Prophylactic Cranial Irradiation: a matter of blinding, ascertainment, side effects, and preferences

Slotman et al (August 16 issue of NEJM: http://content.nejm.org/cgi/content/short/357/7/664) report a multicenter RCT of prophylactic cranial irradiation for extensive small cell carcinoma of the lung and conclude that it not only reduces symptomatic brain metastases, but also prolongs progression-free and overall survival. This is a well designed and conducted non-industry-sponsored RCT, but several aspects of the trial warrant scrutiny and temper my enthusiasm for this therapy. Among them:

The trial is not blinded (masked is a more sensitive term) from a patient perspective and no effort was made to create a sham irradiation procedure. While unintentional unmasking due to side effects may have limited the effectiveness of a sham procedure, it may not have rendered it entirely ineffective. This issue is of importance because meeting the primary endpoint was contingent on patient symptoms, and a placebo effect may have impacted participants’ reporting of symptoms. Some investigators have gone to great lengths to tease out placebo effects using sham procedures, and the results have been surprising (e.g., knee arthroscopy; see: https://content.nejm.org/cgi/content/abstract/347/2/81?ck=nck).


We are not told if investigators, the patient’s other physicians, radiologists, and statisticians were masked to the treatment assignment. Lack of masking may have led to other differences in patient management, or to differences in the threshold for ordering CT/MRI scans. We are not told about the number of CT/MRI scans in each group. In a nutshell: possible ascertainment bias (see http://www.consort-statement.org/?o=1123).

There are several apparently strong trends in QOL assessments, but we are not told what direction they are in. Significant differences in these scores were unlikely to be found as the deck was stacked when the trial was designed: p<0.01 was required for significance of QOL assessments. While this is justified because of multiple comparisons, it seems unfair to make the significance level for side effects more conservative than that for the primary outcome of interest (think Vioxx here). The significance level required for secondary endpoints (progression-free and overall survival) was not lowered to account for multiple comparisons. Moreover, more than half of QOL assessments were missing by 9 months, so this study is underpowered to detect differences in QOL. It is therefore all the more important to know the direction of the trends that are reported.

The authors appear to “gloss over” the significant side effects associated with this therapy. It made some subjects ill.

If we are willing to accept that overall survival is improved by this therapy (I’m personally circumspect about this for the above reasons) the bottom line for patients will be whether they would prefer on average 5 additional weeks of life with nausea, vomiting weight loss, fatigue, anorexia, and leg weakness to 5 fewer weeks of life without these symptoms. I think I know what choice many will make, and our projection bias may lead us to make inaccurate predictions of their choices (see Lowenstein, Medical Decision Making, Jan/Feb 2005: http://mdm.sagepub.com/cgi/content/citation/25/1/96).

The authors state in the concluding paragraph:

“Prophylactic cranial irradiation should be part of standard care for all patients with small-cell lung cancer who have a response to initial chemotherapy, and it should be part of the standard treatment in future studies involving these patients.”

I think the decision to use this therapy is one that only patients are justified making. At least now we have reasonably good data to help them inform their choice.

Thalidomide, Phocomelia, and Lessons from History

In tracing the history of evidence-based medicine tonight (for a lecture I have to give on Friday), a found the story of thalidomide on wikipedia (http://en.wikipedia.org/wiki/Thalidomide ).

(While I recognize that the information provided on this site is uncorroborated, I also recognize that it has been referenced by Federal Distric Courts in various decisions - see http://www.nytimes.com/2007/01/29/technology/29wikipedia.html?ex=1186545600&en=4e6683fb4fac3044&ei=5070 - so I consider it possibility generating rather than evidence corroborating.)

This story is a tragic one of a company with a product to sell (a "treatment looking for an indication" - hmmm...) and its unscrupulous marketing of this product in the absence of evidence of both safety and efficacy.

The story of Thalidomide should serve as a stark and poignant reminder of the potential harmful effects of a marketing campaign, impelled by profiteering, gone awry.

AVANDIA and Omission Bias

Amid all the hype about Avandia recently, a few relatively clear-cut observations are apparent (most of which are described better than I could hope to do in the July 5 issue of NEJM. Drazen et al, Dean, and Psaty each wrote wonderful editorials available at www.nejm.org).

1.) Avandia appears to have NO benefits besides the surrogate endpoint of improved glycemic control (and engorging the coffers of GSK, the manufacturer).

2.) Avandia may well increase the risk of CHF, MI, raise LDL cholesterol, cause weight gain and increase the risk of fractures (the latter in women).

3.) Numerous alternative agents exist, some of which improve primary outcomes (think UKPDS and metformin), and most of which appear to be safer.

So, what physician in his right mind would start a patient on Avandia (especially in light of #3)? And if you would not START a patient on Avandia, then you should STOP Avandia in patients who are already taking it.


To not do so would be to commit OMISSION BIAS - which refers to the tendency (in medicine and in life) to view the risks and/or consequences of doing nothing as superior to the risks and/or consequences of acting, even when the converse is true (i.e., the risks and/or consequences of acting are superior to those related to inaction). (For a reference, indulge me: Aberegg et al http://www.chestjournal.org/cgi/content/abstract/128/3/1497.)

This situation is reminiscent of recommendations relating to the overall (read "net") health benefits of ethanol consumption - physicians are told to not discourage moderate alcohol consumption in patients who already consume, but not to encourage it in those who currently abstain. Well, alcohol is either good for you, or it is not. And since it appears to be good for you, the recommendation on its consumption should not hinge one iota on an arbitrarily established status quo (whether for reasons completely unrelated to health a person currently drinks).
(For a reference, see Malinski et al: http://archinte.ama-assn.org/cgi/content/abstract/164/6/623; the last paragraph in the discussion could serve as an expose on omission bias.)

So, let me go out on a limb here: Nobody should be taking Avandia, and use of this medication should not resume until some study demonstrates a substantive benefit in a meaningful outcome which outweighs any risks associated with the drug. Until we do this, we are the victims of OMISSION BIAS (+/- status quo bias) and the profiteering conspiracy of GSK which is beautifully alluded to, along with a poignant description of the probably intentional shortcomings in the design and conduct of the RECORD trial here: Psaty and Furberg http://content.nejm.org/cgi/content/extract/356/24/2522.