The Positive in the Negative

If things were different, I might be writing this blog about using Selinexor in prostate cancer.

Or,  I might be working on the design of the phase III study of BEZ235 in mCRPC, or the use of AMG-102 plus mitoxantrone in patients following docetaxel for mCRPC.

But, things are what they are and we aren’t talking much about these approaches. Yet, I spent a lot of my time writing protocols and consenting patients and evaluating their progress on these treatments. In the end, they didn’t work well enough to move forward, and they won’t become the standard of care for mCRPC. Not now, not later, not ever.

And yet we still worked hard to analyze the data, confirm it and publish it. These trials didn’t go in the JCO or the NEJM, journals that typically publish the advances in our field that we see from the positive studies. In the case of the BEZ235 and Selinexor studies, we published them in The Oncologist and to be honest, I am grateful that they have a forum for brief reports on negative studies. Further, I encourage my colleagues and trainees to utilize this forum and not let the efforts that went into these studies be in vain. Patients literally put their bodies and valuable time on the line for these studies.

I bring this topic up now because the issue of conflicts of interest among clinical cancer researchers has again surfaced. Sadly, much of the publicity centered on an institution very near to me – Memorial Sloan-Kettering Cancer Center, where I completed my oncology training. I won’t go into the details but will point out that the press on this has me thinking. The editorial from Marcia Angell in The New York Times on September 16, 2018 frames the discussion around two points – one is the conflict of interest of the doctors, and the other is the issue of the failure of pharma companies to publish negative results.

I was curious about this latter point and I guess I can understand how the general public may have a vision that negative results somehow get ‘buried’. I have been part of some unsuccessful trials over the years, but I can honestly say that I have never been told ‘we won’t let you publish that’.  So let’s think about it.

Not publishing negative results could have two motivations:

  1. The authors or study leaders don’t want people to know that the drug doesn’t work against a particular disease
  2. Because the therapy didn’t work, the sponsor of the study doesn’t want to put more resources ( e.g. pay the salaries of people to do the analysis)
I am aware of one phase III clinical trial in prostate cancer that was negative and the results have never been published, that is a discredit to the families and patients who sacrificed their time and faced uncertain drug toxicities to enroll in the clinical trial. But this is the only one that I am aware of in my field of urologic oncology.

Beginning a career in medical oncology (especially as I did in the late 1990s) one is accepting that there will be a lot of failures ahead. Many of our senior colleagues established entire careers and deep respect despite the fact that none of their studies were positive. Even despite all the great progress, we have made in so many cancers, we the clinicians lead losing battles most of the time. Oncology is still a field where most of what we do doesn’t work for most of those who receive the treatment (but it sure is nice to see this changing!).

Thus, failure is a norm.

It is laudable that negative studies get published and I encourage both researchers and journals to not shy away from doing it. While we may wish that the journal that agrees to publish them had a higher impact factor, it is better than not publishing them. Fair to say that a negative study, I guess, doesn’t really have an impact, it is the opposite of impact.

Another way that journals could account for this is by following through on prior publications. I recall an instance where the phase I study of a particular agent appeared to show promise and was published in the Journal of Clinical Oncology with text that said: “phase II studies are indicated”. However, when the follow-up phase II study of that drug was performed and was negative, the JCO refused to publish it.

While the JCO is free to publish whatever they want, myself and my co-authors felt that when a journal publishes something that appears promising and the text of the paper says that further study is required, it is very reasonable, but not an imperative, that the same journal ‘complete the story’ so to speak. Journal editors may find value in doing that. It may actually improve their readability and their credibility. Essentially it is saying “Yep, we said this had promise and should be done, it was done and it didn’t work. End of story”

Taken together, we need to respect and even celebrate the act of completion of trials, even if they are negative. Further, now as a Director of a Division of Hematology & Oncology, it is important to point out that faculty put as much effort into clinical trials that fail as they do those that are positive, and overseeing a negative trial should not be considered a failure. My hope is that leading negative trials in a difficult disease would not hurt someone’s promotion. Many of these studies teach us something about the patients we treat and the biology of their disease. And sometimes they just teach us that what we tried didn’t work. Publishing that will help others move forward, by finding the errors we made in patient or biomarker selection criteria.

I often wonder if we give up too early when we see negative trials and lament the fact that sometimes there aren’t second shots on goal. A good example of this is satraplatin, an oral platinum that looked good and even had a (narrowly) positive phase III study, but not enough to get FDA approval. Patients benefitted from that drug, but they were in the minority. If we could have a satraplatin do-over, I bet it could be a positive study based on what we know about patient selection, available therapies, platinum sensitively and DNA repair, for example.

It’s a good thing that I can go back and find the paper to read about it as I think.

Written by: Charles J. Ryan, MD

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