OK. So now it's almost 10 months since this thread ended. But I am left with the question regarding Hodgkin's Lymphoma - where are the studies that show that it is benefical to continue adjuvant chemotherapy after evidence of no disease (per CT/PET Scans and Bone Marrow Bioposy)? It seems the the oncologist standarly promotes two cycles (total of 4 sessions) past no evidence. If one wanted an "insurance policy" what is to say that one cycle is not enough? Are there any studies that say that other consolidation therapies (perhaps of the alternative variety) along with therapy to boost the immune system are valid; or not?

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There's a recently released book that some of the posters to this blog might find interesting. I just read Jerome Groopman's book, How Doctors Think. Groopman describes some of the common thinking errors that physicians (like all of us) are prone to, using some stunning case histories to illustrate his points. I suspect that there's a lot of variation in how much training in research design and statistical analysis that physicians receive, which would affect how sophisticated their understanding of basic ideas (such as the limits of correlational research to demonstrate causation) is. What Groopman emphasizes is that doctors are taught nothing about the cognitive errors that contribute to medical misjudgments and misdiagnoses. In his book, Groopman laments the fact that doctors are not routinely taught about cognitive errors and ways to dminish them as part of their medical training.

Groopman discusses the role of "managed care," and the use of decision-trees, etc. as additional contributors to a lack of critical thinking by physicians. He also suggests what kinds of questions patients can raise to essentially help their doctors avoid some of those errors. Although these questions won't "cure" the problem, they are a beginning - and Groopman urges patients who don't receive satisfying answers from their doctors to seek another physician.

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randy: here are some references and comments, titled "Doctor, are you FDA-approved?", about your exact topic. I agree in a general sense with what you are saying, but I doubt there is any unbiased evidence that doctors were ever "amongst the top 1% of 1% of intelligent people", that there is "an overall slippage of education", nor that "most doctors" are (fill in the blank). Overall, it would be economically unwise for doctors to try to kill their patients, but the HMO concept has shown that incentives to keep patients healthy don't work, either. As to an MD degree being a "signaling mechanism", that is not the fault of the doctor, but rather of a biased, uninformed, and basically dumb American public.

What would be the characteristics of the individuals in a career entity that you admire?

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i am biased against doctors. let me put that on the table right away.

i think that there was a time when doctors, especially those working in prestigious places, were amongst the top 1% of 1% of intelligent people. i see an overall slippage of education, and all sorts of perverse motivations have cropped up due to economic factors.

most doctors are people who want three things 1) money, 2) prestige, 3) a feeling of being altruistic. they are willing to put up with a tremendous amount of "work" and dedicate years of their lives to pursuit of their MD, but that education has mainly deteriorated into a signalling mechanism.

so i am not surprised to hear you relate this story. maybe your generous interpretation is the right one, but i feel like it is not.

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For the few who still may be interested in this thread (and like David Balin, may one day have need for unbiased thinking about cancer treatment):

@T Savehn: You can guess the current status of the story by the use of the past tense in the preceding paragraph.

DeVita's 6th edition on Oncology was published in 2001. It is a volume with multiple authors, each of whom was assigned his/her chapter(-s) about three years prior to publication. Most of what they write that is not based on personal studies is from citations that are 3 to 10+ years old at the time, plus the 3 years it takes to compile and publish the edition. For instance, there could be no knowledge in that tome of the long-term outcome of Lance Armstrong (treatment 1996) and others like him with non-seminoma germ cell testicular cancer. Check the 8th edition. In a dynamic field like chemotherapy trials, all current info is from researcher-to-researcher communication, and presentation of current papers. Text books are always obsolete at the time of publication.

@T Savehn: (I) object to the "bits of cancer" nonsense set out by some above.

