Monday, August 20, 2007

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.

5 comments:

  1. I was diagnosed with small cell lung cancer in 2002 envolved the rt. broncus and esophagus. I received chemotherapy and responded well. I went on-line to chat rooms and found people like me that then had metatasis to the brain and that was what was killing them. I talked to my oncologist and stated that I wanted to have prophlactic brain irradiation. I went back on-line and found a web site that show the different results for different dosages and frequency. Discussing
    this with the Radiogist Oncologist
    we took the lowest dosage but with
    more frequncy. I experienced no side effects. My CT scans have remained without any growth to the
    tumor and my Oncologist now wants to see me once a year.

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  2. To Dr A.: your statement: "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,"

    What choice do you think someone would make?

    I think that you cannot answer this question until you have walked a mile in a cancer patients shoes. (Not from someone on the outside looking in.)

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  3. I actually suspect that most patients will prefer treatment, for the reason you allude to - that is, the prospect of death looms larger when you're facing it.

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  4. After my friend had this procedure done she lost memory and her ability to walk. She spent the last 15 months of her life in a nursing home because of it. I can only wonder how much better her last days would have been if she had not done this therapy.

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    Replies
    1. Researchers are inherently biased, I have learned, just like pharmaceutical companies. When you get a study published in the NEJM, you wanna/gotta run with that, there are scores of careers that will be made using that study as a springboard. So researchers are not disinterested. They will push things. And they're not always circumspect and rational about it, and that clouds patients' choices. There is only one thing worse than a death sentence: one that comes only after a period of torture. We do not escape death from metastatic cancer, but we can avoid being tortured on the way.

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