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Thursday, December 17, 2015

On Therapeutic Treatments and Outcomes

This Blog's been awfully quiet and boring lately!

This post is another backgrounder for the upcoming post revisiting ketogenic diets and the treatment of cancer:  Ketones are NOT the End of Cancer. Tim Ferriss & Dominic D'Agostino Should Be More Responsible  (link will work when published).   The whole topic of ketone therapy for epilepsy provides a great example with which to discuss various concepts of therapies, and what can or cannot be extrapolated to non-therapeutic contexts.

Here is a very general definition of therapy:  treatment intended to relieve or heal a disorder.  (In this post I'll use therapy interchangeably with treatment or therapeutic treatment.)  Ignoring physical or psychological therapies per se for the sake of this discussion, one could still expand upon the above.   Since this is a backgrounder for a keto-for-cancer post, I'll use conditions that ketogenic diets have been used or suggested for, but some of the scenarios require other examples.

Before moving on, I just want to mention that there's nothing earth-shattering or analytical about this post.  I simply found the Keto for Cancer post getting exceedingly lengthy when including this material.  Also, I'd like to be able to refer to this in the future without necessarily discussing keto for cancer.  Without further ado...

Therapeutic Treatment Can:

  1. cure or reverse a condition
  2. reduce the severity of a condition by mitigating the underlying cause
  3. manage or improve the impact of the condition by reducing symptoms without affecting the cause
  4. slow a progressive condition or minimize/delay complications
  5. be used in conjunction with a primary therapy

These are not necessarily mutually exclusive "categories" for any given treatment, and I may have missed something as well. Furthermore, a comprehensive treatment may involve multiple therapies to address various facets of a condition.   Regardless of the distinctions drawn between therapeutic treatments, they are first and foremost intended to remedy some out-of-the-normal condition.  

1.  Cure:

When we talk about a cure for a condition, we are talking about the reversal or disappearance of signs and symptoms of that condition.  With epilepsy we are talking about the cessation of all seizures.  In this regard, a small percentage of children, usually under 10%, have been cured after a stint on the KD.  Further evidence of a cure is provided by the fact that seizures don't return once children are transitioned to normal diets.    I'm not entirely sure what the track record is for pharmaceutical therapies and/or whether these need to be lifelong, but if seizures do cease entirely the term "cure" is appropriate.   While cure is not always an absolute certainty -- seizures could return, and probably do in some instances, perhaps years down the road -- we can distinguish this from incurable diseases such as many genetic diseases.

When we think of curative treatments for acquired diseases, we think of things like antibiotics for infections.  A cure for either T1 or T2 diabetes would involve the restoration of insulin secretion by the pancreas.  When you start to think of things in the black-&-white of cure vs. not, it seems that the majority of therapies out there do not fall in this category.  One of the easiest ways to define a true cure is that the condition does not return when the treatment is stopped.   

If we were to look at the overall host of conditions, from arthritis, to hypertension, to hypothyroidism, to HIV, to various genetic abnormalities, to degenerative diseases such as Alzheimer's, the vast majority of therapies are not cures. Whether treating the underlying cause or the symptoms, the therapies lessen the severity of the condition in some fashion without reversing the underlying pathology completely or even addressing it at all.

2.  Treat the Underlying Cause:

If a cure is not possible, the next best treatment would be one that attacked the underlying cause of the condition, even if it couldn't wipe it out completely.  Depending on the nature of the condition, this could feasibly produce long term improvements on fewer or lower dose treatments, or perhaps even produce remission-like periods.  I'm not entirely certain, but I believe that the sizeable proportion of children who see a reduction in seizures with a KD will "enjoy" this reduction even after they are transitioned off the diet.  (I base this on the enduring nature of the cure, when it cures).   Other examples might be retroviral treatments for HIV, or cancer treatments that shrink tumor size.   These latter two examples attack the underlying disease/cause directly, but may have limited long term effect once stopped.  I'm going to throw another one out there, that I haven't talked about in a while, and that is early insulin treatment in T2 diabetes.  This seems to improve glucose tolerance to normal or near-normal levels in most subjects (early normoglycemia rates post EIT above 90%) by restoring β-cell function.  It may even be tentatively classified as a cure in many (normoglycemia at 1-2 year seen in ~30-40%).  Still, for the majority, hyperglycemia eventually returns after EIT is stopped (there's no indication of other lifestyle change here ...).  Since the EIT improved the subjects' own insulin secretion this can be seen as treating the underlying issue of relative insulin deficiency in T2 diabetes.

