Skeptic @ MindSay 
A very large clinical trial (~10,000 women) is underway to assess the usefulness of the Oncotype Dx gene profile for selecting treatment for early stage estrogen receptor positive breast cancer: the TAILORx Trial. The trial sponsors will ask women with breast cancer to undergo Oncotype Dx testing (for which they will be billed $3650) and then assign them to three risk groups based on their recurrence score. (The groups are defined using different cut-off’s for this trial than those used for the study done on the NSABP B-20 tumors.) Women in the low risk score group will get hormonal treatment (tamoxifen or one of the newer “aromatase inhibitor” class of drugs). Women in the high risk group will get chemotherapy and hormone therapy. The women in the intermediate group will be randomly assigned to receive either hormone treatment alone or a combination of hormone and chemotherapy.
A least four concerns make this trial seem premature. First, the chemotherapeutic "validation" of Oncotype Dx is based on one small, old chemotherapy trial. Second, TAILORx does not incorporate many other old and new prognostic indicators that might trump Oncotype Dx in some circumstances. Third, not enough information exists about how the Oncotype Dx score might interact in a confounding way with specific hormone treatments, chemotherapy drugs, and regimens. Finally, far too many non-random, non-blinded choices are afforded to patients and physicians in TAILORx to make for decent "science".
TAILORx is based on a retrospective analysis of a small, non-random sample of assays performed on preserved tissue. The ability to use this old material to obtain reproducible gene profiles is an amazing technological feat, to be sure. But only 651 of about 2300 patient results were available. The chemotherapy used in the NSABP B-20 dates to the 1970's. Substantial evidence supports a conclusion that these regimens improve prognosis for many patients. But two of the agents (methothrexate and 5-fu) are not often employed today. The third agent, cytoxan, has lost popularity over concerns that it may lead to late complications like second malignancies. Meta-analysis of the many thousands of patients treated with chemotherapy indicates that the B-20 drugs are not as effective as newer drugs like the taxols and adriamyin.
So inspite of the fact that the paper describing the results for the 651 patients uses the word "prospective" five times, it is actually a retrospective survey, not a clinical trial. This might matter for a woman who is enrolled in TAILORx because she cannot be sure that the Oncoype Dx group studied really is representative of the group she is in. And remember that much of the power of the argument for Oncotype Dx is contained in the one subgroup that contained only 47 patients.
A second concern revolves around the lack of consideration of many other older and newer prognostic variables when deciding whether a patient falls into "Group 2" (the intermediate risk group) as defined here:
Group 2 (Primary study group; ODRS 11-25): Patients are stratified according to tumor size (≤ 2.0 cm vs ≥ 2.1 cm), menopausal status (postmenopausal vs premenopausal vs perimenopausal), planned chemotherapy (taxane-containing [i.e., paclitaxel, docetaxel] vs nontaxane-containing), and planned radiotherapy (whole breast with no boost planned vs whole breast with boost planned vs partial breast irradiation planned vs no planned radiation therapy [for patients who have had a mastectomy]). Patients are then randomized to receive either hormonal therapy alone or combination chemotherapy and hormonal therapy.
For example, tumor size, tumor dna ploidy, quantitative level of estrogen receptor, tumor lymphovascular invasion, per cent of dividing cells ("s phase"), Ki 67 expression and many other features and meaurements have been used to stratify patients for risk of treatment failure. (Some of these features can make a woman with a very small tumor (<1 cm) eligible for inclusion in the trial, an acknowledgement of their possible importance). And of course, clinical features on presentation may predict risk of failure. Mammographically discovered cancers may have a different prognosis compared to those discovered by the patient feeling a mass, for example.
Under TAILORx rules, a 48 year old woman with a palpable 4.9 cm cancer that is high grade with lymphatic invasion, weakly estrogen receptor positive, Ki 67 expression and an S phase of 20 and a Oncotype Dx score of 23 (intermediate risk) could be randomly assigned to tamoxifen alone.
Some will argue that the hypothetical patient described above would be unlikely to have an Oncotype Dx score as low as 23. (The B-20 Oncotype Dx analysis used 18 to 31 to define the intermediate risk group. The range was changed to 11-25 for TAILORx, possibly because her2+ patients are excluded - more on this below.) This is probably true, since the Oncotype Dx score does correlate to some extent with many "traditional" indicators. However, if the above hypothetical patient exists, few cancer physicians would advise tamoxifen alone. This would result in one of two outcomes for our hypothetical patient.
