something to the effect that there is
25    sufficient scientific evidence, et cetera, in
 1    certain cases, and you can add in that in other
 2    cases, there have not been.  And we can use the
 3    example of CLL if you want as the poster
 4    malignancy for which perhaps there is, or just
 5    leave that out.  But rather than -- because
 6    what's implicit in your motion is, and I
 7    understand what you're saying, you're saying that
 8    if we said it just, there is sufficient
 9    scientific evidence that demonstrates the
10    clinical utility, et cetera, that that's far too
11    broad.  Right?
12              DR. KLEE:  Yes.
13              DR. HAUSNER:  And so what I'm saying
14    is, your motion is far too broad the other way,
15    it's too much the other way.
16              DR. KLEE:  Right.
17              DR. HAUSNER:  But what you really meant
18    and what you were trying to reflect, which I
19    agree with, is that it is not yet a closed book.
20    But in order to be consistent with everything
21    else that we said, I propose that you revise your
22    motion something along the lines that I said
23    about saying that there is for certain
24    malignancies scientific evidence that
25    demonstrates the clinical utility of HTASs,
 1    something along those lines.
 2              DR. FERGUSON:  Kathy, and then Dr.
 3    Kass.
 4              DR. HELZLSOUER:  This is Kathy
 5    Helzlsouer.  I think the confusion is that in
 6    number three we changed clinical benefit to
 7    clinical utility, and so we all think we voted on
 8    five, which says clinical utility, which says
 9    clinical utility.  Since we weren't comfortable
10    with the term clinical benefit, and amended that
11    motions, so it's almost now, five is similar to
12    what we did in three, and maybe we need some
13    clarification from Grant as to if you want
14    something else addressed in this.
15              DR. FERGUSON:  Dr. Kass?
16              DR. KASS:  I agree absolutely with
17    that, and perhaps if someone could read to us
18    what we voted on specifically in number three, I
19    think it would become apparent that it was very
20    clearly stated in that what you're trying to get
21    at.
22              DR. BROOKS:  I think it stated promise,
23    so that if we change five to include promise, I
24    think it would be equivalent to three.
25              DR. FERGUSON:  We said clinical utility
 1    for hematologic cancers and promise for solid
 2    tumors; is that correct?
 3              DR. HELZLSOUER:  CLL specifically.
 4              DR. FERGUSON:  Did we say CLL
 5    specifically? Dr. Fischer?
 6              DR. FISCHER:  Yeah.  I don't think
 7    we're going to add much by doing anything with
 8    five.  I think we should just drop it.  The
 9    sentiment in the discussion around this issue was
10    done under three, and I think the semantics are
11    just going to confuse everyone, so I move that we
12    drop five.
13              DR. FERGUSON:  Just a minute.  We have
14    a motion on the table, that's been moved and
15    seconded and you know, we have to -- Roger's
16    rules, is it?  No, Robert's.
17              DR. SUNDWALL:  The motion wasn't
18    seconded.
19              DR. FERGUSON:  It was seconded.  It's
20    been moved and seconded.
21              DR. HAUSNER:  Call the question.  And
22    my point would be that if it's defeated. Then we
23    have a clean slate.  I think quite honestly that
24    Dr. Fischer's idea about quashing it -- I just
25    want to ask Dr. Bagley, is this written in stone
 1    that we have to do anything with these
 2    questions?  The answer is no?
 3              DR. BAGLEY:  No, they are written in
 4    stone, and -- well, soft stone.  But I mean, the
 5    purpose of these questions was to generate the
 6    discussion and to get the sense of the committee
 7    around these issues.  And I think again, the way
 8    three was modified, addresses much of the issue,
 9    I think the discussion around it discusses much
10    of the issue, and I sense a reluctance in the
11    committee to take a definitive vote on question
12    number five in a definitely broad or definitely
13    proscriptive form, and if the committee decides
14    to not deal with that issue and not take a vote
15    on that, that is an acceptable alternative.
16              DR. HAUSNER:  I'd like to call the
17    question on the motion.
18              DR. KLEE:  Or can I withdraw my
19    motion?
20              DR. BAGLEY:  I mean there's no reason,
21    because of it having been made, there is no
22    reason that it has to be put to a definitive vote
23    at this time and put people in an uncomfortable
24    position of voting on something they didn't mean
25    to vote on.
 1              DR. FERGUSON:  Just a minute now.  The
 2    question has been called.
 3              DR. HAUSNER:  Well, unless he
 4    withdraws.
 5              DR. KLEE:  I was just withdrawing the
 6    motion.
 7              DR. FERGUSON:  Okay.  I guess we can do
 8    that.
 9              DR. MURRAY:  I withdraw my second.
10              DR. FERGUSON:  Okay.  The question has
11    been withdrawn.  Not even tabled, I guess.
12    Withdrawn.
13              DR. HAUSNER:  To nail it down, may I
14    make a motion that the committee not consider
15    question number five, just to nail it down?
16              DR. FERGUSON:  You can make that
17    motion.
18              DR. HAUSNER:  I make a motion that
19    question number five not be considered by the
20    committee at this time.
21              DR. HELZLSOUER:  Well, we already did
22    consider it actually.  We considered it in number
23    three,.
24              DR. FERGUSON:  Well, I mean, do I --
25    has it been seconded?  Is there a second to not
 1    considering question number five?  It's been
 2    moved that we not consider question number five.
 3    Is there a second?
 4              DR. KLEE:  I second it.
 5              DR. FERGUSON:  Okay.  There's a
 6    second.  Now, is there discussion?
 7              DR. MURRAY:  I'm a little puzzled by
 8    the problem, because we have come very close to
 9    number five.  I have a question for Dr. Klee.  In
10    your original now withdrawn motion, when you said
11    selecting as it's written here, in selecting an
12    appropriate cancer therapy, what exactly did you
13    mean by selecting? Did it specifically include
14    selecting and excluding?  Because I do have a
15    problem with -- I supported your motion to find
16    that there is not sufficient scientific evidence
17    for selection, but there is sufficient scientific
18    evidence for excluding, so what exactly did you
19    mean by selecting?
20              DR. KLEE:  I was just reading it
21    literally, so selecting was rule in, was
22    predominantly, but I also had concerns about the
23    rule out.  I don't think there was sufficient
24    scientific evidence for many of the disease
25    entities or subgroups thereof to make a statement
 1    like that, so it was across the board that I had
 2    concerns.  But I think it has been addressed as
 3    it has already been discussed in issue number
 4    three where we said there is promise, and we have
 5    one case where it looks like there is some
 6    clinical utility.  So I, that was the basis of
 7    withdrawing this motion, is because it looks like
 8    we can't go further than what we have already
 9    said with issue number three.
10              DR. FERGUSON:  All right.  It's been
11    moved and -- yes, go ahead.
12              DR. BROOKS:  It almost gets to whether
13    we want to say any negative.  In other words, if
14    we want to use five, not as being very similar to
15    three, but whether we want to change it in such a
16    way as to state that we don't think these have
17    proven value in every cancer, because --
18              DR. KLEE:  Is that not captured in the
19    discussion?
20              DR. FERGUSON:  Okay.  Is there any
21    further discussion about removing number five?

<continued in Part 2>

From: (RunnSwim)
Subject: Re: chemo failure,Part 2
Date: 19 Sep 2000

<continuing to answer Dr. Laing; we are in the midst of the Medicare meeting
verbatim transcripts relating to Dr. Klee's motion: >

23              Is there any discussion from the group,
24    the audience, presenters about removing question
25    number five?
 1              DR. NAGOURNEY:  Robert Nagourney.  And
 2    I think both three and five speak to an issue
 3    that Dr. Bosanquet raised, and which confronts me
 4    directly.  We have in one course of discussion
 5    looked over different technologies, different end
 6    points, different utilities for end points.  What
 7    I'm concerned by is that my work, which is
 8    specifically designated on the basis of what I
 9    believe to be a better scientific understanding
10    of tumor biology, the concept of cell death, the
11    measurement of cell death as being a robust
12    predictor of response, my concern here is that
13    HCFA will make a decision that these assays are
14    all the same, and that the measurement of tumor
15    biology can all pretty well be determined.
16              And to use Dr. Weisenthal's analogy
17    where one finds the person on the roadside and in
18    determining whether they're alive or dead, they
19    can do a core temperature, EEG or EKG, or check
20    for pulse or check or response to stimulus, one
21    does not do a sperm count.  You are not looking
22    for proliferative capacity to assess viability.
23    The assay end points that we have sort of skirted
24    over are distinct.  Some measure cell viability,
25    and those have been extremely compellingly argued
 1    in favor of by much of the data, if you really
 2    dissect the data.  Most of what you heard, which
 3    convinced you to these remarkable unanimous
 4    decisions has been Randy Stein, who was not
 5    determined to have been improved in his outcome
 6    by eliminating every other possible combination
 7    of drug resistant phenomenon, but in fact by
 8    identifying an active treatment.
 9              Or Dr. Nalick, who eloquently argued in
10    favor of how well the cells can pick treatments.
11    Pick treatments.  And what I'm afraid of here as
12    a clinician who comes under HCFA guidelines, and
13    who practices medicine, whose father has cancer,
14    you could make a decision that you will approve
15    all these tests and they're all really great, and
16    although I know you are not here to determine
17    reimbursement issues, I will find myself
18    constrained with a difficult and arduous assay
19    which requires larger numbers of drugs under
20    different conditions for prolonged periods of
21    time with subjective and labor intensive tests,
22    to make meaningful selections of cancer
23    treatments.  And I will be reimbursed by HCFA, or
24    my patients will be covered by HCFA at a level
25    that covers the lowest common denominator,
 1    eliminate a drug that has a five or ten percent
 2    chance.  And I will be effectively unable to
 3    provide the best test to my patients.  And HCFA
 4    stipulations say that you either accept HCFA,
 5    Medicare reimbursements for an approved test in
 6    every situation, or sign off HCFA for two years.
 7    What this effectively means is that you reimburse
 8    these all the same, and the cheapest assay
 9    becomes the assay that's reimbursed, then I write
10    a prescription for my father if I don't get this
11    test approved in a way that I can afford to do
12    it.
13              So I think that number three and number
14    five speak to issues that there are different
15    tests here, and when you send your message to the
16    next committee, there is going to have to be some
17    distinction between the fact that some tests are
18    difficult and give information to select
19    treatments, and some tests are easier and give
20    more limited amounts of information.  And that's
21    sort of be skirted over, and it concerns me
22    gravely.
23              DR. FERGUSON:  Thank you.  Is there
24    further discussion or comment on this removing
25    this question.
 1              MR. STRINGER:  I'm Jerry Stringer.
 2    I'm a consultant, although I am here on my own
 3    today.  Just in terms of the committee guiding
 4    the development of the coverage policy, I
 5    actually think it would be important to make a
 6    statement -- you made a statement that it's --
 7    basically that it's reasonable and necessary for
 8    this test on some occasions.  I think as the
 9    experts, it would be nice to know whether you
10    felt that question five, I think says, are there
11    occasions where use of this test would change
12    which chemotherapy agent a patient would get.  So
13    I think that's basically all it says; if you do
14    the test, is there a chance that the treatment
15    would change.
16              Another level of it, does this test
17    have the possibility, or is there scientific
18    evidence that improves patient outcomes in terms
19    of quality of life, and then ultimately the
20    question is, does this test improve patient
21    longevity?  Is there scientific evidence on each
22    of those three steps?  And I think those
23    questions being answered by the experts will help
24    the coverage policy makers in formulating when
25    the test should be covered, and under what
 1    circumstances.
 2              DR. FERGUSON:  Dr. Hausner?
 3              DR. HAUSNER:  I guess I didn't really
 4    reveal my full plan.  If question number five is
 5    deleted at this time, my plan was to add number
 6    five as question number six, what additional
 7    concerns, questions or would the committee like
 8    addressed and basically in a rather clumsy way
 9    be, table it in that fashion.  That was what I
10    was going to do if it were still an open motion,
11    if it were to be defeated.
12              The other comment that I've just got to
13    say, talking about the Randy Stein case somehow
14    or another influencing my opinion, that is a
15    remarkable story, just that.  I don't know what
16    happened there.  That could be explained by
17    somebody trying for sainthood.  I mean, Mother
18    Theresa might have had some effect on that case
19    as much as anything that we were told about.  So
20    that had no influence, although it's a very
21    gratifying story.
22              DR. FERGUSON:  Dr. Fischer?
23              DR. FISCHER:  You know, I feel like I'm
24    dealing with my kids here.  I think, you know, I
25    think the committee went as far as it could,
 1    given the science that it was presented, and I
 2    feel we are getting beat up on right now, and I'd
 3    give you the same recommendation I'd give my
 4    kids, settle down and wait a while.
 5              DR. FERGUSON:  Mr. Kiesner?
 6              MR. KIESNER:  Yes.  I think when I look
 7    at this question, it is very broad, and I think
 8    that the general tenor of what I have heard here
 9    today is that there has been a wealth of
10    scientific evidence which compares very favorably
11    to other diagnostic tests, and the panel believes
12    that there is appropriate clinical application of
13    this, but we have not given you, nor have you had
14    the time nor maybe is it appropriate for you to
15    try to comprehend all of the clinical settings in
16    which these types of tests can be used.  I think
17    that it is appropriate for this committee to say
18    that there is sufficient scientific evidence for
19    human tumor assay systems to be used in relation
20    to selecting or deselecting a given drug.  And
21    then I think it has to go one step further in
22    terms of the policy at some further point in
23    time, and by an entity other than this panel in
24    order to define that specificity.  And I would
25    feel that an answer to number five in that sense,
 1    holds that there has been scientific evidence,
 2    that there has been clinical utility, which would
 3    parallel the answer to question number three, and
 4    that, some indication that this should be used by
 5    HCFA as the sentiment of the committee, to look
 6    in more depth at the clinical setting, and I
 7    think that would be the most appropriate way to
 8    handle this.
 9              DR. FERGUSON:  Thank you.  We're going
10    to call this -- go ahead.  One more.
11              DR. BROOKS:  Yeah.  Just a quick
12    comment.  I mean, I kind of agree with Dr.
13    Fischer.  You know, we are kind of being boxed
14    around the corner here a little bit, because on
15    the one hand you would like it to say that is of
16    utility in selecting and deselecting the
17    chemotherapy.  And I believe that, you know, with
18    my father being a lawyer, if we say that sort of
19    stuff, then we just voted on we wouldn't preclude
20    therapy based on the assay.  So I think it's gets
21    too multiple on their questions.  And if you're
22    saying that you think there is clinical benefit
23    as opposed to utility, then we come back to the
24    other thing, and we certainly could, and I am not
25    proposing any motion, but you know, then we could
 1    have a motion based on benefit, so I think, you
 2    know, there is various issues in this question.
 3              DR. FERGUSON:  I am going to call this
 4    question.  All in favor of this removing number
 5    five?  I believe that it's unanimous.  Okay.
 6              Now, does somebody want to -- I mean,
 7    there are what additional concerns, questions or
 8    issues?  I haven't asked for a motion on that,
 9    but yes?
10              DR. HAUSNER:  My motion is, I would
11    like to make a motion that number five be
12    incorporated as an additional concern for future
13    consideration.  I am a little -- when it says
14    would the committee like addressed by who, I
15    assume it's not by us, but I think that number
16    five is still an open issue for the future as
17    this story continues to develop.  So assuming
18    that it's not us, I make the motion that the
19    committee recognize that the question number
20    five, is there sufficient scientific evidence,
21    et cetera, be addressed at a later date.
22              DR. FERGUSON:  Is there a second?  Dr.
23    Sundwall?
24              DR. SUNDWALL:  Could I amend that
25    before I second it?
 1              DR. FERGUSON:  Sure.
 2              DR. SUNDWALL:  The discussion to me is
 3    either or, which I don't quite understand.  I
 4    think the problem word is sufficient, and I would
 5    support your issue to be on the table for further
 6    consideration if it read something like there is
 7    scientific evidence demonstrating the clinical
 8    utility of ST assays; however, more research
 9    needs to be done to document their utility,
10    particularly in solid tumors.
11              DR. HAUSNER:  I accept that, and maybe
12    you made the motion and I'll second it; okay?
13              DR. FERGUSON: It's been moved and
14    seconded, I guess.  Dr. Sundwall, do you want to
15    read it?
16              DR. SUNDWALL:  There is scientific
17    evidence to demonstrate the clinical utility of
18    STASs; however, more research needs to be done,
19    particularly in documenting their utility in
20    solid tumors.
21              DR. FERGUSON:  Okay.  And it has been
22    seconded.  Now, is there some discussion on that
23    motion?  Yes, Dr. Fischer.
24              DR. FISCHER:  You know, it sounds like
25    the answer is in on hematologic tumors, which it
 1    certainly isn't.  You know, I think lots of
 2    questions come from this, particular tumors,
 3    particular assays, particular drugs, when does it
 4    and when doesn't it work.  We don't know.  I
 5    think we have really been pushed as far as the
 6    committee is going to, and so, I feel quite at
 7    piece about where we are at.
 8              DR. FERGUSON:  Yes?
 9              MS. SIMMERS:  It seems to me that for
10    question six, what really needed is sort of a
11    laundry list of those concerns and questions that
12    we have remaining, but we're not going to come to
13    a conclusion about making a motion about them,
14    but that we want HCFA to know that they are
15    concerns of ours.  And I think this whole issue
16    of clinical trials and their continuation or
17    further research, whichever you way you want to
18    state that, is one of the concerns that has been
19    expressed several times.  And I think if it makes
20    the list, there is not really a need for a more
21    specific motion, but just the sense of that, to
22    be registered with HCFA.
23              DR. FERGUSON:  Okay.  Dr. Brooks?
24              DR. BROOKS:  Yeah.  I just wanted to
25    say that I would agree with the previous speaker
 1    that, you know, rather than have another motion,
 2    although we certainly could have that one motion,
 3    but I would not want that one motion to preclude
 4    giving the additional concerns or whatever that
 5    we may have, that we may want to voice.
 6              DR. FERGUSON:  Okay.  Kathy?
 7              DR. HELZLSOUER:  Yeah.  I guess the
 8    issue for me, that motion, sounds similar to what
 9    we already voted on, so I don't see, I guess the
10    utility, if you will, of rephrasing what we
11    already voted on.  Think the issue that should be
12    reflected is where we changed that was the
13    clinical benefit.  I agree with Dr. Fischer, that
14    we've gone as far as we can with the evidence
15    provided, and my concern is that we don't have
16    the evidence of clinical benefit and that's what
17    still needs to be shown, in whatever ways, and
18    whatever trials, so that's where I have the
19    concern.
20              DR. FERGUSON:  Okay.  Do you want to --
21              DR. SUNDWALL:  Yeah, I would like to
22    withdraw.  I have to look at our FDA and see.  If
23    I can  withdraw my motion, I think that we
24    probably all listed some things we think are
25    issues, and I wonder if maybe the committee needs
 1    to discuss that, or because we are duly appointed
 2    committee members, we couldn't in fact provide
 3    for you those issues.
 4              DR. FERGUSON:  Right.  There is a sense
 5    of, maybe somebody could itemize these things.
 6    There is a sense of the committee that there are
 7    some issues that require addressing for which
 8    patients is this, are these the best tests, when,
 9    when should they be given, what tests, when along
10    their treatment protocols.  I mean, all kind of
11    things of that nature and others, I'm sure.
12    Yes?
13              MS. KRAFT:  I think that's what
14    Dr. Nagourney was getting at is he wants us to
15    define some of our concerns, because all of us
16    that have dealt with Medicare and Medicare
17    reimbursements are concerned with defining what
18    will we be reimbursed for when we order HTA assay
19    tests, and then, will Medicare take the flying
20    leap forward and then define, unbeknownst to us,
21    maybe what tests they will pay for and what they
22    won't.  So one concern of mine is that they, in
23    defining what they're going to reimburse, that
24    they contact some of the scientists and
25    physicians in the audience that are doing this
 1    research, that they find out what is the cost of
 2    producing the test and get some real life cost
 3    data, so when they set what they are going to pay
 4    the physicians for doing these tests, that they
 5    have realistic up to date direct costs.
 6              DR. FERGUSON:  Maybe we could just,
 7    since we're doing pretty well on time, we have 15
 8    more minutes, just put some of our concerns on
 9    the table for HCFA's consideration, as sort of
10    our final.  Yes, please?
11              MS. SIMMERS:  I have three on my list
12    and I'm sure there are going to be many others I
13    agree with.  One, I think this whole issue of
14    continued research, and I believe the stimulus is
15    there to do it, because as Dr. Bagley pointed
16    out, oncology is much different, and I believe in
17    order to convince those that are the gatekeepers
18    of ordering these tests so that it opens up to
19    Medicare beneficiaries, the research will have to
20    support the use of that technology, so it should
21    happen, but it is a continued concern that we get
22    better evidence of the utility and benefit of
23    these tests.
24              I continue to be concerned that the
25    industry work on and continually be cognizant of
 1    accessibility of all Medicare beneficiaries who
 2    are facing a cancer diagnosis, and just not be
 3    some limited accessibility wise, and they look at
 4    ways to address that.
 5              And certainly the policy development,
 6    for those of us who have dealt with carriers on a
 7    daily basis, and for their side of the equation,
 8    the policy does need to be more specific.  I
 9    don't think this is the forum where that happens,
10    because there are processes in place that HCFA
11    has used before to develop those kinds of
12    policies, and I certainly want to see that kind
13    of process go on, so that reasonable and specific
14    policies are set forth.
15              Those were the tree three that I was
16    concerned about.
17              DR. FERGUSON:  Dr. Sunderwall, did you
18    have some?
19              DR. SUNDERWALL:  My only contribution
20    at this time is that I think this particular
21    group of tests under this rubric, whatever STAs,
22    lends itself very well to a national coverage
23    policy.  We have experience from negotiated rule
24    making where in fact this would be, could be done
25    with the right expertise, and I would strongly
 1    recommend that be the next step from HCFA.  I
 2    think it would address most of the concerns
 3    people have about appropriate application and
 4    whether it should be paid for.
 5              And I would just second what Cheryl
 6    just said about appropriate reimbursement,
 7    because I do think that it would be a shame to
 8    give a green light to add this to the
 9    armamentarium of oncologists and physicians, and
10    then find out that it's so underpaid that it's
11    not being used.
12              DR. FERGUSON:  Okay, thank you.
13    Dr. Klee?
14              DR. KLEE:  I had three different things
15    that I'd like to see brought up.  One is this
16    question of monitoring the effectiveness of this
17    program if it's put in place, and perhaps even
18    having a sunset clause and review after a certain
19    period of time, to say, did it really meet the
20    expectations that we had hoped for for this
21    length of time?
22              The second would be to further
23    delineate this question of which tests are
24    appropriate for which type of tumors.  You know,
25    which ones are proliferative, which ones do we
 1    want to have apoptosis markers and such in
 2    there.
 3              The other is a further delineation in
 4    terms of which types of patients are appropriate
 5    for testing.  There are certain tumors that are
 6    going to have universally good response, or
 7    fairly good response, and it doesn't seem like
 8    this would be appropriate for that group of
 9    patients.  And on the other end of the
10    distribution, you've got some that there is no
11    appropriate therapy, or responsive therapy that's
12    going to be coming in, and therefore, treating
13    may not be dependent upon this testing also.  So
14    I think it's along the line of the presentation
15    we had yesterday, that we are looking in the
16    middle part of the distribution rather than the
17    extremes.  We need to define what those extremes
18    are, or what the middle is in terms of disease
19    therapy indications for this particular
20    technology.
21              DR. FERGUSON:  Dr. Fischer?
22              DR. FISCHER:  No.
23              DR. FERGUSON:  Dr. Brooks?
24              DR. BROOKS:  Yeah, a few things.  One,
25    I would go back to ASCO's position and so HCFA
 1    may, I wouldn't require it, but they may wish to
 2    have further clarification on how ASCO views
 3    these tests, just as additional information for
 4    the record, I suppose.
 5              What I would like to say and make
 6    almost a recommendation for is that just as with
 7    certain testing that's done in clinical labs all
 8    the time, whether it be for HIV, hepatitis C, et
 9    cetera, you know, there is a requirement that we
10    keep certain data, that if approved for coverage
11    and payment, that there be a requirement of those
12    who were ordering or doing the tests, that they
13    keep certain data available, and that data be
14    open and available to external groups, as our
15    data is now.
16              And finally, I think coverage, as
17    mentioned by Miss Kraft a little earlier, or
18    perhaps yesterday, I kind of agree with her, that
19    coverage may actually unable further research to
20    go forward.  There will be some type of payment,
21    no matter on what level, and that may shake out
22    which test is better.  It may actually foster
23    further research to enhance the test and allow
24    these tests to be used in clinical trials by the
25    oncology groups, so I think that may well be the
 1    case.
 2              DR. BAGLEY:  I think I gave my concerns
 3    in the beginning.
 4              MR. BARNES:  Just very quickly, I would
 5    like to encourage in conjunction with the comment
 6    about looking at the true cost of the test, that
 7    the work at HCFA go further to look at the net
 8    cost to Medicare, that the economic analysis and
 9    quality of life analysis, which you heard a
10    little bit about, be taken into consideration.
11              DR. FERGUSON:  Okay.  My concerns are
12    mostly which tests for which patients, and when
13    in the course of the disease, which I think need
14    to be still looked into.
15              DR. MURRAY:  I think that my comment
16    perhaps duplicates Dr. Brooks, but I know that
17    it's common practice in many, perhaps all
18    genetics laboratories, cytogenetic laboratories
19    that do prenatal testing, it's common practice
20    for them to follow up with outcomes and to
21    correlate their test result with the fetal
22    outcome.  And I would encourage the laboratories
23    that do this type of testing to make that
24    effort.  Of course you can't demand it as a
25    condition of testing, but our experience in
 1    genetic testing is that obstetricians are very
 2    cooperative and I would expect that the
 3    oncologists would be equally cooperative.  While
 4    that doesn't constitute research and perhaps may
 5    not be publishable to the extent possible, that
 6    should be available for review.
 7              DR. FERGUSON:  Dr. Loy?
 8              DR. LOY:  Based on Dr. Nagourney's
 9    comments, I hope some attention is give to
10    elaborating on the differences between different
11    testing modalities and when there may be
12    appropriate use of each one of those modalities.
13              Then I also have an interest in
14    addressing the appropriate frequency of testing,
15    how many times you're going to allow this as
16    reasonable and necessary, over the course of
17    treating patients.  And then finally, some
18    attention to who is responsible for choosing the
19    drug of choice for testing.  If there was never
20    the intent to use a specific chemotherapeutic
21    agent in the regimen to begin with, then it would
22    seem inappropriate to me that the oncologist
23    should have, the treating oncologist should have
24    some say so about that to begin with.
25              And then finally, I hope that there is
 1    some consideration given to, from a carrier
 2    standpoint, of the documentation requirement.
 3              DR. FERGUSON:  Miss Snow?
 4              MS. SNOW:  My only concern is that we
 5    keep in mind the assessability and affordability
 6    for the beneficiaries.
 7              DR. FERGUSON:  Thank you.  Dr. Kass,
 8    no?  Dr. Hausner, no.  No?
 9              DR. MINTZ:  My concerns have been
10    already stated by others, but I want to use this
11    opportunity to state that I think the sense of
12    the committee was best expressed in motion number
13    three, and that these tests show promise for
14    clinical utility, and that motion deliberately
15    did not state, distinguish between sensitivity
16    and resistance testing, so I think the sense of
17    the committee reflects that it is supportive of
18    both sets of testing.
19              And I would only add that I also hope
20    the coverage is adequate to permit this
21    technology to be used.
22              DR. FERGUSON:  Dr. Bagley.
23              DR. BAGLEY:  I want to do one little
24    bit of parliamentary cleanup work, since in the
25    frenzy of doing the right thing, we may have
 1    gotten ourselves cross wise with Ferguson's, or
 2    Robert's Rules of Order.  We had a motion on
 3    number five, which was seconded.  I believe
 4    someone reminded me that the questions was
 5    called.  We can go back and look at the record,
 6    but I believe the question was called, and then
 7    there was this withdrawal.  And actually I'm
 8    unclear as to whether that's allowable, but I
 9    think we could get ourselves, have a clean record
10    if we consider the fact that motion number five
11    was, the original motion which was, there is not
12    scientific evidence was made, seconded, question
13    called.  If we vote on that and it's voted down,
14    and the committee already then went on to vote,
15    saying their sense on number five was that it was
16    dealt with in number six, I think the record will
17    clearly reflect it, but I think perhaps it would
18    be worthwhile to clean up that issue and vote on
19    that original at motion number five,.
20              DR. FERGUSON:  He withdrew the motion.
21              DR. BAGLEY:  Well, there's a question
22    as to whether that's an allowable procedure after
23    the question's been called, so I think if we
24    voted on it, the committee voted on it, if they
25    vote it down, they could then make a motion and
 1    say see question three in the discussion, that's
 2    our sense.
 3              DR. FERGUSON:  Okay.  I guess we should
 4    vote on Dr. Klee's original motion.  Restate the
 5    motion.
 6              DR. BAGLEY:  That there is not
 7    scientific, that there is not sufficient
 8    scientific evidence to demonstrate the clinical
 9    utility in selecting appropriate therapy.
10              DR. FERGUSON:  All right.  So I am
11    going to call for the vote on that.  All in favor
12    of that?  One vote in favor.  I guess I have to
13    read.  That was Dr. Klee that voted in favor.
14              Do I have to read the -- no.  All
15    against?  And I guess there is an abstainer or
16    two.  Wait a second.  So everybody else voted
17    against, is that correct?  All against, please
18    raise your hands.  Dr. Mintz, you're not raising
19    your hand; does that mean you're abstaining?
20              DR. MINTZ: Yes.
21              DR. BROOKS:  And so am I.
22              DR. FERGUSON:  So we have two
23    abstainers, and I need to read who abstained?
24    Boy, you guys really -- let's see.  Dr. Mintz
25    abstained, Dr. Brooks abstained.  Did anybody
 1    else abstain?  And all the rest voted against.
 2    You want me to restate that?
 3              One voted for this motion, two
 4    abstained, and the rest voted against it.  Okay.
 5    All we all right with Roger's, Robert's?  Do I
 6    get by my badge for going to Congress.
 7              DR. SUNDWALL:  Before people leave,
 8    could I call to the attention something that
 9    people may or may not be aware of, that Dr.
10    Bagley won't be with us anymore in this capacity.
11      Dr. Bagley is leaving government, and all of us
12    who've worked with him I think owe him a debt of
13    gratitude for his fairness, his intellect and his
14    perseverance.
15              DR. FERGUSON:  The meeting is
16    adjourned.
17              (The meeting adjourned at 11:55 a.m.,
18    November 16, 1999.)

