Prediction @ MindSay 
A serious question for women with breast cancer and their physicians is whether chemotherapy should be employed after the initial breast surgery. This decision is particularly vexing for situations where the prognosis is relatively good, but not good enough. Patients whose cancers have estrogen receptors and who do not have any spread to the lymph nodes comprise such a group. And the group is large, perhaps half the women with breast cancer.
A decade or so ago the results from the National Surgical Adjuvant Breast Project chemotherapy trial B-20 were reported. This trial suggested chemotherapy was of benefit before the menopause with a step down in usefulness with menopause and then a continuing decline with age. Thus tamoxifen plus chemotherapy seemed wise up until roughly the age of 60 (the trial did not include women over 70). The chemotherapy employed in B-20 were regimens that date to the 1970's. Many experts believe that newer regimens are more effective.
B-20 revealed that the degree of estrogen positivity was possibly important, with women with lower levels benefiting more from the chemotherapy and tamoxifen combination. The advent of gene profiling, like the proprietary “Oncotype Dx”, seems to have resolved the chemotherapy issue for many patients and physicians. Is this rational or simply another example of the technological imperative?
“The RS [Oncotype Recurrence Score] assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit” is the conclusion in a paper in the Journal of Clinical Oncology in 2006. Based largely on this study, Oncotype Dx appears with favorable mention in the American Society of Clinical Oncologists and National Comprehensive Cancer Network guidelines. Genomic Health, the company that sells the Oncotype Dx test, uses these guidelines and the JCO paper in its marketing.
The 12 page JCO report is chock full of sophisticated analysis, such as “linear fit of the likelihood of distant recurrence as a continuous function of recurrence score” analyses and various multivariate models. But what is the basis for the statement that Oncotype “predicts the magnitude of chemotherapy benefit”?
A glance at “Fig. A2” on page 11 tells the story. Figure A2 gives 12 year “overall survival” comparisons for four groups: tamoxifen versus combined tamoxifen/chemo for all patients lumped together, and the corresponding comparisons for good, intermediate, and poor Oncotype Dx score groups. Seven of the eight groups have 12 year survival ranging from about 92% for the low score tamoxifen alone group to about 82% for both intermediate groups, and the tamoxifen/chemotherapy high risk group.
Only the high Oncotype risk score tamoxifen alone group jumps off the page. This group has a 12 year survival of only 60%. But the tamoxifen alone group with high risk Oncotype scores consists of only 47 patients. Where did these 47 patients come from? They came from a study (B-20) done by the NSABP and reported in 1997 and included 2363 patients with breast cancer, negative lymph nodes and positive estrogen receptors. The 47 unlucky patients were about 2% of the total enrolled patients in NSABP B-20.
Are the 47 patients representative of all the Oncotype high risk patients in B-20? It is hard to say. Samples of the original breast tumors were available for only 670 patients and testing was successful in 651. So, only about ¼ of the B-20 patients are included in the Oncotype study. If this sample were random, probabilistic analysis might be intact. But the absence of material to test was not random. Some of the tumor samples were “used up” in other studies, and not saved in others. Presumably these other studies were focused on something specific and not random.
And what about the “overall survival” of 60%? Is that real? Again, it is hard to say. “Deaths before distant recurrence [was] considered [a] censoring event”. This means that a patient who was killed in an auto crash would be counted as alive but lost to follow up rather than counted as a death. But what if the crash was caused by a blood clot caused by the tamoxifen? And, since both chemotherapy and tamoxifen are thought to increase clots, what if several more patients in the combined group than in the tamoxifen died of strokes or heart attacks?
Oncotype is being used by patients and physicians all over the country to decide upon chemotherapy based on the 47 patients. Perhaps by a coincidence, the 12 year survival for both the Oncotype intermediate and high risk combined tamoxifen/chemotherapy groups was nearly identical at 82%. There were 212 such patients.
However, the 47 high risk tamoxifen alone group had survival 22% less than any other group. What are the possible explanations for the remarkably bad outcome for the 47 patients? Perhaps it is as it seems – tamoxifen alone is inadequate for high risk patients. Still it seems odd that the worst prognosis group had almost exactly the same survival experience as the intermediate group when the treatment was both chemotherapy and tamoxifen. If the understanding is that tamoxifen is good for estrogen receptor positive patients and chemotherapy adds something for some patients, how is it that the combination gives the same results for both intermediate and high risk patients?
Maybe the 47 were just very unlucky and the 117 high risk patients who got the combination therapy were astonishingly lucky to get the same results as the intermediate group. To account for this possibility, tests of statistical significance are performed. Using one of these (Cox proportional hazard test), there is less than one chance in a thousand that the 22% difference in survival is “random”, according to the analysis done by the authors. The tests for statistical significance assume random allocation of treatment. The original B-20 trial was randomized but the Oncotype study was not based on a random sample from that trial and was retrospective.
In addition, the “significance testing” was not said to have been corrected for the fact that many comparisons were made. The degree of confidence one takes away from a retrospective study full of potentially confounding variables and assumptions that violate basic probabilistic underpinnings is not as high as the statistical significance level might otherwise imply.
The authors of the JCO paper claim that their test “predicts the magnitude of chemotherapy benefit.” This seems not quite right. The magnitude of benefit from tamoxifen/chemo was identical in the intermediate and high risk score groups. What the test may have predicted in those 47 patients with high scores was a poor outcome with tamoxifen alone. One would think that the suggestion that Oncotype should serve as the basis for treatment selection for 100,000 women should not be based on the experience of an undefined 47 patient “chunk sample”.