First, the woman would not likely be offered the TAILORx trial. Or, if she were offered the trial and the randomization resulted in tamoxifen alone, she would be advised to withdraw from the trial and receive chemotherapy. Either way, the results from TAILORx will be compromised. If patients on the "edges" of the "groups" are manipulated to get the "right" treatment, the trial results will be of little use, because the "borderline" cases are the very ones that present the most difficult decisions, and the Will Rogers phenomenon will be in play to distort the results.
A third concern that may make TAILORx premature is the paucity of information about how the Oncotype Dx predictive power might be affected by the choice of hormone and chemotherapy agents. The TAILORx protocol allows each physician to choose a chemotherapy regimen and/or hormone agent. Some might still choose the B-20 CMF and tamoxifen regimen for patients perceived to be at lower risk (within the intermediate group), while others might choose "dose dense" taxol containing aggressive treatment for a patient like the hypothetical one described above. There are many reasons why this may lead to errors.
The gene for glutathione S-transferase (GST) GSTM1 is one of the 16 predictor genes in Oncotype Dx. The presence of this gene tends to improve prognosis. The problem is that this gene also affects the metabolism of some cancer drugs. Anticancer drugs that have been shown to be substrates for GSTs are, for example, chlorambucil, melphalan, cytoxan metabolites, and steroids. Indirect evidence for a role of GSTs in modulating drug effects through deactivation of drug-generated hydroperoxides or other reactive oxygene species exists for adriamycin, mitomycin C, carboplatin, and cisplatin, but not taxol. Some have postulated for other malignancies like acute leukemia in children that gstm1 confers a favorable prognosis because it changes chemotherapy metabolism. Oncotype Dx does not identify which patients have one copy of GSTM1 (a null polymorphism) and which have two copies. Remember B-20 chemotherapy often included cytoxan but never taxol.
Another gene in Oncotype Dx is her2. Patients with tumors that express her2 are exluded from TAILORx. This gene is a prototype marker for chemotherapy selection since the drug Herceptin works very well when it is expressed and not at all if it isn't. B-20 contained a number of her2 positive patients and herceptin was not available in that era. So the Oncotype Dx used in TAILORx is a different one than the one tenuously "validated" in B-20. If the her2 gene is a totally independent predictor, the change might not matter. But her2 does interact with other cancer genes, for example the Src family. Src is a family of proto-oncogenic tyrosine kinases originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the Nobel Prize.
Bag1 is another gene in Oncotype Dx and it interacts with the estrogen receptor (alpa) mechanisms which can control cancer growth. Does it interact with tamoxifen (studied in B-20) the same way as the aromatase inhibitors included in TAILORx (but not in B-20)? BAG1 seems to predict respone to tamoxifen but how it predicts benefits from other hormones or chemotherapy is less clear.
TAILORx is constructed on a tenuous foundation based on a very small number of observations (remember the 47 patieint subgroup) and on many exrapolations based on assumptions. Some of these may seem niggling, such as the fact that B-20 used age 70 and tumor size 4cm as cut offs and TAILORx uses 75 and 5 cm. Yet B-20 found a suggestion that age and chemotherapy effectivenes interact and that tumor size affects prognosis.
And, one more thing: how can "partial breast radiation" be allowed in a non-random way? This would imply that partial breast radiation has become an acceptable "standard of care". Where are the appropriately powered randomized trials that support this implication? Don't be fooled into thinking that an analysis of this non-randomly assigned "stratification" can answer any useful question.
Stratification (i.e., prospective randomization within smaller, rigidly predefined clinical subroups) is often employed in clinical trials (though purists might argue that this is unnecessary in trials with a large number of outcome events). But TAILORx is not stratified by rigidly predefined criteria. Rather it will permit thousands of patients and physicians to choose among a rich buffet of treatment options related to local therapy ((type of node sampling (any type among many permitted), type of mastectomy (any type among many), lumpectomy (any type among many), radiation (type of radiation, partial/whole radiation), chemotherapy (literally thousands of combinations and permutations of drugs and doses) and hormones (serms and aromatase inhibitors).)