<remainder of reply to Dr. Laing appears in Part 3>

From: (RunnSwim)
Subject: Re: chemo failure,Part 3
Date: 19 Sep 2000

<Conclusion of reply to Dr. Laing>

Quoting Dr. Laing:

>>Well, I do agree with your assessment of current
chemotherapy regimens.  A better way to deliver them is

Great that we agree about this.

>>But you still haven't sufficiently demonstrated that
these in vitro assays can and do consistently and
reliably provide a better way for treatment delivery.
Ie, what can a cancer patient expect in terms of
survival impact?  (I'm not arguing the predictive
ability of the tests--though I am somewhat concerned
about the relatively low specificity, 71% is pretty
good biologically.)  Will my chances of cure or
long-term remission with a predicted regimen stay the
same or improve?  By how much?  You've so far neatly
avoided answering this.<<

As you know, it's impossible to prove therapeutic
advantage in the absence of the type of prospective,
randomized trials.  Such trials are unprecedented for
laboratory tests and the cooperative groups have been
utterly unwilling to perform these studies, in any

The tests have a specificity (for drug resistance) of
0.92 and a sensitivity (for drug resistance) of 0.71.
To understand what this means in terms of drug
selection requires a long discussion of Bayesian
statistics, but, in brief, what it means is that a
treatment regimen not resistant in the assays is 7 - 9
fold more likely to work than is a treatment regimen
which is resistant in the assays.  Given that the
clinician and patient almost always have a multitude of
regimens which could be selected with a coin flip
(Pepsi Cola vs Coca Cola), it would appear that the
"risk" of looking at assay results is non existent and
a preponderance of evidence indicates that it would be
worthwhile to consider the assay results in drug

>>Are you admitting here that you do not have
sufficient information to assess the overall survival
impact of these assays?  I know you have one study
quoted for leukemia that looks promising, but for other

To determine "survival impact" requires randomized
trials of treatment with and without assay results.
What does exist are many studies showing that patients
treated with regimens showing in vitro resistance live
significantly less long than patients treated with
regimens treated with regimens not showing in vitro
resistance.  This has been shown in solid tumors and in
hematologic neoplasms.  I am showing our own data in
more than 500 ovarian cancer patients with a median
follow up of about 4 years at an ovarian cancer meeting
in Washington, DC this Friday.  E-mail me your postal
address and I'll send you hard copies of the data next

>> But they've always been vastly more interested in
doing the logistically much > simpler trials of
empiric, one size fits all therapy.  This is all they
know. > It has generously supported their careers.  But
it hasn't accomplished > anything.  Not anything of
solid substance.<<

>Unfortunately, it's accusations like this that further
detract from your position--and may be part of what's
kept your assay from attaining the status as a routine
assessment.  You catch far more flies with honey than
vinegar--distasteful but true.<

It is wise not to criticize someone until you've walked
a mile in his/her mocassins.  Just as I shouldn't
presume to know the details of your knowledge of the
literature, you can't presume to know the details of a
21 year career in human tumor assays.  Sometimes it
does take two decades of personal experience to build
up a really good case of cynicism.

>>Again, strawman argument as described above.  However
the burden of proof is on you (and other proponents of
in vitro-based assays) to show that such assays are
indeed better all-around for the
more-difficult-to-treat cancers.  I've seen some
suggestion only for leukemia (the abstract mentioned on
your website)--which doesn't say anything for ovarian,
or breast, or melanoma, or colorectal, or brain cancer,

Our burden is to do the best job we can to show that
the assays are an accurate tool.  It is the burden of
others to decide how much evidence it takes to convince
them to use that tool.

It's a pretty simple thing to show that an estrogen
receptor assay correlates with treatment results in
breast cancer (and it has never been shown that
managing breast cancer patients with receptor assays
improves their survival compared to managing patients
without receptor assays according to the criteria you
demand of drug resistance assays).  But we are talking
30 drugs, hundreds of drug combinations, scores of
diseases.  The matrix is huge.  But overall the
correlation between test results and treatment results
holds up and it holds up in every situation in which
there are enough correlations to allow a comparison.

>>But we still come back to the very same issue:  what
is the overall survival impact of in vitro-directed
therapy compared to empirical therapy?  How many times
do I have to ask this before you answer it?  Do you
even have a firm answer?<<

What's the survival impact of any test in cancer
medicine?  What's the survival advantage of a receptor
assay?  Of a Her2/neu? Of a CA-125?

By the way, has anyone ever done the randomized trial
of treating staph aureus with and without a drug
sensitivity test?

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Subject: Re: chemo failure
Date: 19 Sep 2000

Now, about that Journal of Clinical Oncology article Dr. Laing keeps quoting:

In article <>, T D Laing <>

>1999 Journal of Clinical Oncology review (abstract posted below) seems
>to suggest that a key factor in evaluating such tests, survival impact,
>is lacking and needs to be further addressed:
>Clin Oncol 1999 May;17(5):1625-31 Review of the efficacy of
>individualized chemotherapy selected by in vitro drug sensitivity
>testing for patients with cancer.  Cortazar P, Johnson BE
> Lung Cancer Biology Section, Medicine Branch at the Navy, Division of
>Clinical Sciences, National Cancer Institute, Bethesda, MD, USA.


(Introductory definition:  "CCDRT" refers to Cell Culture Drug Resistance

The Cortazar/Johnson Review (J Clin Oncol 17:1625-31,'99)

The Cortazar/Johnson review represents a substantial amount of work, and
the authors took great pains to be comprehensive, accurate, and fair.  The
paper contains no factual inaccuracies, nor are there any important
omissions of important studies of which I am aware.  The authors have
accurately described the substantial logistical barriers to completing studies
such as this and offer helpful suggestions for future studies.

The take-home messages come through loud and clear.  The studies
analyzed suggest a response benefit, but do not confirm a survival benefit.
The authors conclude that prospective clinical trials "have not yet
demonstrated a clear benefit of chemotherapy using drug sensitivity
testing."  In 2 less comprehensive recent reviews, Markman recently made
the same points, as discussed above (Markman, M. Chemosensitivity and
chemoresistance assays: are they clinically relevant? J. Cancer Res. Clin.
Oncol. 121, 441-442,'95; Brown, E. and Markman, M. Tumor
chemosensitivity and chemoresistance assays. Cancer 77, 1020-1025,'96).

It is, however, extremely misleading to attempt a meta-analysis on the
data.  There are limitations to all studies in which one lumps together data
from various studies and calculates overall means or medians.  In this case,
such lumping is particularly problematic.

The data in the Cortazar/Johnson review which attract the most attention
are those data comparing survivorship with assay-directed versus empiric
therapy.  Indeed, it is likely that the take-home message for most readers
will be that, in a fairly large total dataset of 13 prospective studies and 569
patients (actually only 5 studies and 92 patients, omitting one study which
was inappropriately included, see below) receiving DST-directed therapy,
the median survival of DST-directed therapy was 8.9 months, compared to
10.9 months for empiric therapy and that "only one non-randomized study
showed patients treated with [DST-directed therapy] had a significantly
longer survival than the group of patients treated with empiric
chemotherapy." {n.b. the statistical power of these studies to show a
difference, assuming that one existed, was very low}.

Even more simply and directly, the take-home messages of the above would
appear to be clear:

1. There have been a lot of studies and a lot of patients, providing a
reasonably fair test of the hypothesis that clinical chemotherapy directed by
DST may improve clinical outcome.

2. The data strongly imply that there is no benefit to clinical chemotherapy
directed by DST.

The above are outrageously misleading messages, unsupported by the
studies and data included in this paper.

It is accurate to state that it has not been proven that the use of these
assays improves the treatment of populations of patients in prospective,
randomized trials (which have never been carried out and completed).  It
is not accurate to state nor helpful to imply that the hypothesis has
been adequately tested and found not to be true.  It is also unfair not
to consider at the same time the considerable data which show that when
patients are treated with drugs active in the assays that they have
vastly superior reponse and survival rates than when they are treated
with drugs which are not active in the assays (data reviewed at

To begin with, in the Cortazar/Johnson review, it is not appropriate to
include the study by Maenpaa, et al (authors' reference # 26).  This was a
study of the subrenal capsule assay, which is an in vivo assay which has
never been utilized in this country or anywhere else in the
non-investigational clinical setting.  This assay was criticized in several
publications by several different groups, who reported that the alleged
tumor "growth" measured in the assay was mostly owing to host
inflammatory response against the implanted tumor and was, thus, an
artifact.  To my knowledge, this assay has never been used by any of the
private sector laboratories and has been abandoned as a research tool.

Remaining are 5 studies, 2 of which utilize the "human tumor colony
assay" ("HTCA") and 3 of which utilized the "DiSC" assay. A total of 92
patients in these 5 studies actually received assay-directed therapy.

The HTCA and DiSC assay are completely different technologies.

The HTCA measures inhibition of cell proliferation.  It utilizes very low
drug concentrations.  It is a relatively long-term assay.  It suffers from a
number of serious technical problems (which have been enumerated in a
number of review papers, going back to the early 1980s).  It has a very low
evaluability rate.  And it hasn't been used by any private sector clinical
laboratory in at least the past 13 years, to my knowledge.

In contrast, the DiSC assay measures cell death (delayed loss of membrane
integrity, which is what is measured by the DiSC assay, has been shown to
correlate with apoptosis).  It uses markedly higher drug concentrations than
does the HTCA.  It is a short-term assay.  It poses entirely different
technical challenges than does the HTCA.  It has a very high evaluability
rate, as discussed below.  It has been used by private sector clinical
laboratories since 1987 and it continues to be used by the three most
prominent private sector laboratories which are providing cell culture drug
resistance testing in this country today.

Basically, the authors lumped together 6 vastly differing studies, none of
which had a control patient population which would be accepted in any
journal publication comparing different forms of empiric therapy (i.e. the
typical oncology journal chemotherapy paper), and quoted the following
median survivals for patients receiving assay-directed therapy (in months):
6.2, 7.2, 8.6, 9.1, 24, and 38.5.  They took the median of this series of 6
papers of different technologies and came up with a number of 8.9 (months)
to represent the overall median result of assay-directed therapy upon
meta-analysis.  Then they took the following median survivals for patients
receiving empiric therapy (who did not represent scientifically valid control
groups): 4.2, 7.3, 10.6, 11.2, 19, and 28.  The median of this series came
out to be 10.9 and this was stated to represent the median survival for
patients receiving empiric therapy.

Lumping together non-randomized data from widely varying studies of
technologies which are not in any way comparable for meta-analysis to
obtain parameters such as median survivals and then to make comparisons
of these median survivals is not scientifically justifiable.  Had the median
survival with this sort of fractured analysis showed a "significant"
improvement, there is no way on earth the Journal's editor would ever have
accepted this for publication.  Only because the non-significance of the
finding fit in with the Editor's pre-conceived bias was it published.

Since it was the authors' intention to evaluate the "efficacy" of
DST-selected therapy, it would seem most appropriate to first evaluate the
quality of the data which exist to make this determination.  In order to be
useful to the many hundreds of clinical oncologists who continue to use this
DST in their clinical practices, it would also be helpful to note how the
technologies evaluated in this review compare with the technologies which
are currently being applied as a service to patients.

