Early radical prostatectomy trial: Does it mean what you think it means?

Another study this week added to the controversy about early prostate cancer treatment. The press, as usual, stopped at citing the conclusion: Early prostatectomy does not reduce all-cause mortality. But the really interesting stuff is buried in the paper. Let's deconstruct.

This was a randomized controlled trial of early radical prostatectomy versus observation. The study was done mostly within the Veterans' Affairs system and took 8 years to enroll a little over 700 men. This alone should give us pause. Figure 1 of the paper gives the breakdown of the enrollment process: 5,023 men were eligible for the study, yet 4,292 declined participation, leaving 731 (15% of those who were eligible) to participate. This is a problem, since there is no way of knowing whether these 731 men are actually representative of the 5,023 that were eligible. Perhaps there was something unusual about them that made them and their physicians agree to enroll in this trial. Perhaps they were generally sicker than those who declined and were apprehensive about the prospect of observation. Or perhaps it was the opposite, and they felt confident in either treatment. We can make up all kinds of stories about those who did and those who did not agree to participate, but the reality is that we just don't know. This creates a problem with the generalizability of the data, raising the question of who are the patients that these data actually apply to.

The next issue was what might be called "protocol violation," though I don't believe the investigators actually called it that. Here is what I mean. 364 men were randomized to the prostatectomy group, and of them only 281 actually underwent a prostatectomy, leaving nearly one-quarter of the group free of the main exposure of interest. Similarly, of the 367 men randomized to observation, 36 (10%) underwent a radical prostatectomy. We might call this inadvertent cross-over, which does tend to happen in RCTs, but needs to be minimized in order to get at the real answer. What this type of cross-over does is, as is pretty intuitively obvious, blend the groups' differences in exposure, resulting in a smaller difference in the outcome, if there is in fact a difference. So, when you don't get a difference, as happened in this trial, you don't know if it is because of these protocol violations or because these treatments are essentially equivalent.

And indeed, the study results indicated that there is really no difference between the two approaches in terms of the primary endpoint (all-cause mortality over a substantially long follow-up period was 47% in the prostatectomy and 50% in the control groups [hazard ratio 0.88, 95% confidence interval 0.71 to 1.08, p=0.22]). This means that the 12% relative difference in this outcome between the groups was more likely due to chance than to any benefit of the surgery. "But how can cancer surgery impact all-cause mortality?" you say. "It only claims to alter what happens to the cancer, no?" Well, yes that is true. However, can you really call a treatment like that successful if all it does is give you the opportunity to die of something else within the same period of time? I thought not. And anyway, looking at the prostate cancer mortality, there really was no difference there either: 5.8% attributable mortality in surgery group compared to 8.4% in the observation group (hazard ratio 0.63, 95% confidence interval 0.36 to 1.09, p=0.09).  

The editorial accompanying this study raised some very interesting points (thanks to Dr. Bradley Flansbaum for pointing me to it). He and I both puzzled over this one particularly unclear statement:

...only 15% of the deaths were attributed to prostate cancer or its treatment. Although overall mortality is an appealing end point, in this context, the majority of end points would be noninformative for the comparison of interest. The expectation of a 25% relative reduction in mortality when 85% of the events are noninformative implies an enormous treatment effect with respect to the informative end points.

Huh? What does "noninformative" mean in this context? After thinking about it quite a bit, I came to the conclusion that the editorialists are saying that, since prostate cancer caused such a small proportion of all deaths, one cannot expect this treatment to impact all-cause mortality (certainly not the 25% relative reduction that the investigators targeted), the majority of the causes being non-prostate cancer related. Yeah, well, but then see my statement above about the problematic aspects of disease-specific mortality as an outcome measure.

The editorial authors did have a valid point, though, when it came to evaluating the precision of the effects. Directionally, there certainly seemed to be a reduction in both all-cause and prostate cancer mortality in the group randomized to surgery. On the other hand, the confidence intervals both crossed unity (I have an in-depth discussion of this in the book). On the third hand (erp!) the portion of the 95% CI below 1.0 was far greater than that above 1.0. This may imply that with a study that could have achieved greater precision (that is, narrower confidence intervals) we might have gotten a statistical difference between the groups. But to get at higher precision we would have needed either 1) a larger sample size (which the investigators were unable to obtain even over an 8-year enrollment period), or 2) fewer treatment cross-overs (which is clearly a difficult proposition, even in the context of a RCT), or 3) both. On the other hand (the fourth?), the 3% absolute reduction in all-cause mortality amounts to the number needed to treat of roughly 33, which may be clinically acceptable.

So what does this study tell us? Not a whole lot, unfortunately. It throws an additional pinch of confusion into the cauldron already boiling over with contradiction and uncertainty. Will we ever get the definitive answer to the question raised in this work? I doubt it, given the obvious difficulties implementing this RCT.  

                  

If you like Healthcare, etc., please consider a donation (button in the right margin) to support development of this content. But just to be clear, it is not tax-deductible, as we do not have a non-profit status. Thank you for your support!

Press coverage of health data: Just like Pharma's DTC?

I am warning you now: This is going to be a rant.

Yesterday's Wall Street Journal had a front page story on observational data, and how researchers are growing more concerned about its accuracy even as the volume of such research is growing exponentially. And then today, there was this from multiple news outlets:

The HealthDay story quotes the senior author of the study thusly [emphasis mine]:

"The results of our research allow us to definitively answer the question of whether jogging is good for your health," Peter Schnohr, chief cardiologist of the long-term Copenhagen City Heart Study, said in a news release from the European Society of Cardiology. "We can say with certainty that regular jogging increases longevity. The good news is that you don't actually need to do that much to reap the benefits."