Stratification might make sense if it were based on close to totally objective (not really ever possible in the real world) and independent classifications. Stratification makes no sense if it based on thousands of differing views and biases related to the risks and benefits of a multitude of differing therapies. Those decisions will be largely based on the very risk assessment conderations that the TAILORx trial is supposed to answer.
"Although technological advances will further improve our understanding of breast cancer and will contribute to tailoring treatment to the individual patient, our experience with adjuvant CMF over 30 years confirms that the effects of such a regimen are long lasting and may benefit patients with favourable and unfavourable prognostic indicators, at the cost of minimal long term sequelae." This is how Dr. Bonadonna himself described in 2005 (emphasis added) results from the chemotherapy regimen that is still often called "Bonadonna CMF". "Tailoring treatment" is the holy grail but TAILORx is designed too clumbsily to trump 30 years of better designed clinical trials.
Monks from the Order of the Brothers of the Statistic will study the scripture that flows from TAILORx and will be able to devine all the potential biases and confounders by utililizing probabilistic testing based on dubious underpinnigs that may well result in some very "significant" and small "p" numbers. Cultists who worship at that particular altar of "evidence based" medicine will travel about with their power point slides of life table graphs and p values carried to the fourth decimal point, Genomic Health will turn a profit for the first time and its shares will skyrocket, and another level of the temple known to heretics as the "House of Cards" will have been constructed.
Or maybe the results will look so powerful that even a skeptic like me will be convinced (or fooled).
TAILORx may be another example of the technological imperative in action. TAILORx reflects the fervent need of patients and doctors for a simple "black box" method for making difficult choices. The admonition of H.L. Mencken bears remembering: "For every complex problem, there is a solution that is simple, neat, and wrong."
1. Russell's Teapot http://www.russellsteapot.com
This is a great comic for those who like to have a little fun with Christianity's many logical flaws. If I could describe it in the most brief terms, I'd say that it is an atheist Calvin and Hobbes. The main character is Russell, a young boy living in a world surrounding by religious dogmatism. He also talks directly to Jesus, his pal, and often enquires about some of the more difficult-to-grasp aspects of religion. The great thing about it is that it uses humor to promote logical thinking, which is always a plus in my book.
2. Partially Clips http://www.partiallyclips.com
Partially clips consist of three frames of the same image with different captions. High-quality material here.
3. Toothpaste for Dinner http://www.toothpastefordinner.com
Leading the pack in the intentionally-poorly-drawn division is Toothpaste for Dinner.
4. Married to the Sea http://www.marriedtothesea.com
Sort of like Partially Clips, except one single frame and usually of old-timey wood-cut drawings with funny captions added. Made by the same guy who does Toothpaste for Dinner.
Isn't it weird that I exhibited progressively less effort with the item descriptions?
I doubt everything until it is proven to me.
Yeah I know that’s not very deep of me.
However that is just how I am .
I am strong believer in the old saying seeing is believing.
When I hear people tell stories about seeing ghosts and all that kind of stuff.
Well I kind of always doubt it .
I mean I just cant believe in something that sounds so silly.
I am not saying that stuff like that does not exist I am just saying that I need proof.
As I said I am a skeptic at heart.
Now if I seen cold hard proof then I would believe.
However until a ghost haunts my damn house I will doubt it always.
Oh and I changed my theme again .
What ya think?
I am trying to get back into the swing of things after being forced to cope with the simultaneous assault of holidays, family interaction, and apparently involuntarily allowing my lungs to serve as the substrate in which a particularly nasty pathogen has been allowed to grow and breed in the grand cosmic experiment (joke?) we call life. But luckily it has moved from there into my head where it can do less damage. It may be the pathogens have entered my brain, but as of today, I as a human being am declaring a War on Ignorance. I don't know how we are going to fight it. I don't even know what it means really other than I hate ignorance, and as an American, we seem to have a penchant for declaring war on vague ideas or objects. But in any case, this for now is our rallying point and I will with much appreciation, take into consideration, any ideas to expand, or engage larger numbers of innocent people in this, our noble endeavor. Be creative and help out any way you can. Remember, only you can prevent species self extermination through incompetence. Now, on to the rant.