As the HTCA is not one of the technologies which has been used by the
private sector laboratories, but as (technically-evolved) versions of the
DiSC assay are used, it would appear that the only papers discussing
survivorship which are relevant to present-day clinical practice are the three
lung cancer studies from the NCI which ostensibly utilized the DiSC assay
(authors' refs. 9, 10, 39, 11, 12).  The problems at the core of these studies
are described in the following section.

_The NCI position on CCDRT, based largely on the Gazdar/Shaw studies in
lung cancer_

The NCI (along with Cortazar and Johnson, in their review) has taken the
position that the use of these assays is to be considered investigational.
This position is not based on an examination the relevant literature
reviewed in in the present paper, but appears to be based entirely on a
series of highly-flawed studies published by the NCI lung cancer group
(JNCI 82:117,'90; J Cell Biochem 24:173,'96; Clin Cancer Res

I am very familiar with these three studies, which had their origins in a
parking lot conversation which I had with Dr. John Minna at the San Diego
ASCO meeting in the early 80s.

Although I have tremendous respect for the above investigators and great
appreciation for their efforts over the years, it must be noted that this body
of work suffers greatly from a number of problems which are not relevant
the application of these assays in clinical practice today and which are,
more importantly, not applicable to the data which exist to justify the use of
these assays in clinical practice today (see Part I).

The NCI's three studies were in (1) extensive stage small cell lung cancer,
(2) advanced non-small cell lung cancer, and (3) limited stage small cell
lung cancer.  Study # 1 (JNCI 82:117,'90) can be described as being
modestly "positive."  Study # 3 (Clin Cancer Res 3:741,'97) can be
described as being highly "positive."  However, study # 2 in non-small cell
lung cancer (Cancer Res 53:5181,'93; J Cell Biochem 24:173,'96) was
certainly highly "negative."

As the NSCLC study was, by far, the most "negative" of the three, and it is
worth considering in some detail, to illustrate the problems with drawing
the conclusion that the "efficacy" of DST-directed therapy has been
adequately tested and has been found wanting.  I apologize in advance for
the detailed complexity of the following critique, but it is extremely
important to understand how irrelevant this study was to the use of CCDRT
in the clinical management of cancer patients.

Shaw, et al studied assay-directed therapy of NSCLC.  The Methods
section (Cancer Res 53:5181, '93) stated that the assay "results included in
this report were performed on fresh tumor tissue."  This statement was
added by the authors to the Methods section after I reviewed a
pre-publication draft of this paper and noted the problems with testing
sub-cultured cells (described below).  In point of fact, the description in the
Methods was incorrect and none of the results were performed on fresh
tumor tissue.  All assays were, in fact, performed on short-term cell lines
(i.e. subcultured cells), which had at least one and often more passages in
vitro.  I confirmed this by speaking with Dr. Adi Gazdar (who was the
investigator who actually performed the assays) and, in fact, the authors
confirmed this with their own words in the Discussion section of the paper,
in which they stated "subculturing also specifically excluded fibroblasts and
benign epithelial cells."

This is very important, as the assay used by the NCI was designed (by me)
to be a "total cell kill" (apoptotic) assay and not an antiproliferative assay.

All of the drug concentrations and assay conditions were designed for fresh
tumors and to test the total (largely non-dividing) tumor cell population.
This endpoint is much more robust for specific cell killing mediated
through apoptosis than are cell proliferation assays which measure
non-specific growth inhibition effects.  Once you start working with
passaged, short-term cell lines, you begin to measure tumor cell
subpopulations and you begin to measure antiproliferative effects along with
the more specific apoptotic effects.  All of the other investigators who have
reported excellent correlations with total cell kill assays (more than 1600
published assay/treatment clinical correlation in all with these assays) have
used true fresh tumor assays and not short-term cell lines.  Yet the NCI
applied this technology to cell lines and Shaw then concluded that these
assays don't work, rather than more appropriately concluding that passaged
cell lines don't work (e.g. see Kruczynski,A. and Kiss, R. Evidence of a
direct relationship between the increase in the in vitro passage number of
human non-small-lung cancer primocultures and their chemosensitivity.
Anticancer Res. 13:507-14,'93; Smit, et al. In vitro response of human
small-cell lung-cancer cell lines to chemotherapeutic drugs: no correlation
with clinical data. Int. J Cancer 51:72-78,'92.).

The purpose of the NCI study never was to determine if fresh tumor assays
worked.  All of the considerable literature which supports the use of these
assays in patient management has been based on true fresh tumor
(non-passaged) cell assays.  The NCI used cell lines because the major
expertise of the investigators who carried out the study was in the creation
of lung cancer cell lines, and they wanted to see if they could perform
assays on these cell lines to use in patient therapy.  The results were that
they were able to test successfully only 22% of specimens received,
including only 7% of primary lung lesions!  This contrasts with a 75%
overall success rate reported by earlier investigators who used the same
assay system in fresh tumors (the Wilbur study quoted in the current
review) and a routinely obtained > 95% success rate using improved
methods available today.

By any definition, the NCI studied a sub-population of patients (22% of all
patients and only 7% of patients with tumor obtained from the lung).  What
else is known of this sub-population of patients?

It turns out that these authors had previously shown that patients whose
tumor cells give rise to immortalized cell lines have a very poor prognosis,
relative to patients whose tumor cells do not give rise to immortalized lines
(Ann Intern Med 113:764, 1990).  Fully 62% of the patients treated with
assay-directed chemotherapy in the NCI study had tumors which gave rise
to immortalized cell lines, compared to 24% of all patients and 12% of
patients in whom assay results could not be obtained (the control group).
Additionally, 35% of specimens from metastatic sites could be tested,
compared to only 7% from primary lung tumors.  The authors themselves
noted that "the same factors associated with metastatic potential could
enhance in vitro cell survival."

Thus, the subset of patients actually receiving assay-directed therapy were
largely members of a group of patients previously identified as having a
particularly poor prognosis, relative to a larger group of patients, in a
disease where even the most favorable group itself is known to be
associated with a very poor prognosis.  In a disease such as NSCLC, where
the benefits of chemotherapy are well-known to be marginal at best, one
might reasonably expect the patients most likely to derive benefit would be
those patients with the most favorable prognosis and not the patients with
the least favorable prognosis.  And yet the patients who received
assay-directed therapy were those patients with the least favorable prognosis
and these patients were compared to the much larger group of patients who
had a significantly more favorable prognosis!  What is needed in all studies,
obviously, is a control group that consists of patients who have assays
successfully performed, but whom do not receive assay-directed therapy.
But such a control group is lacking in all studies published to date.

Additionally, all of the work in the past 15 years in the field of total cell
assays in epithelial tumors has been carried out largely on three dimensional
clusters of cells.  I cited the testing of cells in the absence of cell-cell
communication as a serious flaw in a letter published in the NEJM in 1983
(Weisenthal, LM. Human tumor stem cell assay. New Eng J Med
308:1478-79, 1983).  In my laboratory, we throw away the single cells and
attempt to work exclusively with three dimensional, floating, tumor
spheroids.  What was used in the NCI study of NSCLC?  Monolayer cell
cultures (source: personal communication with Adi Gazdar).  Why is this
important?  In some of the most important work in this field published in
the last 10 years, Teicher at Harvard and Kerbel from MD Anderson
independently showed that you can create drug resistant tumor cells in mice
by repeatedly treating the mice with chemotherapy and then harvesting the
surviving cells from the mice, transplanting them into new mice, retreating
the new mice, and so on.  After a while, you get cells which are many-fold
resistant to the chemotherapy, when tested in mice, but absolutely no more
resistant, when tested in monolayer assays in vitro.  But if you test the
same cells as three-dimensional spheroids, they are now many-fold resistant
in vitro, just as they are in vivo.  (The authors call this "multicellular
resistance," and it may be due to any number of things.  For example, cells
can pass glutathione back and forth to each other (analogous to bacterial

The fact that the NCI studies in small cell lung cancer were more "positive"
than those in NSCLC may well be related to the fact that small cell lung
cancer cells, in most cases, do not grow as monolayers but rather do not
attach to the surface of the culture plates - instead growing as floating,
three-dimensional spheroids (the way that all fresh tumors are cultured for
testing in my laboratory).  In contrast, non-small lung cancer cells grow as
monolayers and the studies of Teicher and Kerbel show the biological
irrelevance of monolayer cultures to tumor cell resistance to anticancer

Also very important is the fact that the NCI authors themselves noted that
patients who have tissue easily available for biopsy for testing represent a
population with more advanced disease and a less favorable prognosis than
patients who do not have such superficial tumor tissue available.  They had
previously shown that having tissue available for biopsy is, in itself, a
significantly negative prognostic factor.

Finally, the clinical impact of assay-directed therapy in the (generally
positive) small cell lung cancer studies (JNCI 82:117,'90; Clin Cancer Res
3:741,'97) was certainly attenuated by the fact that the assay-directed
therapy was not given until after 12 weeks and 4 complete cycles of empiric

In short, there are absolutely no findings or conclusions in the NCI
non-small cell lung cancer study which are in any way germane to the vast
contemporary literature which strongly supports the clinical use of these
assays, when they are performed by expert laboratories.  Yet, within the
academic community, it is not uncommon to hear, as I have heard
repeatedly, things like "well, they tried that at the NCI and it didn't work.
If they couldn't get it to work at the Mecca of Meccas, what makes you
think that you can get it to work?"

And that's the problem with these NCI studies.  Good investigators.  Good
institution.  Good journals.  But vaguely-described methods, misleading
analysis, and misleading presentation of data.  And it mainly serves to
reinforce the opinion held by many in academic oncology that cell culture
drug resistance testing has been adequately studied, but has been found
wanting to the extent that further studies are of vanishingly low priority and
that clinical application is not to be supported.

The true state of the field of CCDRT is that there is a compelling body of
data to support its use, but that the question of whether or not the use of
CCDRT in clinical chemotherapy improves the outcome of patient
treatment has never been addressed in any type of an adequate study - using
the CCDRT technologies which are currently being applied to the
non-investigational management of 15,000 cancer patient per year in the
United States.

But, once again, the standard always applied previously to support the use
of medical tests was the acceptable accuracy of the test and clinical utility,
in the judgement of the physician ordering the test, supported by clinical
logic and common sense.  This was also the standard applied by the FDA
in its consideration of a kit for cell culture drug resistance testing (for
which FDA approval was received and for which clinical and literature
documentation of accuracy was inferior to that existing to document the
technologies reviewed at and applied by my

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Subject: Re: chemo failure,Part 3
Date: 19 Sep 2000

In article <>,
(RunnSwim) writes:

>By the way, has anyone ever done the randomized trial
>of treating staph aureus with and without a drug
>sensitivity test?

Bad form to quote onesself, but I just spent some time updating my
understanding of the clinical validation of culture and sensitivity testing in
bacterial antiobiotic therapy.  Using several different search strategies, I am
still unable to find studies documenting randomized comparisons between
treating staph aureus (or any other antimicrobial infection) with and without
the use of culture and sensitivity testing.

Earlier in my career as a medical oncologist, I was familiar with a number of
attempts to prove that treatment of fever of unknown origin was improved when
culture and senstivity testing (rather than purely empiric treatment) was used.
To my knowledge, this was never convincingly documented; yet few would argue
that clinicians should not consider the results of culture and senstivity
testing in this situation, when such information is available.

As I continue to maintain, the demands of Dr. Laing are unprecedented for a
laboratory test.  The traditional standards have always been acceptable
accuracy and clinical utility of the information, as determined by the treating
physician and his/her patient for a given situation.

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 21 Sep 2000

>> What survival impact does a CA-125 have?

>By itself, doesn't mean much.  With ultrasounds, etc., it's a
significant prognostic factor.

But you are not answering the question. You are saying only that it is a
prognostic are not saying whether or not performing the test in
any way alters patient treatment outcomes.  For that matter, how do you know
that ultrasounds (with or without CA-125) alter treatment outcomes in any way?
As compared with just simple clinical follow-up (history, physical, weight,
simple blood and radiographic tests).  Why get the tests if they only provide
prognostic information? The cell culture assay tests provide much more powerful
prognostic information.  They tell you that a given form of treatment has an
above average probability of being associated with a clinical response and/or
with being associated with above average survival.  Likewise, they indicate
that given treatment is associated with a below average probability of response
and/or survival.

>> What survival impact does a 2nd look
> laparotomy have? What survival impact does a CT scan or MRI scan have? Do you
> think that patients live longer when you "follow" results of
> chemotherapy with serial CT scans, as compared to just doing a physical
> exam, simple lab tests, weighing patients, and asking them how they
> feel?  What survival impact does performing a Her2/neu by fluorescence
> in situ hybridization assay have? What survival impact does 2nd line and
> 3rd line and 4th line chemotherapy have? And, again, what survival
> impact does Taxol have?

From my recollection of articles from the past year:  colon cancer
patients with HPNCC-related mutations have an overall better prognosis.
Breast cancer patients with increased cathepsin D expression have a
worse prognosis (same with estrogen receptor or c-myc).  A subset of NHL
patients who do not respond to chemotherapy, have different genetic
alterations than those who do.  The presence of the Philadelphia
chromosome in some leukemias signals a worse prognosis.  Please correct
me if I'm wrong, but don't "prognosis" and "survival impact" mean the
same thing?<

No, "survival impact" means that if you use the tests, then that directly leads
to patients living longer.  This is the standard that you are demanding of the
cell culture assays.  I therefore could demand the same standards be applied to
the tests that you approve of using (but I would certainly respect your
clinical judgement in deciding which tests you perceive to be useful in
managing your patients...just as I hope that you are respectful of the clinical
judgement of the many expert clinical oncologists who make use of the
information provided by the cell culture assays.)

> I can prove to you that patients who are treated with in vitro active drugs
> have a seven to nine fold response advantage and a significant survival
> advantage over patients treated with in vitro inactive drugs.

How many patients and which cancers?  Isolated patients, or prospective

Nearly 2000 published correlations between assay results and treatment outcome.
 In CLL, ALL, ANLL, Hodgkin's Disease, ovarian cancer, colon cancer, breast
cancer, stomach cancer, small cell lung cancer, and non-small cell lung cancer.
Nearly 40 published studies of total cell kill (cell death, apoptotic) assays.
Every single study, without exception, showing above average probability of
clinical benefit with assay "sensitive" drugs compared to assay "resistant"

> These are not
> randomized studies, but, again, I am still waiting for an example of a single
> laboratory test which has been shown to improve treatment results in studies
> where patients are randomized to treatment with and without test results.

>>The Staib study abstract looks closest, but I don't think it was randomized.

There have been no randomized trials.  The closest I or anyone else has come to
this was to have been a prospective, randomized trial in multiple myeloma,
comparing treatment with empiric melphalan/dexamethasone with assay directed
therapy.  31 Veterans Administration hospitals were participating. Two national
investigators' meetings were held. Funding (from the VA cooperative study group
program) was adequate.  Several months into the study, the study was closed
because of poor patient accrual and protocol violations - in the STANDARD
TREATMENT (melphalan/dexamethasone) part of the study (i.e. having NOTHING to
do with the assays).  This study (#VA-280) pretty much wasted three years of my
career, which had been involved with organizing the study, writing grant
requests, obtaining funding, writing protocols, going to meetings with the
biostatistician in Washington and Baltimore, etc.  Several years later I had a
similar experience with a study in NSCLC involving 53 ECOG-affiliated hospitals
(#EST-585).  This doesn't count a half dozen unsuccessful attempts to get major
institutions and cooperative groups such as the Children's Cancer Study Group,
SWOG, and the Gynecologic Oncology Group to even do pilot studies.

But the data are very strong, even without the Holy Grail of the prosepctive
randomized trial to prove that a laboratory test actually influences clinical
outcome (something which has never, to my knowledge, ever been achieved with
any laboratory test).  Someday the "Holy Grail" trial will actually be
supported by some cooperative oncology group, but it may well take a lot of
input and pressure from cancer patients to get them to do this.  For my part, I
am certainly ready, willing, and able to do the testing for the study.

On Friday, Sept 22, I'm participating in a pro and con debate of the clinical
value of "chemosensitivity assays" at the Ovarian Cancer National Alliance
Meeting in Washington, DC (anyone who wants to attend can probably do so by
calling the Alliance at 202-331-1332).  My session is from 1:45 PM to 3:00 PM
EDT.  I am arguing the "pro" side, and Dr. Sharmila Makhija, a GYN-oncologist
at the U of Pittburgh School of Medicine is arguing the "con" side.

I am grateful to Dr. Laing for the opportunity he gave me to "warm up" for the

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Subject: Re: chemo failure
Date: 27 Sep 2000

From: RT Laing

>>I'm not a doctor and I've never claimed to be.<<

Sorry for the misunderstanding.

>>OTOH, as much as you (and I, for the record) distrust meta-analyses, you
say yourself this was a rather well done review.<<

It was well done in the sense that it was inclusive of the relevant literature
of the time; it was poorly done in that most of the studies reviewed were of
long abandoned and outright discredited technologies which have not been used
for the last 15 years by the real world laboratories which actually provide
this service.  As the average reader (like the authors) has absolutely no clue
about differences between technologies, it was horribly misleading.  Case in
point was the U of Pittsburgh Gyn-Oncologist who extensively quoted from this
review in the "pro and con" debate held in Washington, DC last Friday.  She
basically wasted the bulk of her time discussing the Cortazar/Johnson review of
technologies (subrenal capsule assay; clonogenic assay) which are no longer in
use; to the great confusion of the audience.

>>Actually to me it implies that there is insufficient evidence at this
time, not that there is no benefit at all.  That is what the authors
also explicitly state in their abstract.<<

You have to understand how clinical oncology abstracts are written.  What is
most important is not the (very understated) conclusion (which was, indeed,
blandly innocuous), but the data summarized.  The summarized data in the
abstract was enormously misleading...implying exactly what I said it implied in
my criticism...that a given hypothesis had been adequately tested and found
wanting...which is a very different thing than the reality...that the
hypothesis has never been tested in  properly controlled trials.

>> It is  not accurate to state nor helpful to imply that the hypothesis has
been adequately tested and found not to be true.<<

Laing objects:

>Which was what the authors DID NOT STATE in their abstract.<

It was not stated, but it was certainly implied, ... in screaming red letters.
It is one of the most outrageous misrepresentations of data which I have ever
read in such a review.

>92 patients over 5 studies is still too small to say with any confidence, what
the survival impact is.<

Particularly when none of these studies (#1) used the true fresh tumor, cell
death technologies currently applied in the real world and (#2) had any type of
adequate control group.

>> The HTCA and DiSC assay are completely different technologies.<<

>But they are both in vitro assays--the topic of the review.<

But the HTCA hasn't been used by any of the private sector labs providing this
service for the past 13 years and, as the average reader doesn't know this and,
as the authors did not point this out and even implied otherwise (by lumping
together the data for meta-analysis), this was, again, outrageously misleading.

It's like doing a review of the efficacy of surgical procedures in the
treatment of peptic ulcer disease.  In the 1960s, the idea of treating ulcers
by freezing stomachs with liquid nitrogen was introduced.  This was discredited
and abandoned.  Now, imagine someone writing a "comprehensive" review and
failing to note this fact and including data with this procedure along with
data pertaining to other surgical procedures (e.g. a vagotomy and antrectomy).
Now imagine that the abstract (the only part of the paper read by 95% of the the way, I'd be interested in RT Laing telling us whether or not
he'd read the entire review or only the abstract before jumping into this
thread), included (highly negative) data from this procedure, lumped together
with data from other surgical procedures, the net result of which any idiot
could see was highly non-promising, and then concluded with some sort of a
bland, understated conclusion designed to demonstrate the dispassionate
objectivity of the reviewers....

The misleading presentation of data would speak volumes and leave a distinctly
negative impression, not attenuated by the bland and dispassionate conclusion.

>>Why did they not represent "scientifically valid control groups"?<<

I explained this later on in my critique.  But I'll repeat it again...

In addition to not being randomized, which is not necessarily a fatal flaw,
although it is a flaw, the big problem has been that the only people who got
assays (according to the methodology of the studies reviewed...which, again, -
not in a single case - used the type of methods which are actually used by real
world labs) were people who (1) had disease sufficiently advanced that they had
tissues available for biopsy and (2) has cells which actually proliferated
readily in cell culture.  Both of these features have been found to be
significantly negative prognostic factors. In other words, people with advanced
disease are less likely to live than are patients with localized disease, and
people whose tumors grow readily in cell culture have been shown to have
biologically agressive disease, which grows more rapidly in the patient.

Let's say that I did a study of antioxidant medications and treated only
patients with localized disease and biologically indolent (slow growing)
disease.  I then compared these patients with a "control" group of patients
with advanced, metastatic disease which was biologically aggressive (fast
growing).  And I showed a benefit to this treatment, compared with the
"control" group.  Do you think that the Journal of Clinical Oncology would
publish such a study?

Now, let's say that I find 4 or 5 other studies of different forms of
"alternative" therapies, not related to each other, in which similarly
"positive" studies had been published (in each case, with scientifically
invalid control groups).  And I do a "meta-analysis" of these studies.  And I
show that there is a consistent significant advantage associated with
"alternative" therapy in general.  Would the Journal of Clinical Oncology
publish my meta-analysis?