3. Manage Symptoms or Effects:

Treatments of this nature seem to make up the vast majority of treatments, particularly for what are considered chronic conditions and most incurable genetic diseases.  The underlying issue in T1 diabetes is a lack of insulin production.  All current (outside experimental) treatments seek damage control without restoring insulin secretion, and there is no expectation that exogenous insulin in an established T1 (not honeymoon period) will restore β-cells.   Treatments for genetic diseases, such as the GLUT1 transporter deficiency, usually fall in this category.  In the GLUT1 deficiency, KDs (and perhaps exogenous ketones) provide alternate energy for a brain that does not take up enough glucose for fuel.  This is a work around that manages the disease without affecting the underlying deficiency.

All of this is by no means intended to downplay the importance of such treatments.  Absent a cure or the ability to mitigate underlying causes, you still have the symptoms of the disease to deal with.  Insulin and thyroid hormone therapies and corn starch diets for certain glycogen storage diseases are examples of what are considered effective treatments that are not intended to alter the underlying pathology.    In addition to being used as stand-alone treatments, many of these may be used in conjunction with those in other "categories".  

4.  Slow the Progression of the Disease and/or Minimize or Delay Complications

This and the next type of treatment mostly apply to chronic and degenerative diseases.  Currently this would include diseases like Alzheimer's and ALS, and also certain cancers, particularly those very aggressive types and/or late stage diagnoses.  This would also include T2 diabetes to current common knowledge, though newer evidence and understanding strongly challenges whether this disease model.  Still, common treatment protocols are evaluated for retention of β-cell function with the eye on increasing time from diagnosis to insulin dependence of some nature.  

These treatments are hardly futile though they may seem so.  Unless quality of life is considerably impaired by prolonging the inevitable, most would value more time at higher functioning levels.   It is important, however, to compare apples to apples.  Any treatment that is effective at slowing progression of a disease should never be touted as treating the underlying cause or curative.  I am unaware of any medical protocols that even endeavor to do that.  Unfortunately, the dietary "let food be thy medicine" folks -- be they vegan, raw, keto, LCHF, _____-arian, XYZ-free -- do this all the time.

Lastly, there are certain diseases with complications that can be caused by other means and are thus distinct conditions in their own right.  Here I pretty much have T2 diabetes in mind, though I'm sure there are other examples.   Part of the fear of diabetes the unknown of developing complications such as neuropathy, CVD, etc.   The hope is that the treatment for the diabetes, e.g. controlling blood sugars, also results in fewer or the delayed development of such complications.  

5.  In Conjunction with a Primary Therapy

I'm lumping an awful lot in here, and as mentioned previously, many treatments that only treat symptoms certainly fall in this category as well.  But I have two more specific cases in mind.  First, I'm thinking of things like antiemetics for chemotherapy recipients.  The nausea is caused by the primary treatment, so you wouldn't treat a cancer patient who is not undergoing chemo with an antiemetic.  So this is a complementary therapy to mitigate side effects of the primary treatment.   Cancer treatment offers other examples such as drugs to boost the immune system or counter cachexia.    These also don't treat the cancer, but they may make the treatment more effective by keeping the rest of the person in a healthier condition.    Believe it or not, many conventional treatments come with suggestions for supplements that may make the treatment more effective, etc.  My reason for including this here is that ketogenic diets may well be useful in treating some cancers in conjunction with the usual chemotherapy/radiation treatment.  Whether it's as cut-and-dried as antiemetics being useless on their own to treat cancer remains to be seen.   It is feasible that immune boosting therapies may themselves be beneficial to treating cancers, and so too, could various diets, including ketogenic diets.

When all else fails ...

Without going into much detail, and certainly not exclusive of all of the above, I did want to at least mention palliative treatments.  These are treatments essentially to maximize quality of remaining life in the cases of terminal disease.  I mention this specifically because, again, in the case of ketogenic diets for cancer, the few human trials that have been conducted have generally been of "quality of life" type applications.  Yes, tumor progression has been assessed, but this has either not been the primary outcome assessed, and/or results have been inconclusive for treating the cancer per se.  More on that in a dedicated post.

Choosing Treatments?