The problem here is discussing mutations from various cell lines as if they were the same actors. Seminomatous testicular cancers are exquiisitely sensitive to radiation, while radiation has no beneficial effect on testicular choriocarcinoma at all; yet both may arise from the same testicle. Consequently, one observer might say that radiation is a great way to treat testicular cancer, while another might say that it is a terrible treatment; both would be correct, just as both would be incorrect. In the original post, the cell-type of the cancer in question was not revealed; the discussion became more meaningful once the discussants knew that it was endometrial carcinoma, for which there is no known benefit of chemotherapy beyond normalization of tests (complete response).

Lastly, Balin's actual point was that there is a major difference between the position, "There is no evidence that further chemo helps, but that is because we haven't run the clinical trials yet", and the position, "There is no evidence that further chemo helps, because double-blind propsective studies have shown this result."

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I write again, this time to object to the "bits of cancer" nonsense set out by some above.

One of the best works on cancer is DeVita's "Cancer: Principles & Practice of Oncology". Chapter 17, 6th Ed. p. 291 addresses the issue. Under "Adjuvant Chemotherapy" the authors write:

"There was initially great excitement with the concept of using chemotherapy as an adjunct to local treatment. The rationale for adjuvant chemotherapy was to treat micrometastic disease at a time when tumor bulk would be at a minimum, thereby enhancing the potential efficacy of drug treatment. It was assumed that drug therapy, at this stage, would result in a much higher cure rate."

You can guess the current status of the story by the use of the past tense in the preceding paragraph.

Here is a tiny part of the problem. p53 is responsible, at least in part, for causing defective cells to self destruct. It turns out that like little M-Class starfreighter Nostromos the cells in your body each have self-destruct mechanisms that are executed (apoptosis) when the proper command signal (cytokine key) is received from Warrant Officer Ripley (your immune system). But what if the system loses the ability to receive or understand the command? And what if that system isn't just a stupid computer but instead is a pluripotent stem cell (queen) that is churning out huge numbers of immature, useless (to you) and ultimately destructive (i.e. cancerous) daughter cells?

And what if those daughter cells are susceptible to chemo but the queen is not?

In that case the chemo (which is designed to destroy the bulk of the tumor) will set the clock back to a pre-clinical point by debulking the tumor but not killing the queen. For a slow-growing cancer that takes decades to manifest you've rolled back the odometer and may have another 40 years; for an aggressive one you've got months.

So you say "hey, but I'll keep the cancer at bay by taking chemo as a prophylactic". Evolution answers that question. The malignant queen isn't happy to just churn out identical copies of partially differentiated daughters who get blasted to pieces by Ripley. Oh no. She continues accumulate mutations as she rapidly produces offspring; and from time to time she produces sisters whom she sends out into the unhappy world to do the same.

Eventually one of those mutations leads to offspring immune to the chemo. That's why first remissions are generally followed by much shorter second remissions (if at all) which are followed by salvage regimins (experimental Hail Marys) which are followed by palliative care. (Hairy cell leukemia being an exception).

So what then is the point of using a weapon to which both the queen and her brood are immune? Especially if that weapon damages the user and is itself a potent carcinogen quite capable of inducing a high grade cancer like acute myelogenous leukemia in the case of alkylating chemo drugs?

I understand that there are healthy women having mastectomies and hysterectomies because they are more afraid of dying of say uterine cancer (low risk) than they are of dying of diabetes - after multiple amputations - (high risk). And I'm ok with grown ups doing whatever they want with their own bodies. I'm just pointing out the bias at work here described by others that make some people take risks that are, from a Bayesian perspective, foolish.

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D J Balan: Thank you *so* much for taking so much time in researching this question.

You are quite welcome. I'm very sorry for the situation that made it necessary.

@you have a special voice and you should find a way to get it out into the universe.

Thank you for such kind remarks. I have two ex-wives who might wish to debate you. I have a lot of spare time on my hands; following HA's recommendation, my new Blog is here. If any readers would like to have a discussion, or educate me on any aspect of transhumanism or extended life, or request an opinion about medical *issues* (not recommendations for medical therapy or suggestions of diagnoses), please make a comment on my blog, which currently contains only the inaugural post.