Of course they wouldn't.  The studies would be scientifically invalid and the
meta-analysis would be meaningless.  But they published this meta-analysis
because it reinforced conventional (if uninformed) opinion.

>> Lumping together non-randomized data from widely varying studies of
>> technologies which are not in any way comparable for meta-analysis to
> >obtain parameters such as median survivals and then to make comparisons
> of these median survivals is not scientifically justifiable.  Had the median
> survival with this sort of fractured analysis showed a "significant"
> improvement, there is no way on earth the Journal's editor would ever have
> accepted this for publication.  Only because the non-significance of the
> finding fit in with the Editor's pre-conceived bias was it published.

Laing quotes from the Reagen-Mondale debates:

>There you go again.  I found the review cautiously optimistic.<

This cautious optimism was not expressed in the abstract; which is the only
part of the study ever read and understood by 95% of the people who quote it.

Contributing to the "cautious optimism" in the discussion was the fact that I
was one of the pre-publication reviewers (in fact, the newgroup response of
mine which we are now discussing was taken largely from my review at the time).
 It's a common ploy in getting a paper published to mollify a critical reviewer
by tossing him a bone.

> By any definition, the NCI studied a sub-population of patients (22% of all
> patients and only 7% of patients with tumor obtained from the lung).  What
> else is known of this sub-population of patients?
> It turns out that these authors had previously shown that patients whose
> tumor cells give rise to immortalized cell lines have a very poor prognosis,
> relative to patients whose tumor cells do not give rise to immortalized lines
> (Ann Intern Med 113:764, 1990).  Fully 62% of the patients treated with
> assay-directed chemotherapy in the NCI study had tumors which gave rise
> to immortalized cell lines, compared to 24% of all patients and 12% of
> patients in whom assay results could not be obtained (the control group).
> Additionally, 35% of specimens from metastatic sites could be tested,
> compared to only 7% from primary lung tumors.  The authors themselves
> noted that "the same factors associated with metastatic potential could
> enhance in vitro cell survival."
> Thus, the subset of patients actually receiving assay-directed therapy were
> largely members of a group of patients previously identified as having a
> particularly poor prognosis, relative to a larger group of patients, in a
> disease where even the most favorable group itself is known to be
> associated with a very poor prognosis.

To which Laing comments:

>IOW, patients with SCLC may not expect to benefit much from in vitro
assays because they have inherently a poorer prognosis?<

Patients treated with drug active in true fresh tumor, cell death assays have a
7-9 fold greater likelihood of having their tumor shrink and are significantly
more likely to survive for a given period of time.  In almost any situation
where chemotherapy is deemed to be of clinical benefit, information provided by
these assays should be considered in drug selection.
The problem with the NCI studies is that there assays worked only in a small
minority of patients, who had significantly worse prognostic features than the
whole patient population at large.  They got a 7% evaluability rate in NSCLC
primary lung lesions, where real world private sector labs get a >90%
evaluability rate (in part because we are trying to test true fresh tumors and
not trying to subculture cells or create cell lines).

> In a disease such as NSCLC, where
> the benefits of chemotherapy are well-known to be marginal at best, one
> might reasonably expect the patients most likely to derive benefit would be
> those patients with the most favorable prognosis and not the patients with
> the least favorable prognosis.

Laing disagrees:

>That is not necessarily true, however.<

Not necessarily true, I agree (we could discuss theoretical possibilities in
great detail), but not the most important part of my rejoinder.

But let me tell you what I was thinking about... remissions in NSCLC are often
very short lived.  Part of the reason for short lived remissions are rapid
regrowth after maximum response (after we've killed off the "sensitive" cell
population and only the "resistant" cell population remains).  Now, if one is
looking at, for example, one year survival as an endpoint and the average
length of remission for patients with far advanced, rapidly re-growing disease
is only 1-2 months, then the survival implications associated with response
will be small, compared with the survival implications of a response in a
patient with a low tumor burden and slowly re-growing disease.

>>Yes, and to me this would imply that at least for lung cancer patients,
they may not see an increased survival impact from in vitro assays.
THis is why IMHO it's so important to determine which cancers may
benefit most.<<

Look, if you are going to spend $20,000 on chemotherapy because you have
decided that such chemotherapy is of potential benefit, then you'd want to
maximize the probability of benefit by choosing treatments more likely to work
and avoiding treatments less likely to work.  If the disease is not worth
treating, then you shouldn't do a test...but you also shouldn't treat.  If you
are going to treat, then you should strongly consider testing.

Some patients, even with lung cancer, do derive substantial, unequivocal
benefit from chemotherapy.  This is the reason why patients are treated.  At
the last ASCO meeting, a huge randomized trial in NSCLC was reported, comparing
the four most popular regimens.  There was no difference in outcome.  So you
could just flip a coin for one size fits all, first line therapy.  Yet many
patients failing to respond to first line therapy may respond to second line
therapy.  These patients should have gotten the correct treatment in the first
place.  The preponderance of evidence argues that patients will have a greater
likelihood of receiving the most correct treatment if information provided by
cell death assays is considered.

> And that's the problem with these NCI studies.  Good investigators.  Good
> institution.  Good journals.  But vaguely-described methods, misleading
> analysis, and misleading presentation of data.  And it mainly serves to
> reinforce the opinion held by many in academic oncology that cell culture
> drug resistance testing has been adequately studied, but has been found
> wanting to the extent that further studies are of vanishingly low
> priority and that clinical application is not to be supported.

Laing offers qualified support:

>I'm not of that opinion, given the different endpoint of your type of

Thanks for being much more open-minded than average.

> The true state of the field of CCDRT is that there is a compelling body of
> data to support its use, but that the question of whether or not the use of
> CCDRT in clinical chemotherapy improves the outcome of patient
> treatment has never been addressed in any type of an adequate study - using
> the CCDRT technologies which are currently being applied to the
> non-investigational management of 15,000 cancer patient per year in the
> United States.

Laing expresses relief in getting near the end:

>Finally.  Thank you.  It took long enough, but it was a fascinating

Most welcome  :)

> But, once again, the standard always applied previously to support the use
> of medical tests was the acceptable accuracy of the test and clinical
> utility, in the judgement of the physician ordering the test, supported
> by clinical logic and common sense.  This was also the standard applied
> by the FDA in its consideration of a kit for cell culture drug
> resistance testing (for which FDA approval was received and for which
> clinical and literature documentation of accuracy was inferior to that
> existing to document the technologies reviewed at
> and applied by my laboratory).

Laing cautions:

>However, patients choose them because of the implied survival impact
they have.  That's the important difference here.<

Patients choose any form of treatment (including Phase II and Phase I trials of
vanishingly low probability of benefit), because they hope for a cure - in a
literal sense - or at least for a remission which lasts long enough to keep
them going until the cancer research cavalry rides in with a cure...say an
angiogenesis inhibitor cocktail.

The more that patients ask tough questions of their oncologists and the less
often they volunteer for clinical trials designed to answer trivial questions,
the more that the oncology profession will be prodded to open its collective
mind in the case of new paradigms.

In 1982, at his Karnofsky Award acceptance speech, Dr. Emil Frei bemoaned the
fact that "discoverers" were being crowded out of clinical cancer research in
favor of "investigators."

Discoverers have new ideas and new methods.  They often fail, but when they
succeed, they do so in a way which results in a multi-step advance.

Investigators do not have new ideas, but test simple and obvious questions with
trials of low risk (i.e. the question is answered one way or the other, in a
relatively clean least that's the way it is supposed to work in
theory, but my own brief review of the history of clinical trials in ovarian
cancer illustrates how confusing and non-reproducible these so-called
straightforward studies can be).

We have seen the extinction of the discoverer in clinical oncology.
Generations of investigators have trained their successors.  Department Chairs,
Journal Editors, Cooperative Group Chairs, Private practioners alike.  All have
been trained in the investigator mind-set.  The result is that we are reduced
to asking unimportant questions in studies which are increasingly expensive,
wasteful of human resources, rarely definitive, and virtually never
illuminating.  We never learn anything of importance, so we never get the
opportunity to use new knowledge to come up with new ideas.

- Larry Weisenthal
Huntington Beach, CA


From: (RunnSwim)
Subject: Re: chemo failure
Date: 02 Oct 2000

In article <>, T D Laing <>

>And I still don't think you realize that survival impact is indeed the
>most important endpoint of in vitro assays--because patients are
>depending on these assays' predictions to save their lives.  You keep
>trying to downplay this point, which is unfortunate.

I stridently object to your characterization of my responses as an attempt to
"downplay" the importance of survival as an endpoint for all factors relating
to cancer treatment.

It is not inappropriate, however, to state that clear cut survival advantages
have not been shown for most empiric teatment regimens in most forms of cancer,
over other empiric treatment regimens.  This specifically applies to NSCLC.
Also survival benefits have never been shown for the use of any form of
laboratory test, which is what we are talking about here.

I have given as an example the use of first line treatment with carboplatin
plus taxol in ovarian cancer over single agent alkylators, such as melphalan,
cyclophosphamide, and chlorambucil.  Available clinical trials evidence does
not prove the superiority of platinum-based combination therapy over single
agent alkylators.  Nor does it prove the superiority of carbopolatin/Taxol over
single agent carboplatin or single agent cisplatin or the combination of
cisplatin plus doxorubicin plus cyclophosphamide.  Carboplatin/Taxol is vastly
more expensive and much more toxic than are single agent alkylators.

So why is Laing not warning cancer patients to avoid receiving  treatment with
toxic and expensive combinations which have not been proven to be superior to
less toxic and less expensive combinations?  Why is it only imporant to
"protect" patients from _information_ provided by laboratory tests which have
been shown, beyond the shadow of a doubt, to provide information which
consistently correlates with clinical outcomes, based both on response and


Laing uses the example of NSCLC to caution that there are only 47 published
correlations between assay results and clinical response.  It must be
acknowledged that the matrix is huge.  We are not talking about validating an
Estrogen Receptor assay (one disease, one treatment).  We are talking about
more than 30 drugs, hundreds of combinations, hundreds of diseases.  The
permutations and combinations are enormous.  But there have been close to 2,000
published correlations between assay results and response and hundreds of
correlations with survival (not including the to-be-published correlations
between assay results and survival in nearly 500 ovarian cancer patients which
I showed at the meeting in Washington last week).  In every single publication
(which total about 40) in which there were sufficient numbers to make
correlations, patients with favorable assay results had favorable outcomes,
relative to the patient population as a whole and vastly more favorable
outcomes compared to paients with unfavorable assay results.

In the 47 published patient treatment/assay correlations in NSCLC, the patient
population as a whole had, if memory serves, about a 25% overall response rate;
patients treated with drugs active in the assays had about a 65% response rate,
and patients treated with drugs inactive in the assays had about an 8% response
rate.  In other words, there was an 8 fold advantage to receiving treatment
with drugs with good in vitro activity. The expert Medicare advisory panel
formally voted that both response and survival were acceptable endpoints for
validating the activity of the assays.

One might complain (as Laing did) that 47 patients is too small to draw
reliable conclusions.  But this must be judged in the context of the entire
database of nearly 2,000 correlations, consistently showing the same general
overall level of correlation, without any controversy whatsoever, with the
correlations holding up for each individual disease.  In the case of ovarian
cancer, there are close to 350 published correlations.  It is up to each
individual to determine how many correlations are required in each specific
situation in order to make use of the assays.  Obviously, in many rare diseases
(e.g esthesioneuroblastoma), there will never be a lot of published

It again comes down to what standard you use:

1. Proof beyond reasonable doubt (criminal justice standard)

2. Preponderance of evidence (civil justice standard)

It must, additionally, be realized that virtually all cancer chemotherapy
treatments and tests are supported only by the civil justice evidence standard,
and not the criminal justice standard.

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Subject: Re: chemo failure
Date: 04 Oct 2000

>>Yes the matrix is huge, there are lots of choices, and surely you can't
test them all.  Are you limited by the biopsy size?<<

Nothing about these assays is simple. In a typical assay we are able to test 15
- 25 drugs and combinations in 3 or 4 different assay systems at two
concentrations. This requires 8 - 10 hours of medical technologist time and 3
hours of my own personal hands-on time. And then the patient must be treated
and assessed for response and survival.  And then you have a single data point
(one patient one specific treatment).  But we have, conservatively, 100 forms
of cancer, 30 drugs, 1000 combinations.  And you are not satisfied with merely
47 data points (patient/treatment correlations).

Ovarian cancer patients tend to have larger, biopsiable tumors than NSCLC
patients.  The surgeons (gyn oncologists) treat the patients with chemotherapy,
in addition to doing the surgery. Ovarian cancer patients often have 2nd and
3rd operations (unlike NSCLC patients). Ovarian cancer patients not
infrequently receive 2nd and 3rd line chemotherapy (unlike NSCLC patients).
These and other reasons explain why there is more correlation data in the case
of ovarian cancer than in NSCLC.

But, again, the NSCLC data must be evaluated in the context of the bigger
picture (of 2,000 published correlations). NSCLC is predominately
adenocarcinoma (as is ovarian, breast, and colon cancer).  Given that there is
a strong overall correlation and given that the correlation holds no matter in
what diseases it is broken down, and given that there are 47 NSCLC correlations
which are in broad agreement with 350 ovarian cancer correlations and 2,000
overall correlations, is it not likely that the assays are valid for NSCLC as
well as for ovarian cancer?

If you (hypothetically as an oncologist) are not satisfied with the quantity of
data, then you may wait another 5 years before using the assays in NSCLC
patients.  But I don't think that you are in a position to criticize the
decision of

- to be continued

From: (RunnSwim)
Subject: Re: chemo failure
Date: 05 Oct 2000

> 2. The demand that using the laboratory test must be proven to result in a
> survival advantage is totally unprecedented for a laboratory test or a
> radiographic test or, for that matter, for many forms of cancer treatment.
> - Larry Weisenthal
> Huntington Beach, CA

"Steph" objects:

>That's not the issue.
If you are suggesting that these techniques have some merit, the onus is on you
prove the a) efficacy and b) safety.<<

We are, again, talking about laboratory tests.  Laboratory tests are judged by
accuracy and not by "efficacy."  With regard to the issue of "safety," this is
not applicable.  These tests should be used to assist the clinician in
selecting between drug regimens which would be otherwise acceptable in the
absence of information provided by the tests.

As only a single example, the following treatments have been shown, in
meta-analyses of prospective, randomized clinical trials, to be equally
"effective" in the treatment of previously-untreated ovarian cancer:  single
agent alkylating agents, platinum combinations, platinum-Taxol, and single
agent platinum. Furthermore, in the setting of relapsed disease, there are many
"2nd line" treatments available, none of which has been proven superior to the
others.  For example: topotecan, etoposide, Doxil, gemcitabine, vinorelbine,
various 5FU-based regimens, re-treatment with platinum, hexamethylmelamine,
gemcitabine/platinum combination therapy, and so forth. One could literally
flip a coin between these regimens and, on average, do just as well (or
poorly).  But the tests have been shown, consistently, to be associated with a
seven-fold greater probability of benefit when patients are treated with in
vitro active regimens than with in vitro inactive regimens.   So the clinician
considers the test information, considers the individual patient (with regard
to the patient's ability to tolerate different forms of treatment), and
considers the literature and the clinician's own experience.  On the basis of
all these factors, the clinician selects a treatment regimen.  Therefore, it is
impossible for the tests to ever cause "harm," and the available preponderance
of evidence indicates that the information provided by the tests will increase
the probability that less probably effective regimens are avoided and more
probably effective regimens are selected.

This standard of "accuracy" (as opposed to "efficacy") is the standard applied
by the FDA in its approval process for test kits, including a cancer cell
culture drug resistance test kit produced by Baxter.  This kit was approved by
the FDA on the basis of data showing that the results of the test correlated
with clinical response, not on the basis that using the kit improved the
outcome of treatment, which is, as noted, an unprecedented demand for any
laboratory test.

Therefore, the "onus" is on me to provide as much data as I can to show that
the tests are acceptably accurate.  I have been doing this for the past 20
years, and I continue to do it.  Having done so, then this becomes an available
laboratory tool.  It is then up to individual clinicians to determine, for
themselves, whether and when to use this tool in their clinical practices.

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 10 Oct 2000

In article <gyzE5.6$>, "Steph"
<Steph@vancouver.island> writes:

>The insurance companies paid for bone marrow transplantation and high dose
>chemo for breast cancer for  a while. Are you saying that that is a good
>measure of the technique's worth?

You're taking my point out of context.  I was responding to the charge that we
have "failed to convince" people of the value of the service.  This was only a
single point in that specific rebuttal.

>>I'm really not knocking your technique, which is very interesting, and
promising. It's just that promise isn't a delivery.<<

Well, it is being "delivered" each year to a great many cancer patients, with
90% of the tests ordered by oncology professionals who are experienced in
managing patients on the basis of technology.  Absent the efforts of the US
private sector, there would have been no progress at all for the last 15 years.
 And it was respected University based clinical research who brought you bone
marrow transplantation therapy of adenocarcinomas.  On an objective basis, we
laboratory oncologists have helped many more patients, drained far less health
care resources, and produced no toxicity.  Remember my initial anecdote of the
ovarian cancer patient who underwent the ineffective and toxic tandem
transplants at $250K, only to be later rescued by a test costing less than
1/100dth of that amount, which identified a brilliantly effective and non-toxic
outpatient therapy?  There are many more where that came from, as reflected in
the overall survival data.

Most of the most important work in many sectors of medicine is now based in the
private sector.  The universities have their empiric, one size fits all
paradigm.  We have a competing paradigm.  Time will show which paradigm will
prove to be most useful to patients.

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 10 Oct 2000

In article <fyzE5.5$>, "Steph"
<Steph@vancouver.island> writes:

>Most NSLC is certainly NOT adenocarcinoma. SCC and large undiff are the
>majority (unless you are claiming that mucin positivity makes a tumour an
>adeno, whatever else it shows)

I was specifically referring to the lung tumors submitted for in vitro testing
(which is what is relevant to this discussion), where the overwhelming majority
are adenocarcinomas and mucin-positive large cells.  Only a minority are true
undifferentiated large cells and even fewer are squamous cells.  I'll actually
give you our precise breakdown over the past 5 years as to histologic type
within the next day or two.

See also the review below.  You'll see that there is a difference between men
(where the overall incidence is falling) and women (where it continues to

Cancer Epidemiol Biomarkers Prev 1991 Nov-Dec;1(1):29-34

Changing patterns of lung cancer incidence by histological type.

Devesa SS, Shaw GL, Blot WJ

Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland

Using data from five registries covering 7% of the U.S. population, we
investigated lung carcinoma incidence trends from 1969-86 by histological type,
sex, race, age, calendar time period, and cohort year of birth. Among white
men, squamous cell carcinoma was the most frequent histological type, but by
the mid-1980s the age-adjusted rates were decreasing while rates of
adenocarcinoma and small (oat) cell carcinoma continued to rise. Among white
women, adenocarcinoma was the most frequent type, followed by small cell
carcinoma, with rates of all histological types rising over the entire study
period. Similar time trends were seen among blacks. Rates for squamous cell
carcinoma among both sexes and adenocarcinoma among men, however, were
considerably higher for blacks than whites, whereas no racial disparity was
seen for small cell carcinomas. Rates for each histological type were higher
among men than women, although male-female sex ratios diminished over time.
Age-specific rates varied considerably by cohort year of birth; incidence of
squamous cell carcinoma among men increased steadily among those born from the
late 1800s to the first quarter of this century before declining among those
born thereafter. Cohort peaks were also reached, although about 10 to 20 years
later, for small cell carcinoma and adenocarcinoma, suggesting an eventual
reduction in incidence in these histological types as well. For each type, the
peak incidence occurred earlier for men than women. These differing incidence
patterns add to the evidence that the mechanisms of lung carcinogenesis may
vary by histological type.

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 10 Oct 2000

In article <>, T D Laing <>

>our patients believe that this assay imparts survival benefit compared
>to the usual way chemotherapy is offered.  I am not convinced there is
>enough information available yet, at least for some cancers, to support
>this claim.  I think there can be; I think there will be; but until that
>happens I don't think patients should have to pay for it.

Finally, we get down to the nitty gritty.  I'm guessing that one of the
real services provided by Messrs. Laing and Steph (have no idea, as I
write this, of their gender, but I'll be old fashioned in addressing
them in the masculine) is the debunking of cancer cures hawked to
helpless cancer patients, to the undeserved enrichment of their unscrupulous
cure hawkers.

A single one of these assays takes 3 hours of my own time, 8 - 10 hours
of California licensed medical technologist time, another 1-2 hours of clerical
time, typically $75 in two way shipping costs, hundreds of dollars in direct
marterials cost, and hundreds more in amortized equipment, leasehold, phone
utilities, etc.  To say nothing of laboratory debt (mine) repayment.

