February 11, 2003

Barnett S. Kramer, M.D., M.P.H. ,Editor-in-Chief
Journal of the National Cancer Institute
Oxford University Press, Suite 500
8120 Woodmont Ave.
Bethesda, MD 20814-1270

Dear Dr. Kramer:

I just received the rejection letter for my original research article, entitled "Platinum resistance determined by cell culture drug resistance testing (CCDRT) predicts for patient survival in ovarian cancer." I am confident that you gave the manuscript a fair consideration. The fact that you sent it for outside review instead of returning it without formal review shows that you did agree that the work had potential merit. I thank you for this. I am disappointed that the review took so long (> three months), but I, myself, have been tardy as a reviewer; so I have no real complaints about this either. You needn't respond to this letter, but I would be grateful if you did read it and allow me the therapeutic benefit of ventilating about the reviews.

Firstly, it is just so frustrating to be condemned for such things as lacking the data to perform multivariate analyses, when I worked so hard, 10 years ago, to get the Gynecologic Oncology Group to allow me to do the present study through them, which would have allowed the collection of all of these important data. They turned me down cold. Instead, I have devoted 10 years of my life to doing an enormous amount of work, at great personal sacrifice, only to be told such things as "without this information, correlations are not meaningful" and "this manuscript adds no clarity to the field."

Let me tell you that working in "the field" for the past 23 years has never been easy. The Catch-22 is that everyone tells you what studies you should be doing, but no one is actually willing to do, much less fund, the mandated studies. Had this paper been published, I will bet you dollars to donuts that many first rate clinical research groups would have jumped-started "the field" with the present description of the first technology which actually works in the real world. Rather than just shopping this manuscript around, I'll probably just put it up on my website, along with the two reviews you provided. I'm hoping that you would have no objection to this.

I just want to close by stating that I'm really dumbfounded that the reviewers would have the certitude to dismiss the importance of this paper so completely.

I make two very important assertions: Firstly, that the assays truly provide an index of platinum sensitivity. Second, that the assays predict for patient survival.

Reviewer #1 just dismisses everything out of hand, simply because I don't have the data for a multivariate analysis. I "predicted" that reviewers would do this in my original cover letter. I hoped that they would look more closely at the data and implications of the data, but I was not pleasantly surprised at the ability of the reviewers to get beyond this truly superficial objection.

Reviewer #2 appears to be more sophisticated in his/her critique, but he/she totally misses the mark. He says that differences in platinum resistance may just be a surrogate for different rates of cell proliferation in vitro. In the first place, I was careful to state that there is, on average, a net loss of cells during culture. Second, both reviewers utterly dismiss one of the most important findings, that of the fact that specimens from previously-treated patients were significantly (P2<<0.0001) more resistant than specimens from previously untreated patients. I could have easily answered the reviewer's suggestion that perhaps the tumors from the treated patients had different cell proliferation rates by giving the actual data on D4/D0 viable cell ratios in specimens from treated versus untreated patients and well-differentiated versus poorly-differentiated tumors, etc. (which disproves the reviewer's speculation), but I wasn't given the opportunity to provide these data in a revised manuscript.

I am just dumbfounded that neither reviewer appreciated the implications of the difference in drug resistance between treated and untreated tumors for future research in circumvention of platinum resistance. This finding, alone, makes the current paper worthy of being published. The comments of reviewer #2 about the correlations with patient survival are not only unfair, but highly unfair, and show a clear bias to reject, without a thoughtful consideration of the data. He/she states that: " 'Predict' implies that the assay represents an independent prognostic variable, otherwise it does not add much more than currently available factors, for instance what would be added to the knowledge that the ovarian cancer is poorly-differentiated of having an assay performed." Well, duhhh, didn't he/she look at the data in Figure 7?

Looking only at the poorly-differentiated tumors (with both cisplatin and, independently, with carboplatin) the platinum-sensitive patients showed a Kaplan-Meier overall survival of 70% at 8 years, while the platinum-resistant patients were all dead by 6 years, with median survivals of 723 - 1108 days (P2 = 0.0013 for cisplatin and 0.0105 for carboplatin). I would like to have a single example of any prognostic variable in poorly differentiated ovarian cancer which has that degree of predictive utility. I suppose that one could hypothesize that the platinum-sensitive patients tended to have optimal resections, while the platinum-resistant patients had bulky disease, or that the platinum-sensitive patients all had good performance status, while the platinum-resistant patients were the opposite. Are these, however, reasonable objections? Look also at figure 8, where there were huge differences in platinum activity as a function of whether patients survived less or greater than the median. Is there any reasonably probable artifact to explain these data?

Taking everything into consideration, including the differences between treated and untreated patients (which held true when data were analyzed as a whole and when analyzed by histologic subsets), the differences between patients surviving above and below the median, the differences between survival curves analyzed as a function of assay results, and the virtually identical nature of these data when analyzed for cisplatin and, independently, for carboplatin, I am utterly astonished that the reviewers had the certitude to just dismiss everything on the basis of my inability to perform a multivariate analysis to include clinical factors for which there is no reason at all to presume an association which would bias the present findings.

Lastly, I want to remind the editors of the false nature of reviewer #1's assertion (his point 5) that my discussion "should also indicate positive effects [of the modern empiric therapy based on prospective, randomized trials paradigm] such as improvements in median survival with platinum-based therapy." Hello -- that has NOT been proven, as evidenced by the equivalency of survival curves for single agent alkylators versus platinum combinations which I quote in the first paragraph of my introduction.

But what is the point in looking at the data when your mind is already made up? That's the real message of both of these reviews and the unfortunate reality of a clinical research system now dominated by risk-averse investigators more interested in closing doors than opening windows.

Once again, personal thanks for giving me a chance, and thanks for this therapeutic opportunity to ventilate.

Sincerely yours,

Larry Weisenthal