@ Is that right?

I *think* that it is, but you have educated me about thinking as much as I have educated you about medical issues. As to *right*, if you know what that is, tell Mr. Yudkowsky so that he can incorporate it into his fAI and get it built. If there really is such a thing as "time", mine is running out.

Best wishes.

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Retired, Thank you *so* much for taking so much time in researching this question. I am blown away. Alan is right that your former patients are missing out, and HA is right that you have a special voice and you should find a way to get it out into the universe.

You are right that my relative did have metastatic disease, and you are also right that by all accounts she has had a very unusually good outcome, far better than I would have dared expect a few years ago.

As for the substance, here is my current best understanding of what's going on: (i) there *is* in fact some at least some merit to the general "common sense" notion that additional chemo beyond clean scans can have additional cancer fighting effects; (ii) there is no evidence of this for endometrial cancer, but mostly because no one has really looked--the second kind of "no evidence"; and (iii) despite this, the right answer, given that the scans have been coming back clean for a while and all other relevant considerations, is still probably in favor of discontinuing. Is that right?

Thank you again. You have been enormously helpful.Dave

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One more point: the placebo effect. There is very strong statistical evidence that placebos “work”, they just don’t work the way the patient thinks they work. So if your relative thinks that the additional treatment is working or needed, that is an important fact to be considered.

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@ retired urologist. Welcome to the blog. Not only do your posts display an in-depth understanding of the medical issues under discussion, you also demonstrate an uncommon degree of compassion, sensitivity and concern. One imagines that your former patients experienced regret in your retirement.

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DJ Balin, I wrote this post because you seem to be still concerned. As I prepare to post it, I see retired urologist has posted again with much solid information, so perhaps it is unnecessary. I offer it specifically to address your concerns about the level of the evidence.

First of all, it is your relative’s body and mind and dollars that are involved. If he/she feels it is worth it in terms of cost and pain to take additional radiation, chemo or whatever, then go for it.

But I do not think there is any rational, objective reason for recommending this. I will explain why I think so:

By the square root rule (which you probably know since you mention type 1 and type 2 error), it takes a study of 100 patients to get evidence good to 10%. It takes 10,000 patients to get evidence good to 1% uncertainty. Pont one percent (.1%) takes a study of one million patients. And so on. Point zero one percent would require a study of one hundred million patients. Clearly, at some point, the evidence runs out short of absolute certainty. It *could* be true for some small percent of patients that additional therapy does good, say .1%, but it either does nothing for or actually harms the patient in the other 99.9% of cases.However, if this number was as high as even 3%, I am sure we would know about it. You can adjust this number up or down based on your degree of confidence in our medical system. But assuming I am correct in judging that this is a pretty small number, then it comes down to your relative’s judgement of the value of a possible benefit with very small probability (and for which there is no reliable evidence) versus the cost in dollars and pain of continuing treatment. ((Totally irrelevant, but coloring my evaluation, a relative of mine recently underwent cancer treatment. The cost in dollars was very significant, but the cost in pain of both the radiation and chemo was even more so. He/she wanted the pain to stop as soon as possible, consistent with preventing recurrence.))

So the issue of possible benefit comes down to projecting the endpoint beyond the level of precision of the available statistical evidence. Do you think a simple linear projection is close to right, or do you think the curve turns around at small numbers? And do you think your relative falls into that very small subset? (For instance, there is strong evidence, though still very controversial, that a little bit of radiation is good for you.)Given the variability of all the factors involved, I suspect there is always a very small minority that differs from the majority, i.e. that there is a small fraction of patients who would benefit from continued treatment. But I also suspect it is vanishingly small and consider seriously that it could be zero. But I guess (and this is strictly a guess, based on the square root rule cited above) that the current noise level is probably some where between 1 and .1%. So there can be no credible evidence beyond the statistical noise level, whatever it is.