Now, since it has been absolutely impossible for anyone in North America
to get a grant to study anything relating to these assays since the mid-80s,
how does RT Laing feel that the costs should be borne?  In my case, I'm
not a corporation or even a group practice.  I'm supposed to take a sabbatical
for maybe 30 years and pay for the costs of the assays and pay the cooperative
groups $4,000 per patient and hope that they accrue enough patients to complete
a study before I die?  And if I can't do that, I should just be quiet and treat
my ovarian cancer patients with platinum/taxol and then empiric 2nd,3rd,4th,5th
line chemotherapy if I live in the USA and with nothing if I live in Canada?

Well, sorry.  Not independently wealthy. Not willing to pass on the opportunity
to fulfull my life's dream to make a difference in the treatment of cancer.
Secure in the knowledge that 20 years' worth of full time, hard work, with
little support or encouragement, has resulted in a pretty impressive and
convincing body of data, considered as a whole.

Enough to convince the miserly managed care organizations of California to pay
for this, along with most of the major US insurance companies.

Just for interest, we bill for our services just as any private practice
oncologist does. We do our best to collect from insurance, and then bill
patients for co-pays and for any denials. I have a standing offer to testify at
my own expense any time a cancer patient wants to take his insurance company to
court, small claims or otherwise.  I have a 100% success rate (8/8) in
obtaining 100% court ordered reimbursement for the patients who have taken me
up on my offer.  I've never taken a cancer patient to collections or sued a
cancer patient or done anything more aggressive than to send a bland monthly
statement.  This doesn't make me a's pretty much the same way that
most oncologists run their practices.

Of every dollar we receive, 70% comes from insurance companies, 15% from
hospitals, and 15% from patients (but the latter ranges from 0% to 100%).

By the way, the insurance companies wouldn't pay were the data not compelling,
if not 100% definitive (as is the case for practically everything in oncology).

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 10 Oct 2000

In article <>, T D Laing <>

>Yet I remain unconvinced.<

So, what does the "T" stand it... Thomas ... of 'doubting' fame?

That was actually a :)        I can't criticize you, for you've devoted an
astonishing amount of time to this.

Perhaps you'll be motivated to continue to read and think and follow this
field.  Perhaps you'll deservedly lose confidence in the assertions of
academic oncologists that they are doing worthwhile clinical research
into chemotherapy drug selection.  Perhaps you'll be in a position to
support clinical trials into assay-directed drug selection as being of
high priority.

Or not (as we say in California).

>>  You claim that I "downplay" the lack of studies
>> proving a survival benefit.  I have never done so.  I have never ducked
>> the issue. I have merely pointed out the following:
>> 1. There are two alternative methods for selecting a drug regimen for
>> use in cancer chemotherapy.  The first method is to go to the
>> literature and pick a regimen which has been proven to be superior to
>> other available regimens in "one size fits all" empiric chemotherapy.
>> The second method is to use information provided by an assay to choose
>> from between otherwise equally-acceptable treatments.  Laing claims
>> that it hasn't been proven that treating patients with regimens chosen
>> by the second method prolongs lives. I merely point out that, in most
>> cases (e.g. as in the examples of ovarian cancer and NSCLC) it hasn't
>> been proven that the most popular empiric treatments which would be
>> used in the absence of assays are superior to much less costly and less
>> toxic treatments which could otherwise be selected. So what it comes
>> down to is this:  (1) You get treated by a regimen which is
>> economically advantageous to the oncologist or to the medical care
>> system (e.g. which often means a complicated intravenous regimen in the
>> USA versus a simple oral regimen or no treatment at all in Canada -
>> with no definitive data to prove the advantage of one over the other)
>> or (2) you take advantage of assays which have been proven to correlate
>> with both response and survival to help you make the choice between
>> regimens which could otherwise be selected by coin flip or by
>> consideration of what is most financially advantageous to the
>> oncologist or to the medical care system.
>Excuse me?  Patients here in Canada receive standard chemotherapy
>treatment when indicated.  Sometimes it isn't indicated, or the
>oncologist feels it isn't appropriate.  I am well aware of the
>limitations of our healthcare system--its limitations in cancer
>treatment have to do with a lack of trained personnel (oncologists,
>radiation technicians) to serve cancer patients (i.e. timely delivery),
>moreso than anything else.  You yourself have commented previously
>(several times) that for ovarian cancer, no other chemotherapy regimen
>as delivered seems to be significantly better than oral melphelan--now
>you're insinuating that's somehow substandard?  The Canadian healthcare
>system pays only for what's been established as proven--so if you want
>that system to consider otherwise, well, that means you need better
>proof than what exists.  We keep covering the same territory here.

National pride.  But let me tell you a true story.  Shortly after I jumped onto
this thread, I received an e-mail from a Canadian ovarian cancer patient.
She had persistent disease following first line therapy with platinum/Taxol.
Her oncologist recommended no further chemotherapy.  She asked the
oncologist if it would be possible to obtain an assay on her tumor (patients
who have received prior therapy with taxol/platinum but no other chemotherapy
prior to our testing have a survival which plateaus at 5 years following the
assays at about 40%, which is much better than than the survival of _previously
untreated_ patients treated in cooperative group studies).

Here's what she was told...not that the tests were inaccurate, but that the
oncologist was afraid that the tests might identify a treatment for her and the
oncologist didn't want to give further treatment.

As I said, two systems..both with great oncologists.  But the Canadians don't
like to treat at all, while the Americans want to keep giving intravenous
chemotherapy through 5th line therapy, until the very end, whenever they can.

We assay guys (and gals) are just trying to make the whole process more
objective and successful.  I like to think that we are the good guys.

>> 2. The demand that using the laboratory test must be proven to result in a
>> survival advantage is totally unprecedented for a laboratory test or a
>> radiographic test or, for that matter, for many forms of cancer treatment.
>Your patients believe that this assay imparts survival benefit compared
>to the usual way chemotherapy is offered.  I am not convinced there is
>enough information available yet, at least for some cancers, to support
>this claim.  I think there can be; I think there will be; but until that
>happens I don't think patients should have to pay for it.
>> 3. Holding these techologies hostage to a hypothetical series of
>> clinical trials which no one is is willing to support has been a
>> tragedy for clinical oncology, in that it has delayed technology
>> advances and clinical oncology training advances (e.g. the ability to
>> use cognitive skills to individualize chemotherapy) which by now would
>> have led to major improvements in both cancer treatment and new drug
>> development.
>> This is not "downplaying" anything.  It is addressing the issue foresquare.

>"Holding hostage?"  That implies that this technology is adequately
>proven.  We both keep repeating ourselves ad infinitum here, sir.  I
>hope it will ultimately be resolved, but IMHO it does mean more
>correlations for some cancers.  Hopefully that will change very soon.

It is certainly as "proven" as is the one size fits all, empiric chemotherapy
drug selection paradigm, which has in most cases, not been
"proven" at all.  And the testing paradigm's a whole lot more logical.

And a whole lot more
promising.  At least it's different.  Martin Apple had a wonderful quotation
which can be applied to the paradigm of performing prospective, randomized
trials pitting one empiric chemotherapy versus another: "and experiment which
has failed 100,000 consecutive times should be viewed with suspicion."

It's time for a change, and times are changing.

The old paradigm is not worthy of being protected
by thoughtful people like TD Laing.  The emperor
has no clothes.

Stay tuned.  You'll see.

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 10 Oct 2000

In article <>, T D Laing <>

>I know from my own experience, any cell assay takes loads of time.  May
>I ask how many cells are tested per assay?  100?  1000?  A set
>percentage of the total biopsy?

It's quite complicated.  There is a well-described artifact called plating
density-induced drug resistance. This is related to the total metabolic
activity per ml of cell culture, rather than the cell count per ml.  Thus, a
few large and robust ovarian cancer cells provide much greater metabolic
activity than do many "sickly" melanoma cells and vastly more than typical
indolent chronic lymphocytic leukemia cells.  We make Cytospins and we know how
they should look, if the assays are to be optimum.  For example, for a freshly
biopsied and transported ovarian cancer, we'd like to plate only 3 dimensional
cell clusters (we have methods to separate out the 3D clusters from the
discohesive single cells).  Ideally, we'd want 20% of the total area of the
Cytospin "disk" to be covered up with cell clusters, leaving 80% white space.
We know from experience that this will give us the correct metabolic signal at
the conclusion of the culture...where too high a signal warns us of the danger
of artifactual resistance from overplating.

For a "sickly" melanoma biopsied two days previously and delayed in transit,
we'd plate it so that 90% of the Cytospin "disk" was covered by viable tumor
cells.  For a CLL, it would by nearly 95%.  And so on.  But it's a matter of
experience, quality controlled for by testing the post culture metabolic
signal, and then interpreted by comparing apples to apples in our database
(i.e. we pull out a cohort of assays showing similar technical
characteristics...metabolic signal, ratio of viable cells pre and post culture
in the control cultures, degree of 3 dimensionality...average percent cells in
clusters, average size of clusters, average density of clusters...time elapsed
between biopsy and plating in culture, etc.).  So we compare clumpy, good
surviving, fresh, metabolically robust ovarians with others of this kind and
compare non-robust, non-clumpy, non-metabolically robust tumors with others of
their kind. This "apples to apples" comparison greatly improves biological

>> And then the patient must be treated
>> and assessed for response and survival.  And then you have a single
>> data point (one patient one specific treatment).  But we have,
>> conservatively, 100 forms of cancer, 30 drugs, 1000 combinations.  And
>> you are not satisfied with merely 47 data points (patient/treatment
>> correlations).
>Not for NSCLC.  We both know ovarian cancer is different from NSCLC is
>different from leukemia.<<

Well, NSCLC is primarily adenocarcinoma. It tends to be three dimensional.
Oftentimes it is difficult to distinguish from other adenocarcinomas on either
morphologic appearance or cell marker studies.  And breast cancer is an
adenocarcinoma.  As is colon cancer.  As is stomach cancer.  So if the
correlations hold up for all of the above different types of adenocarcinomas,
and they hold up for hematologic neoplasms, then they'll probably hold up when
500 NSCLCs are studied, as well; instead of just 47.  But it comes down to a
preponderance of evidence at any given point in time.  And risk benefit ratio
of using assay information to help in selection between different drug regimens
which might otherwise be chosen on the basis of a coin flip.  But if you are
treating a patient with NSCLC and aren't impressed with the data, then don't
order the test.  But be cautious in asserting that your colleague should not be
ordering the test in an identical situation.  He's/She's trying to help his/her
patient, just as you are.

>>If two drugs/combinations show equal effects,
>I assume you recommend the least expensive/toxic of them?

I take everything into account.  In my reports, I supply assay results, raw
data (in case someone accrues a lot of patients and wants to write up his/her
own study), my own interpretation/recommendations, relevant literature
retrievals (particularly when the in vitro best regimen is something a bit
unusual, I try to find papers where similar regimens have been used, and what
were the outcomes and toxicities), and also the most recent NCI "PDQ"
describing state of the art standard therapy.  So the referring oncologist has
all of the above, and he/she has his own experience, personal knowledge of the
patient, and preferences.  The final call is obviously between the referring
oncologist and his/her patients.

>> Ovarian cancer patients tend to have larger, biopsiable tumors than NSCLC
>> patients.
>So yes you are limited by size of the biopsy.  Biopsy limitations, was
>probably why previous in vitro assays attempted to culture the tumor
>cells first before testing them.  This is an important point for patients to
>know about.

But those attempts at pre-culturing were, by any standard, failures.  Over 95%
of all specimens coming in through our door are successfully tested.  Average
of 15-20 drugs and combinations per specimen. Tested with three different
endpoints at two concentrations.  Results compared with a matched dataset (see
above) of similar assay, derived from an overall dataset now containing 500,000
individual drug tests, all carried out in fresh human tumor biopsies.

But still there are limitations.  I don't like doing assays on "skinny needle"
biopsies.  These are usually technically marginal and only a small number of
drugs may be tested.  So a real limitation is a source of biopsiable tumor.

>> The surgeons (gyn oncologists) treat the patients with chemotherapy, in
>> addition to doing the surgery. Ovarian cancer patients often have 2nd
>> and 3rd operations (unlike NSCLC patients). Ovarian cancer patients not
>> infrequently receive 2nd and 3rd line chemotherapy (unlike NSCLC
>> patients). These and other reasons explain why there is more
>> correlation data in the case of ovarian cancer than in NSCLC.
>NSCLC also seems less amenable to chemotherapy.  The reason why I wonder
>about the ultimate prediction ability for NSCLC, is that the way the
>cancer develops, the tumor cells would already have had time to garner a
>lot of resistance to most drugs.  Your 1992 BJC study suggested 36% of 25
>patients showed partial responses to the predicted drug regimens although
>35 tumor samples from 35 patients were assay-able.

This was a study carried out between 1984 and 1986, if memory serves (dates are
provided in the paper, which wasn't published until about 1992, because of the
need for follow-up, data analysis, etc.). Specimens were sent by regular mail
in unrefrigerated containers from the Loma Linda Veterans Hospital to the Long
Beach Veterans Hospital.  The patients were treated and evaluated at Loma
Linda. We did the testing at Long Beach. 25 of 35 specimens received were
evaluable (compared with our contemporary standard of >95% evaluability).  25
patients received an in vitro best regimen (not all were "sensitive," in vitro,
but all patients got the in vitro "best" drugs, even if they weren't all that
good).  There was a 36% partial response rate in a group of patients with
advanced disease (some with poor performance status and/or brain metastases and
therefore ineligible for other chemotherapy clinical trials of the type being
held at the time).  Patients with "sensitive" assays were much more likely to
respond than patients with "resistant" assays, even though the latter patients
were treated with the "best of the bad."  By today's standards, the technology
was primitive. We tested only a single drug concentration with a single assay
endpoint.  We did not selectively enrich for three dimensional cell clusters.
Specimens were 2 days old and non-refrigerated.  We did not use an 'apples to
apples' database comparison.  7 patients received treatment with 5FU (none of
these 7 responded), because we did not recognize at the time that the DISC
assay is not very good for 5FU (which may be tested accurately with the MTT
assay, which is one of the assays which we apply to each specimen
today...contrariwise, the DISC assay is superior to the MTT assay in the case
of Taxol and docetaxel).  Anyway, despite these problems, the clinical outcome
was at least equivalent to the best of the then-available clinical trials
literature, and probably better, given the patient population.  Most
importantly, today we have many new agents with major activity in NSCLC
(gemcitabine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, and
combinations thereof).  I hope to be able to report contemporary survival data
in NSCLC within the next two years (the first disease to be reported, hopefully
within a year, will be ovarian cancer).

>> But, again, the NSCLC data must be evaluated in the context of the
>> bigger picture (of 2,000 published correlations). NSCLC is
>> predominately adenocarcinoma (as is ovarian, breast, and colon cancer).
>> Given that there is a strong overall correlation and given that the
>> correlation holds no matter in what diseases it is broken down, and
>> given that there are 47 NSCLC correlations which are in broad agreement
>> with 350 ovarian cancer correlations and 2,000 overall correlations, is
>> it not likely that the assays are valid for NSCLC as well as for
>> ovarian cancer?
>It's possible...and the null hypothesis is also possible.

Anything is possible.  What is more likely? Preponderance of data; need for
decision today, while definitive data won't be available for years, etc.

>> If you (hypothetically as an oncologist) are not satisfied with the
>> quantity of data, then you may wait another 5 years before using the
>> assays in NSCLC patients.  But I don't think that you are in a position
>> to criticize the decision of
>It's too bad you didn't finish this.  However I am in a position to
>criticize, as a potential future cancer patient--you assume that the
>relationship holds for all cancers, great hypothesis, maybe even true,
>but I know I would like to see more "published correlations" if I were
>(God forbid) to develop NSCLC.  If I were (God forbid) to develop ovarian
>cancer, I'd probably hand-deliver my biopsy myself (and stick around to
>see the actual testing if I could).  That's the difference.

nb: I had to leave in the middle of writing the above and didn't have time to
save it; so I just sent it unfinished.  I was just going to say that you are
perfectly fine to hold your own views, but should be gracious enough to
acknowledge that other expert and experienced oncologists have reached opposite
conclusions, based on their own understanding of the literature and based on
their own personal experience. It's one thing not to imbibe oneself.  It's
quite another to call for prohibition.

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 10 Oct 2000

In article <>, T D Laing <>

>'m looking at what patients are expecting from this assay.  They
>wouldn't be taking these tests if they didn't believe there were
>significant survival benefit, would they?  So we're back to my original
>> I claim that the tests are sufficiently accurate to be useful in
>> drug selection in most forms of cancer.  Period.
>And patients believe it imparts a better survival benefit.

And so do the expert oncologists who order 90% of the tests performed today
(the other 10% being patient initiated).

Of course patients and doctors do what they do because they hope to see a
survival benefit.  But this hasn't been proven for a great many treatments and
for all tests in cancer; and it never will be proven for many treatments and
most if not all tests (think of the 30 year history of the clinical application
of hormone receptor assays).

You've got four treatments A,B,C, and D which are considered to be state of the
art, best treatments for Non Small Cell Lung Cancer.  You've got metastatic
disease.  You'd like to keep going long enough for the cavalry (say
angiogenesis inhibitors, combined with monoclonal antibodies) to come to your
rescue.  A,B,C, and D have just been proven in a large, multi-group study to be
equivalent, when given as one size fits all therapy.  Yet some patients clearly
have their tumors grow when on A, only to shrink when changed over to B.  These
patients should have gotten B the first time around.  And it has never been
convincingly shown that "state of the art" A,B,C,D are better (when applied as
empiric, one size fits all therapy) than combinations used 15 years ago.

So you have tests which have been shown in 40 consecutive studies to identify
regimens with greater and lesser chances of working, with the in vitro active
regimens being, on average, 7 times more likely to work than the in vitro
negative regimens.  But you note that, whereas there are 350 published
correlations in adenocarcinoma of the ovary and 100 in adenocarcinoma of the
breast and another 100 combined in adenocarcinomas of the colon and stomach,
there are only 47 published correlations in non-small cell lung cancer (85% of
which are adenocarcinomas).  The NSCLC correlations appear to be similar to
those in the other adenocarcinomas.  But is it sufficient convince you to
consider the information provided by the assays?  Or do you just flip a coin
and choose between A,B,C,D?  Or choose a less expensive and less toxic older
regimen not proven to be inferior?

I can't answer that question for everyone.  I can only answer it for myself and
frame the question for others to consider for themselves.

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Subject: Re: chemo failure
Date: 10 Oct 2000

In article <>, T D Laing <>

>Bacterial C&S has had decades to prove itself; herceptin
>treatment, based on her2/neu testing, has shown to prolong survival in
>those breast cancer patients whose tumors express Her2/Neu; hormone
>receptor assays have indeed shown the predictive value of
>presence/absence of estrogen and progesterone receptors.

Bacterial C&S has only "proven" itself as far as correlating with clinical
outcomes, and there are fewer published correlations between the results of
antibiotic sensitivity testing and clinical antibiotic therapy than there are
published correlations between cancer "C&S" and results of clinical cancer
chemotherapy.  Her2/Neu has only been shown to correlate with Herceptin therapy
(just as in the case of cancer "C&S").  It hasn't been shown that clinical
outcomes are improved by performing Her2/neu testing...just that it correlates
with clinical outcomes. Hormone receptor assays have only been shown to
correlate with the results of hormonal therapy; it has not been shown that
performing hormone receptor tests improves clinical outcomes.  After 30 years,
it still hasn't been shown that performing hormone receptor studies makes a
difference with regard to clinical response rates and certainly not with regard
to patient survival.  Same for Her2/neu.  Same for bacterial C&S.  Same for all
other laboratory and tests, of which I am aware.

>> What is the justification for treating patients with carboplatin +
>> Taxol when it hasn't been shown that this is better than oral melphalan
>> (vastly less toxic and costly)?
>Because the majority of oncologists are convinced otherwise, for better
>or worse?

"Convinced otherwise," that's an interesting turn of phrase.  As in, I
suppose, "the majority of oncologists are convinced the cell culture drug
resistance testing in cancer is not of value" (more on this particular point of
view, below).

Why in the world did we enter 10,000 hapless ovarian cancer patients on
prospective randomized trials of Pepsi-Cola vs Coca-Cola, if we were going to
ignore the results of those studies when they did not conform to our
pre-conceived biases?

But we did do the studies.  And they showed no superiority of platinum
combinations over single agent alkylators.  They showed no superiority of
platinum/taxol over single agent platinum.  They showed no superiority of
platinum/taxol over platinum combination therapy not containing taxol.

But "the majority of oncologists" ignore this, because they don't like the
results of the studies.

