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“Not everything that can be counted counts and not everything that counts can be counted.”
-Albert Einstein
Can a blood test for cancer be a dangerous proposition? Depends on the test.
For one ovarian cancer patient, let’s call her Emily, treatment based on blood test results led to her premature death.
After Emily was diagnosed with ovarian cancer in 1994, and both her mother and one of her three sisters died tragically of breast cancer under the age of 40, Emily and her remaining sisters came to the conclusion that breast cancer must run in their family. In an attempt to beat the genetics, they had bilateral mastectomies. In fact, in an act of solidarity, they scheduled their mastectomies in different cities to happen on the same day. At the time, there was no knowledge that BRCA1/2 mutations caused the hereditary breast and ovarian cancer syndrome, but Emily and her sisters weren’t taking any chances. It wasn’t until ten years after their mastectomies, that doctors and scientists reported mastectomies and oophorectomies actually do prevent hereditary breast and ovarian cancers.
Unfortunately, Emily’s outcomes were less optimal when it came to treating her ovarian cancer.
At the time, it was standard practice to follow CA125 (cancer antigen 125) levels in the blood, on women who had completed chemotherapy for ovarian cancer. And while many women like Emily believed it would help them live longer, there were no data supporting this belief. This is not unusual in medicine. Many medical recommendations are based on scant evidence. When facing a patient, doctors struggle with how to discuss standards of care when evidence is lacking. If a patient has a problem, we all want to help; but the best doctors avoid embellishing on the limited knowledge we have on hand.
Obviously, if earlier detection of cancer recurrence leads to improved outcomes, then the earlier the relapse is detected the better. Intuitively, Emily had every reason to believe her CA125 blood test could help her live longer.
However, if early detection does not improve outcome, an earlier diagnosis of relapse simply would lead her to live longer with the knowledge that her cancer was relapsing. Would she benefit from such knowledge? Or be harmed?
A few years ago a randomized trial finally compared outcomes from early versus delayed treatment for relapsed ovarian cancer to answer these questions—let’s call it the “do no harm helps” or DNH trial. A woman like Emily with a rising CA125 level, who is well, without physical evidence of recurrent disease, presents her and her oncologist with a management dilemma. To resolve this, the DNH trial was designed to compare early treatment of relapse based on a rising CA125 with delaying chemotherapy until physical evidence of relapse.
Almost 1,500 patients were enrolled in the DNH trial. All of the women had to have a complete remission from ovarian cancer chemotherapy with a normal CA125 level. They were followed with exams and blood tests for CA125 every 3 months. If they reached abnormal levels, the patients were randomized to two different paths. In the “early” path, patients were told of the rising levels and were asked to start relapse chemotherapy within four weeks. In the “delayed” path, patients continued exams but did not learn of their CA125 results and only started chemotherapy if there were physical signs of relapse.
Those patients in the “early” pathway who were treated with chemotherapy based only on the abnormal CA125 blood test received chemotherapy almost five months earlier than those in the “delayed” path. Due to chemotherapy’s side effects, there was an earlier deterioration in the quality of life for patients in the “early” path, but there was no effect on survival. Both groups of patients died from their cancer at the same time. From these profound data, we can now tell our patients there’s a reason not to have routine CA125 measurements (unless for a research study) after completing their chemotherapy.
Since Emily was being cared for in the mid-1990s, we watched her CA125 carefully. When it was elevated, we performed CT scans. We eventually came across a lymph node that was growing at a slow rate. After talking with her, her family and her team of physicians, Emily decided to undergo chemotherapy again. Unfortunately, due to her weakened chemotherapy-suppressed immune system, this was when she acquired a fungal infection that led to sepsis and a premature death.
Patients can only make good choices if they are given all of the facts. With the limited amount of information we had at the time, Emily’s choice was reasonable. Now we know more. Now we need to discuss the reason for why we might NOT want a CA125. If our patients have a normal history and physical and have a normal CA125 level after their initial chemotherapy, we tell them they have almost a 50 percent chance of surviving five years. Those patients who are informed by their doctors that relapsed disease can be treated but not cured are more likely to decline routine CA125 measurements. On the other hand, those doctors who hedge and lead their patients to believe that cure of relapsed ovarian cancer is still possible can’t persuade their patients not to have routine CA125 testing.
This lack of benefit from earlier treatment with its deleterious effect on quality of life should lead all of us to wonder whether we should think about this in other areas. Early detection using fancier imaging or new blood tests for tumor antigens or for tumor derived DNA, may not always be harmless. Just because a test has some ability to detect cancer, doesn’t mean it should be done. The clinical use of a test needs to be tested.
Early detection does not always mean better chance of a cure. Knowing is not always better than not knowing. It certainly wasn’t for Emily.