Also, there is always a trade off. Many drugs are widely prescribed because they benefit 95% of patients, even though 3-5% have serious adverse side effects. But you should choose if you take the risk or not.

Finally, your particular doctor may or may not be aware of type 1 and type 2 error etc. but the entire medical establishment is not that stupid. So don’t worry about this point.Going on, medical statistics are far from perfect, and could be much further improved in this computer age (with some potential loss of privacy and freedom), but they are pretty reliable at the present time.

Therefore my opinion is: your relative’s choice on continuing treatment, but no statistically supported reason to doubt your doctor’s advice (to discontinue) beyond the noise level.

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@D J Balan: intuition that extra chemo can meaningfully fight cancers that are present but too small to detect has some merit.

Indeed it does, and it has been proven to give statistically significant benefit in some cancers, when carefully balanced against toxicity. Endometrial is not one of them. I have spent the morning reviewing aspects of endometrial carcinoma and it's treatment. To address your specific question directly (which I should have researched properly for the first comment I made), there has never been a human, controlled study addressing the issue of further chemo in women with advanced endometrial carcinoma who have experienced a complete response (CR) to chemo. Chemo is not normally recommended in the earlier stages of the disease authoritative current summary so I assume your relative had metastatic disease. The studies that have been done, and that have achieved CR's, used either fixed protocols for numbers of doses, or weekly protocols that continued until either CR or toxicity weekly until response. In this study, which is recent, the opening line is: "There is no generally accepted standard chemotherapy in treatment of advanced and recurrent endometrial carcinoma," so that gives a clue as to where we stand with the issue.

I reviewed about 200 studies in all; these are the most relevant, authoritative, and informative. I cannot make a link to the summary list of the others because it requires my professional subscription info for access.

Your relative has achieved an outstanding, and unusual, response. I wish her continued good health. If you would like for me to research some other aspect, please ask.

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Retired, Thanks for the thoughtful new comments. I hope you don't think I'm being pedantic, but I still don't feel like I've got a final resolution on this question. Constant seems to have found a citation (with which you have not found any fault) that extra chemo beyond the point of clean scans *does* help for at least some patients with Hodgkins disease. My relative does not have Hodgkins, so this is not directly on point, but it does seem to suggest that the "common sense" intuition that extra chemo can meaningfully fight cancers that are present but too small to detect has some merit. Ben A. has made a similar point. Maybe someone has done a similar study for my relative's cancer and conclusively found the opposite effect, but that's not what the doctor said. So as I sit here right now, I still don't know what the real answer is to this question (if it helps, the cancer is endometrial cancer) and the doctor doesn't seem to know either.

Note that I am not at all saying that I think the right answer is more chemo. It's totally possible to conclude that there may be some additional benefit to more chemo but that beyond the point we're at now (clean scans for a long time) those benefits do not justify the costs. But I'm really concerned (both for my relative and for humanity) that it seems like this decision is being made not based on a full weighing of the costs and benefits, but on an analysis that seems to refuse to consider, for no good reason that I can see, one possibly relevant factor.

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*First*, my apologies to Constant and Statistician, as suggested by David Balan. Their comments, especially those of Constant, have merit with regard to the question asked: are there conclusive studies that show chemotherapy beyond the point of detectable disease to be of no benefit? I allowed myself to speak from the point of view of the real practice of medicine rather than stay on topic, and I criticized those who did. My bad. I will try to do better in the future, as I sincerely enjoy participating with this group of obviously intelligent and informed people.