Recently, the US Supreme Court re-wrote the Federal Rules of Evidence regarding
litigation in science and medicine. This was the result of the Daubert vs. Dow
Chemical decision.  In a nutshell, the Supreme Court found that data trumps the
opinions of putative experts.  So it doesn't matter of what the "majority of
oncologists" are convinced.  What matters are the data.  And the data
unanimously and without any controversy whatsoever confirm that the results of
cell culture assays based on the cell death endpoint strongly correlate with
and predict for clinical outcomes.  We ourselves won a court case on this
against Medicare.  This goes for acute lymphoblastic leukemia, acute
non-lymphocytic leukemia, chronic lymphocytic leukemia, ovarian cancer, colon
cancer, stomach cancer, breast cancer, non-Hodgkin's lymphoma, and non-small
cell lung cancer.  True, there are greater numbers of correlations in some
diseases than in others, but, in each case, the differences are statistically
significant and in precise accord with the predictions of Bayesian statistics.
The p value on cumulative meta-analysis is less than 10-E8.
Overall, patients treated with drugs active in the assays are 7 fold more
likely to respond and, in many cases, significantly more likely to live.  You
might object that this doesn't prove anything for pancreatic cancer or renal
cell carcinoma or rhabdomyosarcoma or a hundred other cancers.  You might also
object that correlations have not been proven for all possible drugs and drug
combinations.  This is correct and, in many cases, correlations never will be
proven, simply because this work is so very hard to do (which is why its taken
us 20 years just to get where we are now) and there are too many cells in the
matrix to fill.

But, more on this later.

>> This is perhaps the most eqregious of double standards in the history
>> of cancer medicine.  For twenty years, these technologies have been
>> held hostage to a hypothetical series of clinical trials which no one
>> has been willing to support.
>Unfortunately that's because in vitro assay proponents failed during that
>time to convince those who needed to be convinced, that the newer
>apoptotic endpoint assays were superior to cell growth assays.  The
>addition of apoptosis to the cancer paradigm is relatively new.  I
>sincerely hope that changes, BTW.

I beg your pardon. Just because you and "Steph" are not convinced, please do
not generalize this.  In point of fact, we have convinced a very large critical
mass of expert oncologists and the vast majority of insurance companies and
managed care companies.  90% of our referrals come from oncologists who are
very experienced with managing patients on the basis of the data provided by
these assays.  10% is from patients who seek this out; but I don't do any
"marketing" at all, to either oncologists or patients.  I've assiduously
avoided these internet discussion groups and I blundered into this discussion
quite accidentally; but I couldn't let the misprepresentations by "Steph" stand
without comment.  I really wish that I hadn't come across this, but here I am.
Once we finally wind this up, you'll not hear from me for another 5 years on
Internet cancer newsgroups (though people wanting to read my opinions can check
out my frequent contributions to the biomechanics and physiology of competitive
swimming on

>> In the same period of time, we have made virtually NO progress in
>> identifying superior chemotherapy regimens, based on the paradigm of
>> randomized clinical trials pitting one form of treatment over a new and
>> putatively improved form of treatment to be given in one-size-fits-all
>> chemotherapy in a disease (cancer) which absolutely everyone concedes
>> is highly heterogeneous. In addition to the loss of patient benefit,
>> the lost opportunities with respect to technology improvement to
>> improve both drug selection and drug development are incalculable.
>> This is not sophistry.  As Howard Cosell used to say, this is telling
>> it like it is.

>It is sophistry to insist that these assays have conclusively
>demonstrated survival impact for *all* types of cancers, IMHO.

Straw man, again. When did I say the above?  When? When? When?

What I said was that the assays have been conclusively demonstrated to
correlate with and predict for clinical outcomes, just as in the case of other
useful laboratory tests.  You are the one demanding conclusive proof of a
survival impact.  I point out that such proof is lacking for all medical tests
and for probably the majority of cancer treatments.  When my younger brother
was diagnosed with stage I Hodgkin's Disease after developing shortness of
breath running uphill at mile 20 of the Catalina Marathon, he underwent
mediastinoscopy under general anesthesia solely for the purpose of obtaining
tissue for cell culture drug resistance testing...despite having a form of
cancer that was 85% curable with "standard" chemotherapy.  85% is only good
when you are talking about cancer.  If you had a 15% chance of dying from your
next bout with the flu, you'd want to improve those odds.  So my brother
received a novel chemotherapy combination never before (or since) given to a
Hodgkin's Disease patient (mitoxantrone, vinorelbine, vincristine, prednisone,
followed by bleomycin/vinorelbine, vincristine, prednisone).  He got this
because the "ABVD" drugs didn't look to be the best.  I don't think that there
will ever in my lifetime be a prospective randomized trial of assay directed
therapy in Hodgkin's Disease....or in 95% of the other forms of cancer, as
well.  I also don't expect to see a prospective randomized trial of Her2/neu
testing or ER testing, as well.

>> If a physician does not feel that this testing is a useful tool in drug
>> selection, then he/she shouldn't order the testing.  Just as in all
>> areas of medicine.
>> I don't have a problem in the world with Steph or anyone else of
>> similar point of view not using the tests.
>Unless they comprise the majority?

Several ways to answer the above:

1. Supreme Court Daubert v Dow Chemical decision: "Objective data trumps
opinion of majority of experts."

2. Bertrand Russell:  "On any new and important development in science, the
majority is almost always wrong"

3.  In 20 years of doing this and discussing it with literally hundreds of
oncologists (including many of the most respected opinion leaders in clinical
oncology), I've never talked to a single one who was familar with and
understood the data.  Maybe one in 20 could intelligently discuss Bayes'
Theorem (without which one cannot make any sense of the literature in this
complex form of testing applied to patient populations with pre-test
probabilities ranging from 2% to 95% probabilities of clinical benefit).  Not a
single person knew BOTH the literature and Bayes' Theorem. The majority of
clinical oncologists still refer to these tests as "clonogenic assays," even
though clonogenic assays have not been used by any of the major laboratories
involved in this testing for at least 15 years.

>> A tool is only useful in the hands of someone who
>> understands both the tool and the data which support the application of the
>> tool.
>No--a tool is only useful when it has proven itself to others.

Well, it's proven itself to the tune of greater than 12,000 non-investigational
patient assays per year, a number which will grow substantially over the next
decade, as the published database continues to enlarge and as the failings of
the empiric, one-size-fits-all paradigm become increasingly impossible to

Everyone has his/her own comfort level about everything important.  While we
may wish to delude ourselves into thinking that medicine is cut and dry and
scientifically proven, this is not the case.  Virtually nothing has been
proven.  What we almost always base decisions on are the preponderance of
evidence.  You've got a patient with cancer.  He/she needs you to make the
right decision to give him/her the best chance.  But there is not one right,
proven decision.  There is only a preponderance of evidence and your judgement
and experience.  Excellent oncologists in the USA give complex intravenous
chemotherapy regimens in situations where their equally expert colleagues in
Canada wouldn't give any chemotherapy at all.  Yet a case could be made for well as for the use of cell culture testing to help with the

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 12 Oct 2000

In article <9MPE5.1501$>, "Steph"
<Steph@vancouver.island> writes:

>Is it 7-fold greater than when compared with "standard" therapy rather than
>drugs showing poor in-vitro activity?

Varies with pre-test probability precisely according to Bayesian predicitions,
but, taken overall, patients with "senstive" assays have a 1.5 - 2.5 X
probability of responding to chemotherapy compared with the group as a whole
(which has a 1 X probability of responding); patients with "resistant" assays
have a 0.2 - 0.25 X probability of responding to chemotherapy than the group as
a whole, and patients with "Sensitive" assay have a 7.5 X - 12 X probability of
responding to chemotherapy than do patients with "resistant" assays.  Thus,
there is a 7.5 to 12 fold advantage in being treated with an assay "sensitive"
regimen compared to an assay "resistant" regimen.

>As to whether any "objective response" other than a complete response is
>worth anything, that's another discussion............

The tests don't change the biology of the disease, they only help to define
this biology prior to treatment.  The tests correlate with and predict for
response and they correlate with and predict for survival.  If the best that
can be currently achieved with available drugs is a partial response, then the
tests will identify drugs with greater and lesser probabilities of producing
partial responses.  Most people would infer that, other factors being equal,
patients would in most cases be better served with receiving drugs more likely
to produce such a response than less likely to do so.

If you feel that there is no possibility that a drug exists that will provide
the patient an acceptable level of benefit (e.g. if you feel that the best that
can be achieved is a partial response and you don't feel a partial response is
worthwhile) then you shouldn't order the test and you shouldn't give
chemotherapy.  On the other hand, if you think that it is possible to identify
a drug regimen which is capable of producing a durable complete response or if
you feel that the best possible outcome is a partial response and you feel a
partial response is worthwhile, then you should consider ordering the
test...unless you feel that there is insufficient proof of the accuracy of the
test in the intended setting, in which case you should also not order the test.

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 14 Oct 2000

In article <>, T D Laing <>

>> It is certainly as "proven" as is the one size fits all, empiric
>> chemotherapy drug selection paradigm, which has in most cases, not been
>> "proven" at all.  And the testing paradigm's a whole lot more logical.

>Logical, yes, but high-dose chemotherapy with stem cell rescue for
>breast cancer, seemed very logical too at the time.

This last exchange, I think, sums up the basic points of contention.

Your analogy with high dose chemotherapy for breast cancer is not appropriate.
You are merely citing a failed idea in cancer treatment to warn that seemingly
good ideas may fail.  Everyone is well aware that this has occurred easily a
thousand times in the history of cancer treatment research.

But the real issue is this: People are sick today. Choices must be made today.
How are those choices to be made?

You have pointed out, over and over and over and over and over, that it has not
been proven that performing cell culture assays to identify drug regimens
improves the results of cancer treatment.  I have never disputed this point.
What I object to, however, is the implication in this statement that the
ALTERNATIVE method of drug selection (i.e. the choice of an empiric drug
combination identified through prospective clinical trials) has itself passed
the same test that you demand of the assay-selection paradigm.

I've quoted two examples: ovarian cancer and NSCLC.  I could cite many more.
In both of these neoplasms, relatively inexpensive and relatively non-toxic
treatment regimens (with off-patent drugs) exist which have been abandoned in
favor of more complex and toxic and vastly more expensive treatment regimens
with on-patent drugs.  Two decades of prospective, randomized trials have
failed to establish the superiority of the new empiric treatments versus the
old empiric treatments.  Yet, because the results of these trials did not
confirm the pre-conceived biases of the clinical oncology establishment, these
trials have been ignored or otherwise explained away, and the newer, more
complex,  more toxic, and much more expensive treatment regimens continue to be
used and this use is unchallenged.  You and Steph are apparently giving the
oncology "establishment" a free pass just because they are the establishment
and not because controlled research supports what they are doing.

Now, let's get back to the cancer patient who needs an effective treatment
today. And the oncologist who wants to provide that effective treatment.

So the choice is between two unproven methods of drug selection: (1) An
empiric, one size fits all regimen and (2) a regimen selected with the help of
information of assays which have been persuasively shown to correlate with and
predict for both response and survival (and if we have to go through all 40 or
so of these studies in order to make this point, I am willing to do so...and
this number continues to grow; as I sit here, I have two manuscripts on my desk
in which journal editors have asked for my peer review; these studies again
showing positive correlations).

So you've got to make the choice today: do you use method (1) or method (2)?

Comparing this with high dose chemotherapy/stem cell transplantation is
entirely odious.  High dose chemotherapy is almost unbearably toxic, can cause
the patient great harm, and is unbearably expensive.  The assays do not cause
harm and are almost certainly highly cost effective (e.g. Mason, JM, et al
(1999) The DISC assay. A cost-effective guide to treatment for chronic
lymphocytic leukemia? Int J Technol Assess Health Care 15:173-84).  If you
claim that the assay selection method must be proven to improve outcomes, what
do you do in the situation where the only alternative is empiric therapy with
regimens which have also not been shown to improve outcomes?  But remember the
difference is that the empiric therapy paradigm HAS BEEN more than adequately
TESTED (in thousands of patients in scores of randomized trials) and has been
proven to have failed.  The worst thing that can be said about the laboratory
assays is that they have never been tested in tightly controlled trials
designed to show that they can improve outcomes...but, again, it is NOT
irrelevant to note that this is an unprecedented criterion for any laboratory

I am not exaggerating when I claim that holding these assays hostage to a
series of hypothetical randomized clinical trials which no one is willing to
support has been the greatest lost opportunity in cancer treatment research
over the past 20 years.

The current dialogue between TL Laing and Steph illustrates nicely the mindset
which has retarded progress in this field.  It's a Catch 22.  Don't do the
assays until you prove that they do something which no laboratory test in
history has been proven to do and which the existing empiric method of drug
selection has itself been DISPROVEN of being capable of doing.  And, by the
way, don't expect us to lift one finger or appropriate one dollar to support
these unprecedented clinical trials which we demand of you.

What is being protected here?  Vulnerable cancer patients from unscrupulous
purveyors of unproven technologies?  When the alternative is what?  Some sort
of sacred scientific standard which has not been met by the alternative methods
of drug selection?  Looking at the preponderance of data, is there any doubt
that the technologies are capaple of identifying treatments with greater and
lesser probabilities of working?  Is there any doubt that, had one hundred
expert laboratories been providing this service over the past 20 years that we
would now have vastly better technologies and a very good handle on the
situations where these technologies are most advantageously applied?  What is
the threat to anyone if this genie finally gets out of the bottle?  If it
doesn't work in certain or many situations, won't this come out sooner rather
than later?  And if the use of these tests is confined to selecting from
between a list of reasonable drug regimens which would, on average, produce
equivalent results, what are the risks to patients?  How does the amount of
money which would be spent on the assays compare with the amount of money now
spent on empiric treatments (which are often ineffective)?

In point of fact, notwithstanding all of the above, there are, in addition, now
emerging studies which point in the direction of improved treatment outcomes
with assay directed therapy.  This is in the case of breast cancer, ovarian
cancer, and chronic lymphocytic leukemia.  None of these were randomized
studies, but the only justification for using, for example, taxol/carboplatin
in NSCLC is that, compared to non-controlled historical experience (not
confirmed in prospective randomized studies), taxol/carboplatin seems to be
producing better results.  Well, if taxol/platinum-relapsed ovarian cancer
patients who receive assays do better (survive longer) than the previously
published series of _previously-untreated_ patients, then this evidence can be
added to non-randomized studies showing superior survival with assay directed
therapy and strong correlations between clinical response and survival with
assay results to make a strong case for considering assays as an alternative to
empiric therapy...realizing, again, that the decision must be made today and
that this is not just some sort of endless, theoretical exercise.

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 14 Oct 2000

In article <>, T D Laing <>

>Do you assess metabolism by MTT or another similar assay?  (I've seen
>MTT mentioned on one website.)

We test cells with 4 endpoints: DISC (delayed loss of membrane integrity), MTT
(mitochondrial metabolism), ATP (lost almost immediately at the moment of cell
death), and measuring redox potential of culture medium (living cells reduce
culture medium electrochemically).  Each endpoint has advantages/disadvantages
for certain types of tumors and certain types of drugs.  In 95% of the drugs we
test and report out, we have at least 2 successfully-completed endpoints on
which results are based.

TD Laing goes on to ask follow up questions about 3D clusters and why the MTT
assay works for 5FU.

First the 3D clusters:

3D clusters better recapitulate clinical drug resistance patterns than do
clonogenic or monolayer cultures.  Thus we discard the single cells (whenever
possible, and only test the clusters (to the extent that this is possible).
This is the opposite of the situation existing with the old clonogenic assay,
in which the single cells were tested and the clusters were thrown away.  There
is now a pretty large literature on this:


Invasion Metastasis 1994-95;14(1-6):50-60

Impact of multicellular resistance on the survival of solid tumors, including

Kerbel RS

Cancer Research Division, Sunnybrook Health Science Center, Toronto, Ont.,

One of the reasons for the development of cancers and their relentless
malignant progression--even in the face of highly toxic anticancer
therapies--is an enhanced ability to bypass mechanisms responsible for
precipitating cell death. The latter include active cell death mechanisms often
referred to as programmed cell death or apoptosis. Active cell death is a
genetically controlled, intrinsic suicide process, and evidence is rapidly
accumulating that cancers are more resistant to undergoing apoptosis than
normal cells. This may be a major factor explaining the ability of small
numbers of tumor cells, e.g. tumor emboli, to survive transit in the
bloodstream and form distant metastases in ectopic organ sites. In addition,
because many therapeutic agents ultimately kill tumor cells by inducing
apoptosis, acquisition of an apoptosis-resistant phenotype could be a generic
mechanism of drug or radiation resistance in cancer patients. It follows that
uncovering the basis of the enhanced survival capacity of tumor cells is
fundamental to gaining a better understanding of tumor progression, metastasis
formation, and response to therapy. In this respect many of the principles
thought to regulate apoptosis in cancers have been established using
conventional, two-dimensional monolayer cell cultures of 'liquid' tumors, i.e.
unicellular model systems. Suppression of apoptosis in solid tumors, however,
may be governed by different cellular and genetic mechanisms. Evidence is
presented in support of this hypothesis, and that multicellular architecture
may render individual tumor cells within solid tumors less susceptible to
apoptosis. This multicellular resistance--which may represent a form of group
protection--can also be induced or acquired during cytotoxic drug chemotherapy
or cytokine-mediated growth inhibition of solid tumors. It follows that
disruption of solid tumor multicellularity may provide a means of enhancing the
therapeutic destruction of small solid tumors such as occult micrometastases.
Such disruptions may be brought about by a variety of so-called antiadhesive


With regard to 5FU in the MTT assay, this is very interesting.  MTT actually is
metabolized by a Krebs cycle enzyme, succinate dehydrogenase.  This occurs
mainly/only in the mitochondria.

Mitochondria continually replicate themselves throughout the cell cycle (even
when the cells are mitotically quiescent).  This replication requires
mitochondrial DNA synthesis.  5FU works by inhibiting DNA synthesis and RNA
synthesis.  It has been assumed (based on studies in continuously proliferating
cell lines) that chromosomal DNA synthesis is the main target of 5FU.  But the
paradox is that 5FU is effective in certain common solid tumors (prototype
colon cancer) with very low growth fractions and very low chromosomal DNA
synthetic rates.  Why should it work?  My hypothesis is that inhibition of
mitochondrial DNA synthesis is an important target of 5FU.  The MTT assay is a
specific mitochondrial probe and is therefore much more sensitive at detecting
effects of 5FU than are cell death endpoints which measure total cell
metabolism or membrane integrity.

Contrariwise, with Taxanes, we see assays where 80% of the cells have been
undeniably and conclusively killed by paclitaxel or docetaxel, but where MTT
formazan metabolism actually INCREASES in the total cell culture.  I think that
cells which survive short term Taxane exposure may actually have their
mitochondrial metabolism "reved up," producing the artifact of increased MTT
signal in a setting where 80% of the cells have been killed.  For most drugs,
the different cell death endpoints agree, provided that a relatively "pure"
tumor population is present.  But for certain drugs (e.g. 5FU and taxanes) one
or other endpoint may be superior.  Hence a reason why we use multiple

- Larry Weisenthal

From: (RunnSwim)
Subject: Re: chemo failure
Date: 22 Oct 2000

From: T D Laing

>>I want to see the best options--and make sure they really are the best.<<.

Nice note to close on.  Thanks for the opportunity to talk about this.

My participation in this thread was, as noted, quite inadvertent and

I do think that it can be inappropriate for people like me on the "supply side"
of cancer medicine to go touting their services in this setting.  It's great
that there are people like you and Steph around to keep things in line by
asking tough questions and offering critical and appropriate commentary.

I am, however, repeatedly amazed at the power of the Internet to serve as a
neural network to connect the brains of creative and energetic people (many of
them not "professionals") to solve problems (one of those certainly being
misplaced clinical research priorities and another being full access to health
care information and yet another being flawed health care delivery policies).

The concept behind holding gargantuan cancer research meetings was the idea
that the existing collective knowledge of the world's scientists was sufficient
to allow for major progress, if only all of the brainpower and information
could be assembled in one place and in one time.

I don't know that this ever worked; it doesn't often work today, for reasons
ranging from information overload to agendas influenced by commercial and
political concerns to the homogenation of thought among scientists, beget by
generations of peer-review, where conventional wisdom is rewarded and
contrarian ideas are punished, meaning that, after a number of generations, the
university faculties end up looking, talking, writing, and thinking all alike.

The great thing about newsgroups and other methods of Internet communications,
is that it gets everyone into the loop, and it is not censored a priori by a
peer-review system with fatal biases.  Of great additonal importance is that it
brings into the loop large numbers of smart, motivated, energetic
non-"professionals," with a collective power to do great things,
intellectually, practically, and politically.

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Date: 27 Nov 2001 07:03:39 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

Some days back, I was asked how I recommend that these assays be used in breast
cancer and melanoma.  Here goes:

These assays take 3 hours each of my own personal, hands on time.  Plus an
average of 8 hours of California-licensed medical technologist time.  So I can
only do about 50 per month (considering also that I have to do a certain amount
of business-related stuff, such as helping patients get their insurance
companies to pay for this testing, studying new drugs, R&D, etc.).  Since the
end of December, 1992, this quota has been completely filled. 90% of our
referrals are from other physicians.  10% are patient-initiated.