You know what's wrong with our public schools. I am referring exclusively to primary and secondary schools here, mind you- no public universities or colleges. Our schools are managed under a completely different ethos than our universities. Many of our universities still hold international prestige, yet our schools seem to be slipping further and further into an educational abyss. But we can't seem to bring ourselves to make the connection that maybe we need to take a few lessons from those parts of the educational system that do work.
1. Create an environment that is rich with active scholarship and has true academics on the faculty. Teaching at a public school is, for too many, a job. I understand that many people who teach are good people who love children and want to see kids succeed. Those are good and necessary qualities. Maybe they need to be part of a cooperative team for early grades. But all of our children need to be exposed to educated adults who are passionate about the material they are presenting. They need to be active scholars, doing research, writing, and keeping up with professional news related to their field or even branching out into other fields of interest. They should have academic freedom and academic passion. The children should be able to see that and be guaranteed quality information in the process of their education.
2. Relax rigid pacing rules on student achievement. Especially in the higher grades. Too much emphasis is placed on being finished with these classes by this deadline so you may graduate with "your class". Half the people I know didn't bother to show up for their college graduation ceremony. The majority of those that did, attended more for the benefit of proud family members than for themselves. The students should have more opportunity to learn at their own pace. This is not to say that the educators should not bother students who are slouches, but there currently is far too much social pressure to accomplish goals on a certain schedule.
3. Split classes into certain time periods on certain days like a college schedule. If I am someone who likes to get everything out of the way at once and have my evenings free, I take all morning classes. If I am someone who has difficulty sitting through two or three long classes and staying focused, I will split mine up throughout the day. Your overachievers and your hyperactives are both satisfied within reason.
4. Provide more variety in classes. Every once in a while a class that most people would consider "fun" would help students- prior to college- get used to the idea that there are some interesting ideas in the world, and a good education is the only way to find them.
5. Differentiate teacher pay according to area of specialty and student achievement. It's funny how we are so big on standardized testing and cracking down on teachers who are not giving our children a quality education, but I believe only one state had the gonads to actually pay teachers more who have students which exceed expectation. If a teacher is phenomenally successful educating his or her students, and another with the same amount of experience has students just staying above minimum proficiency, most schools will pay them the same. And we have to face reality people, no offense intended, but to get someone really academically qualified to teach AP Physics in High School, you may have to offer to pay him or her more than you pay the Gym Coach. Right now, most places have a flat "teacher" pay rate that doesn't differentiate for subject area. Colleges do differentiate. College physics professors tend to make a little more than college philosophy instructors.
6. I am not sure if this is only a local practice in the state of Georgia, but currently most school systems local income is derived primarily if not solely from property taxes. How egalitarian is this? Rich, well-to-do, suburban kids with educated parents and a relatively carefree life in a wealthy subdivision gets to go to the school with all the best amenities and all the best teachers because it has a lot of money to dole out on the little darlings since the wealthy owners of homes in the subdivision pay a hell of a lot of property tax. Meanwhile, the poor little rural country school has students who come from uneducated families, are miles away from resources like (good) libraries or museums, have to deal with struggles at home and in a community that is slowly crumbling while being too poor to even realize that there is much more out there. These kids have the fewest resources at school as well and are more likely to have less qualified faculty. After all, a small shack on a tiny dirt plot, miles away from anything except acres and acres of cotton, peanuts, and soybeans, does not have a value that brings in large sources of property tax revenue for the school district. This is an antiquated and harmful system that reinforces socio-economic divides in our culture. It should be abolished in favor of a more fair system of school revenue. And no, don't sell me that baloney about privatization. It would have the same result of poor kids going to shoddy schools and rich kids going to snobby schools.
There are more ideas where those came from. We really need to have the guts in this country to let go of "tradition". Scrap the whole damn system if you have to and start over. I don't care if it worked for you when you were growing up, because a) it didn't work for half the country because they were too ignorant to see that Bush was a moron...twice and b) it isn't working now. Where's that American pragmatism I have heard about? That's actually the subject of an upcoming post. In the meantime, keep you mind open...but not so open your brains fall out. And by the way...I am a public school teacher and I approved this message.
Until next time, keep your powder dry.
The Southern Fried Skeptic
"The skeptic does not mean him who doubts, but him who investigates or researches, as opposed to him who asserts and thinks that he has found."
-Miguel de Unamuno
More substance to come soon.
The Southern Fried Skeptic