And then at the very end it says this:

The study was slated for presentation Thursday at a meeting of the European Association for Cardiovascular Prevention and Rehabilitation, called EuroPRevent2012, in Dublin.

Data and conclusions presented at meetings should be considered preliminary until published in a peer-reviewed medical journal.

So, let recap. WSJ says that observational data are of concern because they can be tough to confirm, so we should be skeptical. HealthDay and others insist that this observational study shows definitively that jogging prolongs life, so what are we supposed to believe?

The problem and the disconnect, I believe are not with the studies themselves. The problem is with the way these stories are reported and the end result of that: Just like direct-to-consumer advertising from Pharma, these stories call us to immediate action, even when the results are preliminary. We rail against Pharma's DTC, but take this kind of press coverage as a given. This type of reporting, where half-baked data are presented as the final word, disappointingly enabled by the investigators themselves (who doesn't want 15 minutes of fame?), makes observational data look like something they are not. On the one hand, we are told that here is the result. On the other, after some contemplation and peer review, we realize that the study did not show what it was said to have showed. Bingo, the sweeping conclusion is that all observational studies are bad and biased, so let's just throw out the baby with the bath water.

The press are doing a huge disservice to the public and to science itself by presenting everything in such black-and-white terms. We know that it is the initial message that grabs attention; hence "jogging adds years to your life." To make the next message stick, something powerful needs to be cooked up; hence, "Analytical Trend Troubles Scientists." Saying that "well, we overstated what the jogging study showed" isn't nearly as sexy. How about we back up a bit and say it like it is: the devil is in the details, and those details don't make nifty headlines.

I am grateful to Gary Schwitzer for slapping this kind of sloppy reporting, but he cannot eliminate it alone. We all must speak out against it. We abhor Pharma's DTC marketing practices. Why do we give the press a free pass for the same behavior? Cover accurately or don't cover at all!  

If you like Healthcare, etc., please consider a donation (button in the right margin) to support development of this content. But just to be clear, it is not tax-deductible, as we do not have a non-profit status. Thank you for your support!

Whores, psychopaths and newsmen

Prostitution is legal in Las Vegas. Before antibiotics, people with tertiary (or neuro-) syphilis were considered to be pleasantly demented. Fitting neither of these criteria, fringe politics today is nevertheless mercenary and surreal. And loud. What we have is malicious fabrication rammed down the public's throat by a bunch of whores and psychopaths.

Consider Rush. A tool of the extremist right, he spews hatred day in and day out. Take Beck. With an actor's flair he incites his adoring public to the heights of fanatic hatred worthy of an Orwell novel. Taken together, their sociopathic rhetoric is validating and mainstreaming the psychotic margin that has always existed in our nation. And people listen, get worked up into lather and start Facebook discussions about presidential assassination. They are actors in well financed sinister entertainment masquerading as political commentary.

Some politicians seem to follow. Take Bachmann and Wilson and Franks. Bachmann, who advocates a hunger strike to make sure that we fail to reform and provide access to healthcare for all citizens. A Christian stance? I do not think so. Then, the illustrious Wilson calling the President a liar? In the Congressional chamber? Absurd! Finally, Franks referring to the leader of the free world as "the enemy of humanity". Is this not madness?

David Brooks in an editorial in the NYT today reminds us of the impotence of these "spittle-flecked" Quasimodos. Much like I said before, he contends that their claims of vast followings of Republican armies are simple delusions. I hope so. Nevertheless, their noise is giving me a headache. Let's use the power button. Off.

Medical ethics in the era of H1N1: A need for a national conversation

In the UK the H1N1 pandemic is bringing to the forefront the public's concerns for healthcare rationing. In a recent article for the BBC news, Daniel Sokol, a medical ethicist, discusses the issue with frightening lucidity. He cites several probable scenarios and asks how they should be handled. For example, when 5 critically ill patients are "competing" for a single ICU bed, how should the allocation decision be made? Should it be on the basis of viability? Age? Value to society (that is, should a healthcare worker take precedence over another patient?) While he argues for transparency in such choices, he acknowledges the uncertainties inherent in our understanding of disease. Thus, a patient who is 99% likely to die may still surprise us 1% of the time and survive.

These are very thorny issues that we very well may get confronted with in this coming flu season. How will we handle them? The Brits at least appear to have the emotional maturity to start the discussion in explicit terms, so that they can wrestle with some of these issues before the 11th hour. Are we? In the US we cannot even seem to get beyond the demagoguery of grandma killings at this most important healthcare juncture. What will we do when we are actually confronted with having to make these very real and concrete choices? The culture of "me-me-me" will only impede us from electing the rational path.

The time to think through these conundrums is now because come fall and winter it will be too late. Revolts have been fomented over lesser issues; do we really want to leave this to the last minute? As a nation we need to take a deep breath, arm ourselves with courage and open our eyes and ears. Not everyone will be pleased with everything, but at least we will have a clearer idea of what we can expect and, perhaps, in turn this clarity will allow for better personal and societal choices. The press needs to help lead this discussion in a measured non-sensationalized way. This is our opportunity to grow up as a nation. If we do not take it now, the results may be more devastating than we can imagine.