"I’m confused as to why this drug is part of my chemotherapy treatment,” a patient battling breast cancer commented as she handed me an article she had found on the Internet. “If you’re confused, try being an oncologist,” I replied. From the look on my face, she knew that I was not joking.
A few months earlier, a pooled study (meta-analysis) of the results of several adjuvant (early) breast cancer trials concluded that two widely-used, but heart-unfriendly anthracycline -type chemotherapy drugs, called doxorubicin and epirubicin, benefited only a minority of women with aggressive tumours that made large amounts of an enzyme called “ Topo II ”, and a protein called HER-2 . The majority, whose tumours did not overproduce these substances, fared as well, or better, with an older, less toxic combination of drugs known by the acronym “CMF”.
Finally, we appeared to have a way of determining what kind of chemotherapy to administer to individual patients…that is, until new studies contradicting the meta-analysis trickled in. As a result, I decided to stick with the “old” approach until there was further clarification. Understanding my dilemma, the patient agreed.
Was this an isolated case of opposing results in medical science? Not by a long shot. In fact, the chances are better than even that a review of scientific or medical studies will end up leaving one unsure of what to believe.
As another example, just last month, Canadian researchers reported that, if taken together, the antidepressant drug, paroxetine (Effexor), works against the antiestrogen, tamoxifen; the longer women took both drugs, the less effective tamoxifen was to prevent recurrence and death from breast cancer. Oncologists quickly advised their patients of the finding because the scientific rationale appeared unassailable: paroxetine irreversibly blocks a key liver enzyme that converts tamoxifen into its active cancer-fighting form.
Yet, within a short time, other studies failed to show this anti-tamoxifen effect, whether for paroxetine or many other drugs that block the same tamoxifen-metabolizing liver enzyme.
How do we account for the fact that so many well-conducted, scientific studies, carried out by honest and competent researchers, contradict one another? While often no underlying reason is apparent, in many instances the answer lies in subtle, but significant, differences in populations under study, or the methods employed to study them.
A case in point may be the latest study to look for evidence of chronic cerebrospinal venous insufficiency (CCSVI). Using Doppler ultrasound to look for blockage and to measure blood flow in the jugular veins of 56 patients with multiple sclerosis and 20 healthy controls, a team of experienced German and British researchers found criteria for CCSVI in only 1 patient with MS and none of the controls. Moreover, none of the 76 subjects was found to have jugular narrowing (stenosis).
These findings not only disagree with those of Dr. Paolo Zamboni , but also with independent studies by American, Polish and Jordanian investigators that showed a high incidence of jugular venous anomalies, including stenosis, in patients with MS as compared to healthy control subjects.
How do we account for this stark contrast? While the populations of MS patients and healthy subjects appear to be reasonably similar in all the studies, at least two major differences in methodology could account for the negative findings in the German/British study:
As opposed to the other studies, it only examined the jugular veins high up, near the angle of the jaw, where additional veins, called collaterals, often branch off the jugulars to maintain blood flow even if there is a blockage. Moreover, as the exam was limited to the top of the neck, it would not have picked up decreased blood flow due to severe jugular narrowing lower down, especially at the base of the neck, near the head of the collar bone, where vein anomalies often occur and there is little or no collateral circulation to maintain blood flow.
It assessed jugular vein narrowing in the “sagittal” plane (the ultrasound probe is placed parallel to the length of the vessel). The Zamboni technique uses the “transverse” plane ( the probe is placed at a 90 degree angle to the length of the vessel) to look for narrowing, webs, or abnormal valves that Dr. Zamboni believes are often missed in the sagittal plane examination.
Thus, as exemplified by all the examples cited, no matter what field of science and medicine we consider, even minor differences in how studies are conducted can, and often do, produce opposing results. This leads to confusion, debate and, all too often, strong disagreement over the “right answer” to crucial issues.
However, in the case of CCSVI, I believe that there is a simple solution to this dilemma: when looking for vein abnormalities, every study, whether involving ultrasound or MR scanning, should follow the technical methods developed by Dr. Zamboni; be blinded to prevent observer bias; and always include selective venography, where dye is injected into the vein and an X-ray taken. It is the gold standard for detecting anatomical vein abnormalities against which all other techniques must be compared.
If all investigators, including the seven teams recently funded by the U.S. and Canadian Multiple Sclerosis Societies, abide by these simple rules, the chance of producing conflicting results will be minimized to the smallest extent possible. After all, patients with MS, and their loved ones, deserve to know the unambiguous truth about CCSVI.