The test costs about $3650. About 100,000 women may have er positive, node negative cancer diagnosed this year. That’s $365 mil for just one test in a complicated setting where many other images and tests will be required. Oncotype Dx should be verified by a prospective randomized trial that is appropriately stratified. Such a trial is underway.
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Date Line July 6, 2007
IRAN! Bush accuses it of wanting nuclear capabilities for the purpose of making nuclear weapons. Bush, of course, has an ideal track record of assertions: he has yet to be correct on anything.
Iran, one of the world leaders in oil production, has imposed gasoline rationing. Iran does no produce its own gasoline; thus it cannot hope to have a mechanized military capability of any meaning other than defensive.
Iran, one of the world leaders in oil production, has declared it is going to promote dual usage, hybrid, vehicles. Apparently, Iran�s leadership sees no long-term future in gasoline production.
Iran, one of the world leaders in oil production, wants nuclear power, nuclear electric production capacity; Iran, one of the world leaders in oil production, wants hybrid, fuel efficient vehicles.
There is only one rational conclusion, Iran, one of the world leaders in oil production, is attempting to free its oil reserves for export in a period which promises much higher energy prices.
What are the possible reasons for a nation which boasts forty CENT per gallon gasoline to be looking to cut its consumption?
Could it be the Iranians foreseeing a collapse of domestic production throughout the Middle East? Would that require an expansion of American disruption of Middle East oil production; we have witness this in Iran, under our oil industry President and Administration.
Could it be the Iranians foreseeing the reality behind persistent reports, denied by the Bush Administration, that global reserves are depleting at a much higher than anticipated rate?
Could it be the Iranians foresee a a profit in selling carbon credits to the richer, very wasteful, nations? America would certainly be their primary market.
Whenever a nation behaves contrary to rational understanding, it is time to check what we are basing our understanding upon. To date, we have based our actions and understanding on the Evangelical concept of reality.
The Evangelicals promote a literal reading of a "divine" document, the authors of which view as fluid.
Evangelicals fail to adhere to any of precepts and commandments they assert should be taken literally. In fact, as I have previously pointed out, Evangelicals follow the teachings of one whose real purpose might well have been their self-annihilation.
The choice made is between superstitious "faith" and unsupported "belief", or three elements of the divine spirit: "Knowledge, Wisdom, and Understanding." Do we live by assertion, or by reality?
Upon what basis have we built society? Do we rely upon witch trials, burning people at the stake, inquisition through torture, and all the other Evangelical, Right-wing, derived techniques? Certainly the Bush Administration believes we should; but they get everything wrong.
It is time that we study reality. It is time we moved in the direction of universal peace and government. No need for a single sovereign state; rather a union of sovereign states, a Global Union of States.
That is, in essence, the prediction which the Evangelicals say should be taken literally. Why are they working against it? Why are they working for a Global Destruction of States? Why do they persist in their desire for inflicting the most harm on the most people?
Evangelicals are interesting. Osama Bin Laden is clearly an Islamic Evangelical with the same agenda as those Christian Evangelicals who hold that Mormons and Catholics are not Christians. The problem, of course, is the one which Gandhi pointed out: it's a great religion, too bad nobody practices it.
Islam is a great religion, but once again we have the problem that none follow the Koran teachings; most simply find the hate passages and follow those. It is no wonder that the Khazar King, given the option of selecting a religion for his people, rejected both the Islamic and Christian faiths. Why follow followers, when you can follow the one they both acknowledge as the true leader.
SIGH, once again, drifted from the subject. Look to the small mentions in the news. Ask the question "WHY?" And continue to ask it until you have an answer which works.
Einstein did not necessarily like the answers Relativity provided; it is clear that he ignored many subsequent findings in his search for that one simple formula which would provide causality. Causality, reality, are often difficult; one truth, the Right-wing causes of the problems.
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FOOTNOTE Observation: Einstein had a series problem with Quantum Physics; most reality based physicists acknowledge Quantum probabilities are a rational approach to reality. What they fail to acknowledge, what Einstein should have realized, is that Quantum Physics is relative in the most amusing sense.
To any seeking a solution to the probabilities which comprise the basis of Quantum Physics: Their perspective is the problem with the quest for any Unified Field Theorem.
Quantum Physicists view the universe relatively, they view reality relative to the perspective of the observer, rather than the perspective of the particle being observed.
Reality, planets and such, are observed in their own right. Nuclear particles must be deduced and therefore they cannot be observed until the are observed. The observer has the problem of guessing when and where a particle will be at any moment of observation; hence it is a science based upon probabilities.
Quantum Physicists are the Evangelicals physical science.
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In the not-too-distant future, we will all see these labels on products containing wheat gluten (especially pet foods!):
"This product was made with wheat products from the U.S. and/or Canada."
| Well today hasn't been very thrilling. In fact it's been a rather dull day in all. I've been out for a walk but the weather wasn't good enough for photography so there's not any new pictures there I regret to say. I'm still nicotine free but the pangs aren't going away more is the pity but ah well they will in time I guess. So what have I got for you journal readers today. Well I bought the latest edition of my favourite magazine on estoric matters today. Some of you know it already it's called prediction, it's not as good as it was but I still read it every month. It's gone a bit too light weight for my tastes recently with some stuff edging on the side of fluffy. It has an article which when I get time I am going to copy for Tina on a topic she and I were discussing recently, it seems you aren't alone on that topic hun so you might find it interesting. It's astrology pages say that February is going to be a good month for me so here's hoping! The only other thing I have done is got a bit bored and created 5 more icons for Livejournal use. I'm going to relax tonight and not do much except for a soak in the bath a bit later, it might help with the side effects from my nicotine withdrawl. Anyway there is all my news below are the Livejournal Icons
Hugs to all who want them
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