When it comes to treatment, there is no one size fits all, even for seemingly simple things like what to take to relieve your run-of-the-mill headache.  It is always going to be a balance between benefits and adverse effects (immediate and/or potential) of treatment versus the outcome predicted for doing nothing.  People respond differently, so being human, doctors rely on statistics and practical experience -- both their own and that of other doctors -- when making recommendations.  This is the purpose of reporting case studies, clinical trials (moreso latter phases, but all can provide some useful information) and FAERS, the database for reporting adverse effects.   And let's not forget the patient!   An injection may be better than a pill on paper, but if the patient is unlikely to stick themselves, the pill is better for them.  One can envision various similar scenarios with treatments of different dosing schedules, etc.    Even seemingly innocuous side effects to one person could be prohibitive for another, and we all have different discomfort thresholds for things like pain, digestive upset, energy levels, etc.

In an ideal world there could be a hierarchy of treatments that is individualized to maximize benefits while minimizing costs (and I'm speaking mostly of non-financial ones).   The goal should always be cure, but beyond that there's not much cut and dried even if we limit ourselves to "time tested" remedies.

Let's, for a moment, take a relatively non-controversial condition as an example.  You have an abscessed tooth ... a bad infection!  This causes much pain.  Now imagine treating this periodically with some sort of anesthetic (e.g. benzocaine, novocaine, etc.).   All this does is dull the pain, but it does nothing to treat the infection causing the pain.  In this scenario, managing the symptoms is likely harmful in the long run as the infection will progress.  Ditto if you were to start popping anti-inflammatories.  Those might alleviate the pain for longer periods compared with topical anesthetics, and they do at least target an intermediate underlying cause of the pain, the inflammation, but they still don't treat the infection.  Bottom line, untreated, the infection likely worsens and can lead to permanent damage in the form of necrotic (dead) tissue, bone and eventually tooth loss.   Prior to tooth loss there are more drastic measures that can be taken ranging from locally applied antibiotics to gum surgery and even tissue reconstruction (e.g. bone grafting) to save the tooth.  The fact remains that had the infection been treated properly at or near its inception, the infection would likely have been cured with no long term effects.

Broadening this, if one were to have some sort of intractable infection, in a body part less expendable than a tooth (unless you talk to some dentists who may try to convince you that loss of a single tooth is equivalent to losing a finger), one can imagine that antibiotics to keep the infection knocked down may buy some time until an effective antibiotic is available.  Once it does become available, however, the "old treatment" is no longer a viable consideration.

Here is where I think we find many corollaries for T2 diabetes.   If you go to the Joslin website to this day, T2D is described as an incurable progressive disease.   While a 100% reversal may not be possible, the progression they describe is not inevitable, and there is much evidence for long-standing reversal of the disease to well within normal ranges at usual carbohydrate intake.  The oral medications such as sulfonylureas are for managing the hyperglycemia, but they appear to do nothing to treat the underlying pancreatic dysfunction ... and may even worsen it.  I might add that simply avoiding carbohydrates is not a cure either.   Unlike oral hypoglycemics, however, low carb and ketogenic diets are often promoted as a cure for diabetes which is simply not true.   Only a treatment that restores β-cell function can be considered a cure.  So the question is (and I'm not suggesting hard answers here in this post), how best to treat the condition.  Much as folks proposing/promoting all manner of treatments would like to believe, there is much unknown about the long term efficacy vs. "doing nothing", etc.  If it is possible to restore β-cell function, is managing hyperglycemia (by any means) not the equivalent to treating the pain of the tooth infection?  Does the underlying pathology worsen despite a reduction of symptoms in the immediate term?

One thing I'd like to see is a better re-evaluation (or maybe this exists and I'm just unaware) of older treatments.  Per my previous post on therapeutic safety, if more negative outcomes were accepted back when a treatment was the only option, when, if ever, are these re-evaluated when other treatments become available?   Should we even go so far as to remove some older treatments from the market, or include information with packaging that newer/safer treatments may be available?  

One last thought regarding lifestyle approaches and the "let food be thy medicine" adage.  While there are certainly those promoting certain foods for "healing" or as so-called superfoods, the vast majority of diets to "fix" or "cure" this or that disease focus on removing certain foods from ones diet.   Such approaches are generally untested, especially in anything that might be considered the long term in a broad population.  In every case I can think of, it's virtually impossible to find even a single human culture that even a segment of the population consumed such a diet.  We know that fasting, starvation and carbohydrate restriction were all treatments for diabetes (both types in various stages) prior to the discovery of insulin.  We also know that frank diabetes was a death sentence back then.  It is important to keep this in mind.  

Sorry for fading away at the end here, I'm trying to balance putting a few thoughts out there with not going into the details in this post.  

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