Since January 1, 1993 (to September 30, 2001), we've received just under 800
breast cancer specimens and 330 melanoma specimens (most of the latter from 2
prominent melanoma centers, which, between them, have easily contributed the
majority of the important clinical publications in melanoma treatment over the
past 10 years...why they haven't written up their case series with these
assays, I don't know; but they keep ordering assays (all of which are performed
on a fully charged, non-investigational basis).

Of the breast cancer assays, 240 were on previously-untreated patients (mostly
with stage II and III disease; smaller numbers of untreated stage IV and stage
I). Of the remaining 500+ cases from previously-treated patients, 160 were
mastectomy specimens from patients who had residual tumor following neoadjuvant

If one restricts one's choices of therapy only to "proven" regimens, one is, by
definition, limiting oneself to treatments originated a minimum of 5 years
previously, and more often 10 or more.  CMF dates back to the "Cooper Regimen"
of the late 1960s.  Cyclophosphamide/Doxorubicin to the mid-70s.  Even
CTX/doxorubicin -> Taxol is 10 years old.

But there are MANY new drugs and even more new combinations which have received
clinical trials in breast cancer.  And many more which have received clinical
trials in other forms of cancer.  And some which have yet to receive any
clinical trials at all.

Here is what I believe:  I think that one could, at random, construct two or
three drug combinations chosen from the following list of drugs and, on
average, achieve approxiately the same results:

cyclophosphamide, ifosfamide, melphalan, thiotepa
cisplatin, carboplatin, oxaliplatin
vinorelbine, vinblastine, etoposide, paclitaxel, docetaxel
doxorubicin, epirubicin, pegylated doxorubicin, mitoxantrone
gemcitabine, topotecan, irinotecan, mitomycin c
fluorouracil, FU/leucovorin, methotrexate

Now, most of the "sensible" (e.g. cyclophosphamide + ifosfamide would be a
nonsensible combination) combinations would have at least moderate direct
support from the literature.  I'd hesitate to recommend a combination such as
topotecan + mitoxantrone, for which there are, to my knowledge, no published
clinical trials in any disease and for which there would be serious toxicity
concerns, but there certainly are scores of completely reasonable and rational
regimens which could be constructed from the above drugs.

When we have sufficient cells, here is the breast cancer panel which I usually
try to test:

cyclophosphamide, ifosfamide, melphalan, thiotepa
cisplatin, etoposide, gemcitabine, gemcitabine + cisplatin (often highly
synergistic, and found to be a very active regimen - even in heavily treated
patients - first identified as active in precisely one of the assay systems we
use - and which I originated, and a phase II breast cancer trial published in
the Journal of Clinical Oncology), gemcitabine/oxaliplatin
fluorouracil, 5FU/leucovorin, trimetrexate/5FU/leucovorin
irinotecan, topotecan, paclitaxel, docetaxel
gemcitabine/melphalan (often highly synergistic ... gemcitabine inhibits DNA
repair ... and the combination active in the clinic in drug refractory patients
when given to patients with favorable assay results); gemcitabine/5FU,
doxorubicin, epirubicin, Doxil, mitoxantrone
vinorelbine, vinorelbine/high dose tamoxifen (the one p-glycoprotein inhibitor
whic h actually works in non-toxic doses...and vinorelbine is the drug most
often potentiated...notice to Dr. Ling...high dose tamoxifen rarely potentiates
cisplatin in the assay, even though most clinical trials of high dose tamoxifen
with chemotherapy have studied cisplatin/high dose tamoxifen...with the
platinum trials being mostly a bust, as nicely predicted by our in vitro
vinorelbine/mitoxantrone (sometimes synergistic), vinorelbine + mitomycin +
high dose tamoxifen (sometimes synergistic, see above).
Sometimes additional drugs/combinations, as the situation dictates.

I only test drugs in combination when there is an appreciable incidence of true
synergy.  Most drug combinations (e.g. CTX + doxorubicin) are only additive and
not synergistic, therefore studying them in combination doesn't provide any
useful information.

This information is used to determine first line adjuvant therapy, 2nd line
adjuvant therapy (following first line neoadjuvant therapy), first line therapy
of metastatic disease, and 2nd, 3rd, 4th line therapy of metastatic disease.

Not infrequently, the in vitro best regimen is something which causes headaches
for the referring oncologist, reimbursement-wise.  It is, as I said, a tribute
to their selfless idealism that they keep ordering the tests, despite such
problems for them.

With respect to melanoma, about 130 of the 330 specimens were from
previously-untreated patients. The remainder from previously-treated patients.
Most of the latter referral were for 2nd line therapy, following relapse from
first line "bio-chemo" (cisplatin, dacarbazine, vinblastine; IL-2/interferon

For melanomas, here is the most typical panel of drugs tested:

carmustine, high dose tamoxifen, carmustine + high dose tamoxifen (carmustine
is not potentiated as often as is vinorelbine, but significantly more often
than cisplatin).
dacarbazine, MTIC (ative moiety of dacarbazine and temozolomide)
cisplatin, gemcitabine, gemcitabine + cisplatin, oxaliplatin, gemcitabine +
docetaxel, paclitaxel, paclitaxel + high dose tamoxifen
vinorelbine, vinorelbine + high dose tamoxifen
FU + interferon alpha
topotecan, irinotecan (these latter are RARELY active, as is single agent
gemcitabine and vinorelbine without tamoxifen), irinotecan + cisplatin
dactinomycin, bleomycin
melphalan, gemcitabine + melphalan
Sometimes additional drugs, as appropriate.

<gotta stop now. late>

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Date: 27 Nov 2001 20:02:07 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

In article <QXHM7.105350$>,
<> writes:

>i would like to hear more of what you have learned from the melanoma tests.
>....what are the vinorelbine + tam results in melanoma and how do they
>compare to the plat (also very disappointing, although I thought cis alone
>was supposed to be pretty active in assays????)?  why is temodar missing?
>(or is it?)  overall, your sentiments/any interesting results?

Cisplatin has very modest activity in melanoma as a single agent (and even in
combinations).  Occasionally, it can produce a striking result.  More often it
is inactive or produces brief, minor responses or even mixed responses (some
tumors shrink, while others continue to grow).  High dose tamoxifen very
infrequently adds anything to cisplatin (either in our assays or in the
clinic).  High dose tamoxifen is very interesting; it (putatively) does three
things: (1) p-glycoprotein inhibitor (the is the membrane "pump" which rids the
cancer cell of unwanted molecules, such as "natural product" (derived from the
environment, e.g. Taxol, vinblastine, doxorubicin, etc.) type drugs); (2)
protein kinase c inhibitor (a key enzyme in some complex intracellular
molecular reactions, putatively playing a role in cell proliferation and death
and drug action and cellular resistance to this), and (3) angiogenesis
inhibitor. We've screened high dose tamoxifen with a variety of drugs and the
one it potentiates most often (for whatever reasons) is vinorelbine.
Vinorelbine (and vinblastine) have very poor activity in melanoma, but high
dose tamoxifen dramatically potentiates vinorelbine, albeit rather infrequently
(20% of the time for modest potentiation and maybe 10% of the time for dramatic
potentiation). Temodar (temozolomide) is basically an orally-active form of
dacarbazine.  Both share the same active moiety (MTIC).  We test and have a
database for dacarbazine; we test MTIC on an investigational basis (database
still small). We are working on temozolomide, although I think it will turn out
that dacarbazine and temozolomide will prove to be highly cross resistant
(meaning that we probably won't learn a whole lot more by testing temozolomide
in addition to dacarbazine; but I don't yet have the data to be sure about

- Larry Weisenthal
Huntington Beach, CA


Cancer 2000 Feb 1;88(3):584-8

A clinical trial of intravenous vinorelbine tartrate plus tamoxifen in the
treatment of patients with advanced malignant melanoma.

Feun LG, Savaraj N, Hurley J, Marini A, Lai S

The Sylvester Comprehensive Cancer Center, University of Miami and VA Medical
Center, Miami, FL 33136, USA.

BACKGROUND: The aim of the current trial was to assess the efficacy and
toxicity of weekly intravenous vinorelbine tartrate with daily oral tamoxifen
in the treatment of patients with advanced or metastatic malignant melanoma.
METHODS: Thirty-one patients were treated with vinorelbine tartrate, 30 mg/m(2)
intravenously, weekly every 13 weeks and then every 2 weeks thereafter until
progression of disease or severity of toxicity warranted discontinuation.
Tamoxifen, 10 mg orally, twice a day was administered daily starting on Day 1
of chemotherapy with vinorelbine tartrate. Thirty patients had cutaneous
melanoma with metastases and 1 patient had ocular melanoma with metastases.
Eight patients had received prior chemotherapy. RESULTS: Of the 30 evaluable
patients with cutaneous melanoma, 6 achieved a partial response, for an overall
response rate of 20% (95% confidence interval, 7-38%). There was no response in
the patient with ocular melanoma. Major sites of response include the adrenal
gland, lung, tonsil, and cutaneous/subcutaneous tissues. Three patients had a
prolonged duration of response lasting > or = 12 months. Side effects generally
were mild and tolerable. Grade 3 or 4 hematologic toxicity occurred in 26% and
13% of patients, respectively. Nonhematologic toxicity included mild fatigue,
paresthesia, and local arm discomfort from infusion. CONCLUSIONS: Weekly
intravenous vinorelbine tartrate plus daily oral tamoxifen appears to be active
in the treatment of patients with malignant melanoma. Further clinical trials
in malignant melanoma patients treated with vinorelbine tartrate and tamoxifen
appear warranted. Copyright 2000 American Cancer Society.

From: (RunnSwim)
Date: 27 Nov 2001 20:02:07 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

In article <QXHM7.105350$>,
<> writes:

>>Here is what I believe:  I think that one could, at random, construct
>>two or three drug combinations chosen from the following list of drugs
>>and, on average, achieve approxiately the same results
>Are you saying all your assays give essentially the same results???

No, you miss the point.

Example: Doxorubicin is active in some patients; not in others.  Taxol is
active in some patients, not in others.  Sometimes both are active in the same
patient.  Sometimes one but not the other.  Sometimes neither.  On AVERAGE,
each will work (in the assays and in the clinic) about the same percentage of
time (i.e. single agent therapy with either one will produce roughly a 50%
"response rate" ("response" is at least a 50% reduction in the product of two
perpendicular tumor diameters).  So you could flip a coin and choose either one
and give it to 100 patients and you will get approximately the same result.
But, on an individual patient basis, it is quite different.  Some tumors are
sensitive to one or both or neither.  This is what the assays help to sort out.

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Date: 27 Nov 2001 21:11:49 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

In article <QXHM7.105350$>,
<> writes:

>how can you test ifn-a in an assay??????? indeed, i just read very recently
>of somebody getting back an ifn & il2 screen from oncotech and was wondering
>*what* was being measured?

I co-founded (original 4/7 share, now highly diluted) Oncotech in 1985.
The assay they use was developed by me and is a modification of the
DISC assay. (nb: I left Oncotech in January of 1992 and have no
association with them whatsoever, save for my original stock ownership;
they regard me as a (nettlesome) competitor; although I only perform
50 assays per month and they perform probably close to 1,000 per month
(their core technology requires less than 5 minutes of MD/PhD-type time,
while, as noted, our much more complex testing requires 3 hours of
my time).

Investigational BRM assays are carried out without charge to the patient
in which tumor cells are continuously incubated for 7 days in the
presence of endogenous, tumor-infiltrating effector cells.

The DISC assay is the only assay reported to be capable of distinguishing
between specific cytolytic effects on different cell populations in a
heterogeneous mixture of tumor cells and normal cells.

The principle is that patients whose tumors contain endogenous effector
cells which respond to cytokine stimulation by producing tumor-specific
cytotoxicity will be more likely to benefit from cytokine therapy than
patients whose tumors do not contain effector cells capable of being so
stimulated.  Note that I do not expect that this assay will be perfect,
but it may well be useful, if patients so selected have a higher than
expected probability of benefiting from cytokine therapy.  To date, the
main line of evidence supporting the biologic validity of this assay is
the fact that the in vitro patterns of cytokine activity seen in our
assays are quite consistent with known clinical patterns of cytokine
activity (see references below).  In addition, cytokines are never active
in the complete absence of effector cells, but effector cell content does
not predict activity, as long as at least some effector cells are
present.  Tumors with endogenous E:T ratios of 0.1 are no less likely to
be "sensitive" to cytokines in the assay than are tumor with endogenous
E:T ratios of 5.  Tumors with E:T ratios of 0 are, however, always
insensitive.  Finally, dexamethasone, 1 uM, abrogates cytokine activity
in the assay.

Our results must also be interpreted with the knowledge that we have yet
to perform a clinical trial to determine to what extent the in vitro
findings correlate with clinical response to cytokine therapies.  A
bibliography describing published results with this assay in the study of
biologic response modifiers is listed below.


Einhorn S, Fernberg J-O, Grandér D, Lewensohn R (1988) Interferon exerts a
cytotoxic effect on primary human myeloma cells. Eur J Cancer Clin Oncol 24:
1505-1510 (nb: used DISC assay)

Lepri E, Barzi A, Menconi E, Portuesi MG, Liberati M (1991) In vitro
synergistic activity of PDN-IFN alpha and NM + IFN alpha combinations on fresh
bone-marrow samples from multiple myeloma patients. Hematol Oncol 9: 79-86 (nb:
used DISC assay)

Weisenthal LM, Nagourney RA, Kern DH, Boullier B, Bosanquet AG, Dill PL,
Messenger JC, Moran EM (1989) Approach to the clinical circumvention of drug
resistance utilizing a non-clonogenic in vitro assay measuring the effects of
drugs, radiation, and interleukin-II on largely non-dividing cells. In: Amadori
D, Ravaioli A, Ridolfi R (eds) Strategies in cancer medical therapy: biological
bases and clinical implications (Advances in Clinical Oncology, V.1.). Edimes,
Pavia, Italy, pp 91-111

Weisenthal LM, Dill PL, Pearson FC (1990) Tumor and patient-specific activity
of biologic response modifiers (ImuVert, tumor necrosis factor,
alpha-interferon) in fresh specimens of human neoplasms detected by a sensitive
and specific in vitro assay. Proc Am Assoc Cancer Res 31: 299(Abstract)

Weisenthal LM, Dill PL, Pearson FC (1991) Effect of prior cancer chemotherapy
on human tumor-specific cytotoxicity in vitro in response to immunopotentiating
biologic response modifiers. J Natl Cancer Inst 83: 37-42

Weisenthal LM (1991) Effect of prior chemotherapy on biologic response modifier
activity. J Natl Cancer Inst 83: 790-791

Weisenthal LM, Dill PL (1992) In vitro effect of interleukin-2 on fresh human
tumor cell cultures measured by the DiSC assay. Proc Am Assoc Cancer Res 33:Abs

From: (RunnSwim)
Date: 27 Nov 2001 20:02:05 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

In article <U2RM7.642$>, "Steph"
<steph@vancouvers.island> writes:

>Larry, I told you who to contact, and Dr Ling may well take up your offer.
>Or was it just a debating tactic?


Someday, a successful, prospective, randomized
trial will be carried out.  But it will only happen
when the lead investigator, responsible for treating
the patients, originates the idea and has a fire in
his/her breast to see it completed.

As I said, I'm not some big corporation.
I can't pay off oncologists or institutions
to carry out well-run trials the way that
Bristol, or Lilly, or even IDEC can. And
they have, in addition to financial resources,
patented proprietary products.  I don't have
the financial resources and I can hardly raise
the capital, given that the technologies are not
patented or proprietary.  I'm willing to spend about
$50,000 per year over a 5 year period (cost of
doing these tests at my own, non-reimbursed
expense) (and it will be a big sacrifice, as I have
two kids to put through college over the next 5
years, and my income is that of a typical
successful Southern California oncologist, but
not more than this).

Let me tell you of my personal experience in trying to get trials done.

The issue that you always bring up is the lack of
prospective, randomized trials, to prove that
assay-directed therapy is superior to standard,
empiric, protocol therapy.  I have pointed out that
never before has this been a criterion for acceptance
of any laboratory test.  For example, tests such as
hormone receptors, Her2/Neu, bacterial antibiotic
sensitivity testing, and all other such tests have only
been shown to correlate with clinical outcomes.  It
hasn't been shown that performing these tests improves
clinical outcomes in prospective, randomized trials,
where patients are treated with and without benefit of
the information provided by the tests.

I would like, however, to tell you of the experiences
of me and of one of my former colleagues, Dr. Robert
Nagourney, with respect to attempting to organize
entirely unprecedented clinical trials to "prove" the
superiority of assay-directed therapy.

One should not criticize a man until he's walked a mile
in the man's moccasins.  I (and Nagourney) have made
heroic efforts to get oncology institutions and
cooperative groups to formally study these technologies
(which are public-domain and non-proprietary).  This
included travelling at our own expense to cooperative
group meetings; making presentations; writing letters;
offering to do the tests for free, of course; with no
success.  I had a 31 institution Veterans
Administration cooperative group trial in multiple
myeloma which was to be a prospective, randomized trial
between standard chemotherapy and assay-directed
chemotherapy (you can look it up - VA CSP#280).  This
took more than three years in writing proposals, making
presentations, writing grants, recruiting 31 VAs across
the country to participate, having two national
investigators' meetings, writing protocols and manuals,
having many meetings across the country with the
biostatistical section of the VA, etc.  Result: study
closed because of poor accrual and protocol violations
in the standard therapy arm of the study which had
absolutely nothing to do with the assays.  Later on, I
organized a 40+ institution Eastern Cooperative
Oncology Group study (you can look it up...PB-585).  It
was to document the performance of the assay in
non-small cell lung cancer, as a prelude to a
randomized trial.  Result: 5 patients accrued in 7
months and study closed.  Since then, I and/or
Nagourney have made presentations (in some cases,
several times) to the Children's Cancer Study Group,
the Pediatric Oncology Group (we should have been the
ones to do all those studies in pediatric A.L.L. which
were subsequently done by the group at the Free
University of Amsterdam, which are extensively quoted
in my review...but we never were given the chance,
because there was NO ONE in this country who would
support these studies), the Southwest Oncology Group,
the Gynecologic Oncology Group, and CALGB.  Did you
ever see the movie "Voyage of the Damned," about a
group of Jews who are trying to escape Nazi Germany and
who are turned away at all ports in the USA, where they
then have to return to Europe, where 700 of the 900 or
so were ultimately killed?  That's what it felt like,
shopping around clinical trials to test these
technologies in the mid to late 80s and early
90s....when I quit shopping them around.  So I did the
best that I could, which was to give encouragement to
the European groups who were interested in testing the
technologies -- and thank heavens they were able to -
collectively - document every single thing I'd ever
published (mostly in the early 1980s) and document
every single claim I'd ever made.

The ability to design and perfect laboratory
technologies and the ability to organize and complete
successful clinical trials are probably skills located
on different chromosomes.  Dan Von Hoff and Syd Salmon
had a terrible technology, but great skills at
organizing clinical trials.  I wish that I'd worked for
a supportive Hematology/Oncology division chief who was
an effective investigator in the cooperative
group clinical trials system.  Alas, this also was not
the case.

Right now, I have the benefit of 20 years' worth of
focused, full time experience.  If provided with one
gram of tumor, there is a 98% chance that I will be
able to report out the results of tests performed on a
median of 15 or more drugs and combinations within a
clinically relevant time frame.  I have proven that I
can obtain these results from specimens shipped by
FedEx from anywhere in the country and, if proper care
is taken, from Europe and/or Asia, as well.

There are absolutely no practical barriers to
performing the clinical trials that everyone would like
to see.  But I just don't have the financial resources
to pay anyone to do them and I don't have the time
resources to go through the whole process of getting
trials organized and funded through the existing
cooperative group/NCI clinical trials system.  What I
need is to be introduced to a skilled and effective
investigator who is willing and able to quarterback the
clinical trials which everyone would like to see and
which I would really like to do before I die.

So it appears, Steph, that this won't be you, since
you have no interest in even learning about this. This
is by no means a criticism; life is short, focus is difficult,
and there are only so many things that one can to with
excellence.  No, it was no "debating tactic."  It is a
committment to do what I think is more than my fair
share to support these elusive trials (how many of your
colleagues have shelled out their own personal money
to fund clinical trials of non-proprietary diagnostics or
therapeutics?).  But I can't do it alone. I need committed
clinical investigators with patient resources and track
records and, most of all, a sincere interest in seeing the
project through to completion.

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Date: 27 Nov 2001 20:31:47 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

In article <hnSM7.643$>, "Steph"
<steph@vancouvers.island> writes:

>Larry, call Ling.
>You may be pleasantly surprised.

O.K., I'll do just that.

The way that I prefer to do it is as follows:

I'll get together a bundle of information, including my to-be-published,
up-to-date review; a number of sample assay reports; survival data from a
preliminary paper in ovarian cancer on which I'm working, and (because of his
truly seminal work in multi-drug resistance) some of our high dose tamoxifen
data.  I'll introduce the letter by saying that you suggested that I contact
him (I need to do this, otherwise I'll feel like I'm making a totally uninvited
"sales call," which, as I've said, I just don't do).  If I just identify you as
"Steph, from the internet newsgroup," will he know you
you are?  Or can you e-mail me privately and give me a more complete name (I am
very professional about respecting confidentiality and keeping private
communications private)?  This may take me about two weeks or so to get
everything together (you only have one chance to make a first impression, as I
have again learned with the unfortunate way that my appearance on this
particular thread announced itself), but I shall do it.  Thanks.

