October 30, 2002

Editor-in-Chief
Journal of the National Cancer Institute
Oxford University Press, Suite 500
8120 Woodmont Ave.
Bethesda, MD 20814-1270

Dear Editor:

Enclosed for your consideration is an original research article, entitled "Platinum resistance determined by cell culture drug resistance testing (CCDRT) predicts for patient survival in ovarian cancer."

1. All authors of this research paper have directly participated in the planning, execution, or analysis of this study.
2. All authors of this paper have read and approved the final version submitted.
3. The contents of this manuscript have not been copyrighted or published previously.
4. The contents of this manuscript are not now under consideration for publication elsewhere.
5. The contents of this manuscript will not be copyrighted, submitted, or published elsewhere, while acceptance by the Journal is under consideration.
6. There are no directly related manuscripts or abstracts, published or unpublished, by any authors of this paper.

The Methods section is extraordinarily long (7067 words). This was necessary to describe in clear detail how everything was done. It was written with the intent of serving as a procedure manual for other investigators who wish to confirm and build upon this work. Presumably, material from this section could be published only on your internet site, should space limitations prevent publication in the print journal.

I belatedly discovered that we deviated slightly from your specifications for the figures. Specifically, the two bar graphs contain some gray-shaded bars and all of the figures have the figure title printed on the same page as the figure. In the event that the manuscript is accepted for publication, I would certainly revise these figures to meet your specifications.

I would like to make several statements of a somewhat personal nature, which might be described as being preemptively defensive. I make these statements on the basis of my experiences during 23 years of full-time work in the field of inquiry described in this paper.

Firstly, I wish to defend my introductory statement that 30 years of prospective, randomized trials in ovarian cancer have largely been a waste of time, money, and human lives. During the past two years, three separate review papers have directly stated that platinum-based combination therapy has been proven superior to single agent alkylator therapy. This erroneous conclusion is entirely based on a meta-analysis by the Advanced Ovarian Trialists Group in which the published findings were misleadingly obfuscated. With some effort, I obtained the actual data, which are enclosed. Anyone without a vested interest in the prospective, randomized clinical trials system would readily conclude that the alleged superiority of platinum combinations has been by no means proven. Nor would an objective reviewer conclude that platinum/taxane therapy has been proven superior to single agent platinum. So the truth is that, after 30 years of criticizing assay-directed therapy because it hasn't been proven to be superior to empiric therapy (not because the trials have been done and failed, but because no one will agree to support the trials), the proponents of the paradigm of identifying the best empiric treatment for the average patient through prospective randomized trials are left with a basket of unproven conclusions which have ascended to the entirely undeserved status of "standard therapy."

Secondly, it is entirely predictable that reviewers will want to dismiss the enclosed study because it was performed by a physician in private, solo practice, unaffiliated with a major cancer group or hospital. They will note the absence of "central pathology review." They will be suspicious of the unconventional method for determining death dates. They will note the lack of information regarding precise chemotherapy given, response data, and progression-free survival data. They will be suspicious of the stringency (and honesty) of data collection, review, and interpretation. Even if they are willing to get past all of the above (by carefully reading and objectively considering our very stringent and eminently verifiable methodology and data), they will fall back on the time honored criticism that we still don't have prospective, randomized trials of "standard" versus assay-directed therapy.

I would ask you, in your capacity as a journal editor who is interested in the true advancement of knowledge, as much as in the necessity of quality control gatekeeping, to walk a mile in my moccasins and to be willing to evaluate the present research on its own merits, without comparison to the way that the study might have been done had I had the good fortune of working at MD Anderson, with an abundance of financial, institutional, and collegial support.

In 1992/93, I was unable to convince the Gynecologic Oncology Group to allow us to participate in (i.e. be piggy-backed on to) planned studies of CCDRT in ovarian cancer, despite my vigorous attempts to persuade them to do so (I proposed to do the assays at my own personal cost, but I didn't have the resources to pay the GOG, as did a GOG-sponsoring, venture-capital-backed corporation). Therefore, I sought a mechanism wherein we could carry out rigorous, verifiable, prospective clinical correlation studies in the course of providing CCDRT as a service to patients and clinicians in the setting of a for-profit, private, and independent laboratory. I am certain that I succeeded, using the methodology described in the enclosed paper.

Back in 1986, I had the very unpleasant experience of having a manuscript reviewer state that the data presented in one of my papers appeared to be too good to be real. Although the paper was, indeed, published by one of the ancestor journals of the present JNCI (Weisenthal, et al. Laboratory detection of primary and acquired drug resistance in human lymphatic neoplasms. Cancer Treat Rep 70:1283-95,'86), I was unable to get any support to continue this work, which has now been confirmed and reconfirmed by other laboratories in more than a score of peer-review publications in journals such as Blood and Leukemia Research and which also led to a current prospective, randomized trial of assay-directed therapy in chronic lymphocytic leukemia in the UK, which has now accrued more than 300 patients.

The point I am making here is that the present work was carried out in the context of an unaffiliated, solo medical practice simply because there was no other alternative. But I knew from the beginning that I would face major credibility problems and that I needed to find creative solutions to the challenge of doing high quality clinical research in my situation. I am confident that I have succeeded in addressing and answering the most serious and problematic issues relating to the methodology. All I want in return is a fair review, by objective reviewers who are willing to go outside the proverbial box to judge this body of work on its own merits, without unfair references as to how the work might have been done differently at MD Anderson.

In the latter context, I do want to point out that my private laboratory was first established with the partial support of an NIH Small Business Innovative Research Grant, in the amount of $50,000. This allowed me to purchase HEPA hoods, incubator, minus 70 freezer, and microscope, all of which were extensively used in the present study and which I would have been otherwise unable to acquire. The purpose of the SBIR program is to provide seed money for exactly this type of research; that is, research which can be eventually supported with private sector resources and, I would add, research which allows the investigator to take his or her time to do a good job and which gives the investigator the freedom to follow his or her own path of inquiry, limited only by the ability of the investigator to raise private sector funds to continue supporting the work. The present paper represents an enormous amount of work in a laboratory which has been 100% self-supporting ever since the original $50,000 NIH grant in 1993.

The present work didn't cost the US taxpayer a penny beyond the initial seed funding and the work is 100% public domain, non-proprietary in nature. Indeed, I have gone in the Methods section to exceptional lengths to describe our methods in precise detail in the sincere hope that many other laboratories will be able to confirm our findings and build upon them to improve cancer research and treatment.

Sincerely yours,

Larry Weisenthal

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