For the most part, the *practice* of medicine does not work like a science. It is extremely regulated, and severely policed, at several levels. I can assure you that the "fancy consulting oncologist" was aware not only of the studies that Constant has cited, but of all the studies ever published on the subject, many of which you could not read without being a subscriber to the journals, or going to a library that subscribes. He also was aware of his limitations in choosing chemotherapy regimens. While in the USA doctors may *legally* use any FDA-approved drug for any purpose they see fit (e.g., anti-hypertensives can be prescribed for growing hair), such use does not eliminate the civil liability, nor the professional risk of loss of license (regulated by one's peer doctors). In the case of dangerous drugs such as chemotherapy agents, there can even be criminal liability if the doctor is deemed to have caused loss of life by going outside proven guidelines. At least in the USA, you will not see an oncologist adding extra agents to a protocol or going beyond the goals of a protocol unless the patient is enrolled in a federally-approved human study group. I do not know the cancer-type of Balan's relative, and if I did, I surely would not be aware of the current chemo protocols; the oncologist did.

The method by which one could get the desired info from the doctor is this: once he had said, "there was "no evidence" that additional chemo, after there are no signs of disease, did *any* additional good at all, and that the treatments therefore should have been stopped a long time ago and should certainly stop now," the question would have been: "Are there any human-study protocols in progress investigating the use of chemo for this type of cancer beyond the point of undetectability, for which my relative could apply for enrollment?" I suspect that the oncologist was discussing the *particular* cancer in question, rather than cancers in general. In fact, I'd bet on it. The evidence that extra chemo beyond remission helps the outcome of Hodgins Disease (Constant's citation) is applicable to Balan's situation only if his relative has Hodgkins Disease, and is deemed to fall into the same group as discussed.

Lastly, unrelated to the discussion of evidence, but related to patient-doctor communication, those who have survived medical specialty training tend to be very defensive about justifying their opinions to those who are not in the fraternity. The many years of sleep deprivation, intellectual abuse, and stress related to providing services affecting human outcomes when one is still a novice tend to cause an attitude, whether or not expressed, of: "We'll discuss this on an equal level once you have your union card." It is similar to a career Marine being questioned about his battle plan by a lifelong civilian. I *realize* it is not right; I'm just saying.

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To kill the last abnormal cell, virtually all of the normal cells would die as well, along with the patient. If the immune system cannot handle the goal load of abnormal cells, there will be no success in the long run.

I think this is both true and irrelevant to the question of target duration of therapy. When drug therapy is used in the adjuvant setting (e.g., secondary to the resection of the primary tumor) it is often the case that there is no detectable disease remaining. One gives drug therapy with the idea of destroying undetected disease. Whether the specific drug therapy is a chemotherapy, an immunotherapy, or a specific antibody to some cell-surface marker overexpresed by cancer cells is irrelevant. In all cases, optimal duration of therapy is determined empirically. For example, the drug Herceptin is currently being evaluated in the HERA-2 study, which tests a one year course of Herceptin vs. a two year course of Herceptin. In this study, patient's primary tumors have been excised and they retain no detectable disease. Thus, retired urologist's statement:

I am saying that if our current methods cannot detect any other cancer cells, there is no defensible reason for further use of a harmful therapy

is not strictly accurate. This is simply what adjuvant therapy is. You are treating people with no detectable disease with the aim of preventing recurrence. Very toxic therapies are used in this setting all the time. As a practical matter, duration of therapy has been limited by therapeutic index. But as we develop therapies which, although potentially harmful, are not *as* harmful as chemo, it may make sense to extend the duration of adjuvant therapy, particularly in patients with high risk of recurrence (which does not necessarily correlate with the presence of detectable cancer cells).

(note: I am not an MD, but do work in drug development)

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Yes, I know that hypothesis testing is evil and will lose you points on this blog, but you're the one who admitted to trying to talk to an outsider!

The original problem was communicating with the doctor. I think the phrase "null hypothesis" would have helped you distinguish the two notions of "no evidence" to him. It's not a very precise belief; it's not like I have a hypothetical dialog in mind. But your response seems like such a dramatic non sequitur, I thought I'd try again.

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