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Date: 28 Nov 2001 17:55:15 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

>>I guess that is the beauty of a newsgroup like this where all can have
their say.<<

I've never liked the idea of requiring the posting of "credentials" before
one's views may be heard or given credence on internet newsgroups, particularly
those where many or most people prefer to be anonymous.  There are just too
many smart, if uncredentialed, people out there to lose the richness of their
contributions. This is, to me, the real beauty of these newsgroups.  Anyone who
chooses to jump into a thread has the opportunity to have an equal voice.  To
paraphrase Martin Luther King, Jr.: It's a world where people are judged by the
content of their ideas, rather than by the paper hanging on their office walls.

Loren Buhle, the founder of THE first cancer information internet website
(Oncolink, at the U of Pennsylvania) said it best:

Internet newsgroup information should be treated exactly like a conversation
between strangers overheard on a subway.  You are not a fool to listen (as long
as the conversants are talking loudly and publicly and obviously don't mind
being overheard). You are not a fool to join in the conversation, so long as
the participants welcome your input.  You are not a fool to consider what is
being said and to be stimulated to think and to research the subject further
after you get off the subway car.  But you would be a fool to change your life
on the basis of what you have just heard, without further due diligence on your

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Date: 02 Dec 2001 03:21:17 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

>>You seem an honest scientist doing research in basic science that may
have, perhaps by accident, some implications for future oncologic
Unlike antibiotics and bacteria, cancer tissues and citotoxic drugs
are not good material to try to translate in vitro results to in vivo
usage. Drug metabolites, immune system reactions, pharmacokinetics,
body distribution, barriers passage, etc, etc, are much more important
in cancer treatment than in antibiotic treatment, and are all absent
in vitro.<<

It's hardly by accident.

The first thing to do is to disabuse yourself of the notion that this is, or
ever was intended to be, a scale model of chemotherapy in the patient.  .... of
course, it is not!

You give several reasons why this is not a scale model of chemotherapy in the
patient.  I could give you a dozen more (not that I'm smarter than you, but
I've mad e this a virtually full time job for 22 year and completely full time
job for 14 years; so it stands to reason that I'd be able to figure things out
a little more extensively than you).

22 years ago, I formulated the following hypothesis:

1.  Rigorously standardize conditions of the assays. (in this case, I settled
on a 96 hour duration of cell culture; certain plating densities which were
worked out empirically over a period of years for different types of tumors,
and many other parameters).

2. Build a database.

3. The hypothesis is this:

Patients with tumors showing above-average sensitivity to drugs in vitro will
have an above-average probability of responding to chemotherapy in vivo.

Patients with tumors showing above-average resistance to drugs in vitro will
have a [[below]]-average probability of responding to chemotherapy in vivo.

In 1979, this was only a hypothesis.

22 years later, there are more than 2 score high quality, peer review studies
which confirm the above hypothesis -- unanimously and without controversy.
Whether the endpoint is response or survival.

Carl Sagan said that extraordinary claims require [[extra]]ordinary proof.

My hypothesis was a very ordinary claim, which is supported by extraordinary
(extensive, broad, deep and uncontested) proof.

- Larry Weisenthal
Huntington Beach, CA

From: (RunnSwim)
Date: 02 Dec 2001 10:29:28 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

Gee whiz, flying fingers strike again:...typo correction follows....

>>Patients with tumors showing above-average sensitivity to drugs in vitro will
have an above-average probability of responding to chemotherapy in vivo.

>>Patients with tumors showing above-average resistance to drugs in vitro will
have an above-average probability of responding to chemotherapy in vivo.<<

The last sentence should obviously have read "below-average"...i.e. above
average in vitro resistance correlates with below-average probability of
clinical benefit.  As stated previously, drugs with good in vitro activity are
about 7 times more likely to work than drugs with poor in vitro activity.

- Larry Weisenthal

From: (RunnSwim)
Date: 02 Dec 2001 10:33:31 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

>>Carl Sagan said that extraordinary claims require ordinary proof.<<

Sorry for all the spam...hope that this is my last utterance on this
thread...but I misquoted the late Dr. Sagan.

The quote really was "extraordinary claims require extraordinary proof."

- Larry Weisenthal

From: (RunnSwim)
Date: 02 Dec 2001 10:25:24 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

>>Unlike antibiotics and bacteria, cancer tissues and citotoxic drugs
are not good material to try to translate in vitro results to in vivo

Despite these concerns, the actual published data show that the
sensitivity/specificity ("accuracy") of cell culture drug resistance testing in
cancer is every bit as good as it is for antibiotic therapy of bacterial
infections.  There are, in fact, more publshed correlations documenting the
predictive accuracy of cell culture drug resistance testing in cancer than of
antibiotic "culture and sensitivity" testing.  The latter, like the former,
have never been proven (in randomized trials) to improve results of therapy;
just as in the case of all laboratory tests, they have only been shown to have
a useful degree of accuracy in predicting for clinical drug effectiveness.

- Larry Weisenthal

From: (RunnSwim)
Date: 21 Nov 2001 17:14:07 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

From: "Steph" steph@vancouver.island

>>I'll be happy to read it when it's published. Do
you cite any randomised trials of in vitro testing
versus no testing, in an unselected patient

Do you ever use culture and sensitivity testing to
identify the best antiobiotic to use in bacterial
infections?  If so, can you kindly cite the
randomized trials that prove that treatment with
assay-directed antibiotic therapy is superior to
treatment with empirically-selected drugs?

Does your pathology staff ever use panels of
immunohistochemical stains to classify and
subclassify tumors, and do you then use this
information to select therapy?  If so, can you
cite the randomized trials that prove that
performing these (very expensive) tests improves
the results of your chemotherapy?

Do you or your colleagues ever perform estrogen
receptor and progesterone receptor studies to
determine whether hormonal therapy, chemotherapy,
or both are to be given?  If so, can you cite the
randomized trials which prove that performing
these laboratory tests help patients?

Do you or your colleagues ever perform CT scans,
MRI scans, or ultrasound studies solely for the
purpose of measuring the size of tumors, in order
that you can tell whether or not chemotherapy is
working? This is certainly done on a routine basis
here in the States.  Yet I think it is very likely
that patients would do just as well (or just as
badly) if their oncologists just spent a few extra
minutes really taking good interim histories
("feeling better, or worse?"), good physical
examinations, and obtained routine and relatively
inexpensive blood studies and radiographs.  Where
are the randomized trials to show that getting the
CT and MRI scans makes a difference?

For that matter, just point me in the direction of
a single randomized trial to prove the "efficacy"
of ANY laboratory or radiographic test which is
currently or ever used in the past by oncologists.

You asked me a specific question.  Which obviously
has very general implications.  It leads to a
whole other series of questions.

Q: How do oncologists choose between different
forms of chemotherapy which would all be expected
to produce similar results?

A: Sometimes on the basis of toxicity differences.
Often on the basis of personal experience and
personal biases. Often with consideration to which
treatments will provide favorable insurance
payments to the treating physician. Oncologists
are, in effect, running retail pharmacies, where
they  (or their institutions) buy drugs wholesale,
negotiating the best deal, as in any well-run
business.  Insurance reimbursement for different
chemotherapies may range from below the actual
wholesale  cost, to ten or more times the actual
wholesale cost. Obviously, pharmacists want to
sell the drugs  with the highest profit margin (or
at least avoid selling drugs which lose them
money), and this factor  certainly does play a
role in many treatment decisions. Remember, in
virtually all forms of cancer,  there are a wide
range of treatments which would produce
approximately the same results if chosen  by
random selection. So it is not clearly unethical
for an oncologist to be aware of different profit
margins with different treatments, although this
certainly has at least the appearance of a
conflict of  interest.

But, getting back to randomized trials, where are
the trials which show that therapy selection with
knowledge of profit margin is just as effective as
therapy selection blinded as to profit margin? Or
therapy without any profit implications, for that

It has never been shown that platinum-based
therapy is superior to single agent melphalan in
ovarian cancer. A meta-analysis of all the
randomized trials showed no significant difference
between platinum combinations and single agent
alkylators.  Two large randomized trials showed
the equivalency of (1) single agent cisplatin
compared to cisplatin/Taxol and (2) equivalency of
single agent carboplatin, compared to
platinum/Taxol, and also compared to
platinum/doxorubicin/cyclophosphamide.  Therapy
with platinum/Taxol produces thousands of dollars
in profit for private oncologists, for hospitals,
for medical schools, and for cancer centers.
Therapy with oral melphalan would produce no
profit at all.  Therapy with single agent
carboplatin would produce much less profit.  And
yet everyone in the USA gives platinum/Taxol.  Why
is this, in the absence of proof of efficacy in
randomized trials?  I could make the same analysis
in many if not most other situations as well.

Q: Getting back to CCDRT, of what benefit is this
if there are many treatments which  produce the
same results?

A: Notice that all the "rigorous clinical trials"
have identified are the "best" treatments for the
"average" patient. This has been referred to as
the lowest common denominator theory of cancer
chemotherapy. But cancer is not an "average"
disease. Cancer is far more heterogeneous in
response to various individual drugs than are
bacterial infections. The heterogeneity of human
cancer  is shown both by the fact that some
patients derive great benefit from treatments
which fail to help  (and often harm) the majority
of patients who receive the treatment. And many
patients fail to benefit  from 1st line
chemotherapy, only to derive great benefit from
2nd or even 3rd line chemotherapy.  These patients
should have received the correct treatment the
first time around. Everyone agrees that  the
earlier in the course of the disease that the most
active treatment is given, the better the result
for  the patient.

Q: So what is the evidence which shows that these
tests help patients?

A: There is considerable evidence validating the
clinical relevance of the tests

However, there have been no clinical trials
performed to prove that when drugs are selected on
the basis of assay results, the results of
therapy  is then improved. This means that the
trials have never been done, not that the trials
were done and  the assays were shown not to be

Q: Why haven't the trials been done?

A: The most promising assay technologies (see
below) are all public domain, non-proprietary
technologies. Prospective, randomized, controlled
clinical trials cost millions of dollars. We are
talking hundreds of potential drug combinations
and scores of diseases. As correctly noted by Dr.
Maurie Markman of the Cleveland Clinic, proof of
"efficacy" in one clinical situation wouldn't do
anything at all to prove "efficacy" in a different
clinical situation. And the trial to prove
"efficacy" in  even one clinical situation would
become instantly irrelevant with the indroduction
of the first new  drug which wasn't available for
testing at the time of the trial which proved
"efficacy." No one is  going to spend his/her own
money on such trials when the result is that one
hundred laboratories  (some with the vast
resources of very large biomedical companies) will
immediately go into business  to compete with the
pioneer labs, if and when the pioneer labs
complete successful trials.

Q: What about getting grants from the NCI or the
American Cancer Society to do these  studies? What
about using the huge cooperative group clinical
trials network?

A: Major attempts have been made to obtain grants,
design studies, and recruit investigators. These
attempts were unsuccessful owing to many factors
quite beyond the control of the investigators and
laboratories which tried to get the studies done.

Q (accusatory statement): You sound as if you are
trying to cop out. What if everyone that
performed laboratory tests had your attitude.
Patients would be victimized by lots of  unproven

A (retort): The tests are not "unproven." There is
a vast, diverse, and entirely consistent
literature  documenting the correlation between
test results and treatment results. The tests have
been shown -  without any challenge whatsoever -
to identify relatively "good" and relatively "bad"
forms of  chemotherapy. It simply hasn't been
proven that using the tests improves clinical
outcome (again,  because the relevant trials
haven't been performed; not because they were
performed and the results  came back negative). We
must remember that we are considering laboratory
tests, which provide  information, and the tests
themselves are only tests and not treatments. To
my knowledge, there are  no laboratory or
radiographic imaging tests in all of cancer
medicine which have been proven to  improve the
results of treatment (this includes tests such as
estrogen receptors, panels of monoclonal
antibodies to characterize tumors, bacterial
culture and sensitivity tests, and even serial CT
and  MRI scans performed for the purpose of
measuring the size of tumors to gauge their
response to  therapy). The standards used to judge
the utility of laboratory and radiographic tests
have always  been (1) acceptable accuracy of
clinical correlations and (2) clinical utility, in
the judgement of the  physician ordering the test.
Demanding proof of "efficacy," as opposed to proof
of accuracy, is  completely unprecedented for
laboratory tests in cancer (and in almost all
areas of medicine, for that  matter). Cancer is a
disease which has always been managed on the basis
of "best evidence" and  not on the basis of
"conclusive evidence," which is lacking in
virtually all situations in clinical  oncology,
including those situations in which clinical
trials to identify the best treatment for the
average patient have been performed and published
and meta-analyzed (e.g., see discussion of  Taxol
in ovarian cancer elsewhere on this web site).

Q: Why haven't universities and cancer centers
taken the lead in developing assays and
performing clinical trials?

A: One needs to understand the history of research
into cell culture drug resistance testing
(CCDRT): One must begin by understanding that
there is a clear divide between CCDRT based on
cell proliferation as an endpoint and CCDRT based
on cell death as an endpoint. Historically, the
cell proliferation endpoint received great
attention, as a result of studies by Salmon, Von
Hoff, and  others during the late 1970s and early
1980s. These studies occurred during the heyday of
the  oncogene discovery period in cancer research,
where oncogene products were frequently found to
be associated with cell growth, and where cancer
was most prominently considered to be a disease
of disordered cell growth. In contrast, the
concept of apoptosis (programmed cell death) had
yet to  become widely recognized. Also
unrecognized were the concepts that cancer may be
a disease of  disordered apoptosis/cell death and
that the mechanisms of action of most if not all
available  anticancer drugs may be mediated
through apoptosis. When problems with
proliferation-based  assays emerged, there was
little enthusiasm for studying cell death as an
alternative endpoint. These  factors explain the
abandonment of research into CCDRT by American
universities and cancer  centers by the mid-80s.
However, clinical laboratories began to offer
CCDRT as a service to  patients in the USA by the
late 1980s, and studies of CCDRT continued in
Europe and Asia.

Q: So what has happened since the American
universities and cancer centers abandoned
research into CCDRT?

A: Assays based on the concept of cell death (as
opposed to cell proliferation) have been proven
to  identify treatments associated with relatively
good and relatively poor results (both with
respect to  shrinkage of tumors and with respect
to cancer patient survival) in a wide range of
human cancer,  including leukemia, lymphoma,
ovarian cancer, breast cancer, gastrointestinal
cancer, and many  other forms of cancer. Patients
treated with drugs active in the assays have, on
average, a 7-fold  greater chance of benefiting
from treatment with drugs showing good results in
the assays compared  with treatment with drugs
showing poor results in the assays.

>>You are right, I have no personal experience,
although there is plenty in the BC Cancer

O.K., then, let's talk in specifics, rather than in
generalities.  Tell me about this experience.  For
starters, what specific technology(ies) was/were

>>Very nice of you to be so patronising.<<

I did not mean to be patronizing.  I was just
reacting with (I believe, justifiable) anger when
I read the following quote, attributable to you:

>>his own experience is that the tumors
 reaction to the chemo drugs in the petrie dishes
at the labs don't always  mimic that same tumors
reaction within the human he didn't
recommend this approach as valid.<<

You assure me that you did not really say the
above (which is an irresponsibly misleading
statement); with that understanding, I apologize
for the patronizing tone of my previous retort.

- Larry Weisenthal Huntington Beach, CA

From: (RunnSwim)
Date: 24 Nov 2001 01:08:30 GMT
Subject: Re: Taxotere or methotrexate for breast cancer?

Steph's points:

I'm not sure what Steph's points are.  He has yet to offer one single specific
crticism to which I can respond (save the criticism of the absence of
prospective, randomized trials, to which I have responded).  Re-reading
everything he has written on this thread comes down to the fact that he works
at the greatest cancer center in North America and none of the 100 clinical
oncologists or 100 bench oncologists are in favor of this testing. What is
missing, however, is an understanding of what is the level of knowledge or
expertise of these clinicians and scientists.  I have, as mentioned, been a
full time worker in this field since 1979.  I believe that I have read every
relevant paper or editorial ever published on the topic.  I am completely
unaware of a single relevant publication ever emanating from British Columbia.

It is, I think, completely relevant to note that there are many expert clinical
oncologists at many very fine clinical oncology institutions who have had a
vast personal experience with managing patients on the basis of these assay
results for a period of many years.  Because Southern California is the
"Silicon Valley" of this testing (all the established labortories are located
here), there has been much greater experience and scrutiny with this testing
than anywhere else.  As a result of this scrutiny and experience, virtually all
of the third party payers, including all the managed care organizations,
California Blue Shield, and Medicare provide coverage for this testing.  This
would never have happened had these agencies (through their technology
assessment committees and mechanisms) agreed with the uninformed and
non-specific opinions advanced by Steph.  Steph has tried to characterized
these tests as being "interesting research," but has cautioned that many
researchers are very excited about their particulary "baby," only not to have
the baby ever grow up.  Well, "interesting research" just doesn't get covered
by California Blue Shield or Secure Horizons or by Medicare.  And this
particular baby has been growing bigger and stronger for 20 years, and no one
has ever published anything to contradict the claim that the tests do correlate
with and predict for response and survival, in a very wide range of neoplasms.

Once again, I ask only for specific criticism, to which I can then respond.  If
the only specific criticism is the lack of prospective, randomized trials, then
let's make this very clear.  There is very little in all of medicine which has
been proven in prospective, randomized trials, and even less in cancer
medicine.  Steph implies by his criticism that the treatments given and tests
used by oncologists have been "proven" on the basis of unambiguously-decisive
prospective randomized trials.  This is by no means true.

T.L. Laing offers the interesting point of view that it was the overhyping (not
by private laboratories but by two well-respected university clinical
investigators, who both went on to become Directors of NCI-Designated
Comprehensive Cancer Centers and Presidents of the American Society of Clinical
Oncology) of proliferation-based assays in the 1970s and early 1980s which has
effectively "poisoned the well," in the fashion of thalidomide.  I agree
completely with what Laing wrote about this.

One thing Laing wrote, however, is quite ironic:

>>....(With the exception of known correlates of course,
such as herceptin for her2/neu+ tumors, tamoxifen for er+ tumors, etc.) ....<<

"Known correlates?"  That's precisely the data which exist with respect to cell
death assays in cell culture drug resistance testing.  Over 2,000
peer-reviewed, published correlations between assay results and clinical
response and patient survival.  With every single study (some quite large and
published in very prestigious journals) showing that above-average activity in
the assays predicts for above average probability of clinical benefit in the
patient, and vice versa.  No challenge whatsoever. No controversy whatsoever.
With a 7 to 1 advantage (7-fold greater probability of clinical benefit) for
treatment with assay-positive drugs compared with assay-negative drugs).

There have never been randomized trials to prove the benefit of obtaining
her2/neu or estrogen receptor or any other laboratory test as well.

But I'd love to do such a trial.  Steph said that he'd support such a trial.
While I don't have a million dollars to pay his institution to carry out a
randomized trial in 500 patients, I would be willing to do the following

1. Fly to British Columbia, at my own expense, and present a grand rounds-type
seminar to anyone at his institution who was interested in learning about this,
including Steph.

2. Host anyone from his institution who wished to visit my laboratory,
including paying for (coach class) airfare and accomodations.

3. Assist in writing protocols, designing data report forms, and other
necessary things.

4. Paying for all the assays out of my own pocket.

The only thing I can't do is pay honoraria, or pay per patient charges, or
things like that.  I'm not a company, or a corporation; I'm just a medical
oncologist whose private practice consists of providing cell culture drug
resistance testing as a service to oncologists and their patients.  My
technologies are not patented; the above study will end up costing me several
hundred thousand dollars over a period of 5 years, and what will happen after
it is successfully completed and published is that I will have motivated a
hundred other institutions to open up labs to compete with me, but I am willing
to do this, as I feel that I have a responsibility to do it, if I can.

Until someone, like Steph's BC Cancer Center, is willing to meet me half way on
this, for the sake of progress in cancer treatment and for the sake of future
patients, I am going to continue to go right on doing what I'm doing now, which
is to use my expertise in these technologies to help cancer patients receive
the treatment which is most likely to work for their own individual neoplasms.
And I am going to continue to respond to misleading characterizations of this

<I still haven't been able to get to the specifics of the breast
cancer/melanoma examples offered a couple days ago.  Right now, my wife is
sitting impatiently in my office wanting me to get home to our dinner guest, so
that we can get to bed at a reasonable hour, before getting up at 3:30 AM
tomorrow to drive up to Fresno to watch our 15 year old compete in the
California State High School Divison I cross country championships...right now,
I'm looking at Monday as the day when I'll respond to the breast
cancer/melanoma query).

- Larry Weisenthal
Huntington Beach, CA

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