MD, PhD, FMedSci, FRSB, FRCP, FRCPEd

systematic review

Do you think that chiropractic is effective for asthma? I don’t – in fact, I know it isn’t because, in 2009, I have published a systematic review of the available RCTs which showed quite clearly that the best evidence suggested chiropractic was ineffective for that condition.

But this is clearly not true, might some enthusiasts reply. What is more, they can even refer to a 2010 systematic review which indicates that chiropractic is effective; its conclusions speak a very clear language: …the eight retrieved studies indicated that chiropractic care showed improvements in subjective measures and, to a lesser degree objective measures… How on earth can this be?

I would not be surprised, if chiropractors claimed the discrepancy is due to the fact that Prof Ernst is biased. Others might point out that the more recent review includes more studies and thus ought to be more reliable. The newer review does, in fact, have about twice the number of studies than mine.

How come? Were plenty of new RCTs published during the 12 months that lay between the two publications? The answer is NO. But why then the discrepant conclusions?

The answer is much less puzzling than you might think. The ‘alchemists of alternative medicine’ regularly succeed in smuggling non-evidence into such reviews in order to beautify the overall picture and confirm their wishful thinking. The case of chiropractic for asthma does by no means stand alone, but it is a classic example of how we are being misled by charlatans.

Anyone who reads the full text of the two reviews mentioned above will find that they do, in fact, include exactly the same amount of RCTs. The reason why they arrive at different conclusions is simple: the enthusiasts’ review added NON-EVIDENCE to the existing RCTs. To be precise, the authors included one case series, one case study, one survey, two randomized controlled trials (RCTs), one randomized patient and observer blinded cross-over trial, one single blind cross study design, and one self-reported impairment questionnaire.

Now, there is nothing wrong with case reports, case series, or surveys – except THEY TELL US NOTHING ABOUT EFFECTIVENESS. I would bet my last shirt that the authors know all of that; yet they make fairly firm and positive conclusions about effectiveness. As the RCT-results collectively happen to be negative, they even pretend that case reports etc. outweigh the findings of RCTs.

And why do they do that? Because they are interested in the truth, or because they don’t mind using alchemy in order to mislead us? Your guess is as good as mine.

Imagine a type of therapeutic intervention that has been shown to be useless. Let’s take surgery, for instance. Imagine that research had established with a high degree of certainty that surgical operations are ineffective. Imagine further that surgeons, once they can no longer hide this evidence, argue that good surgeons do much more than just operate: surgeons wash their hands which effectively reduces the risk of infections, they prescribe medications, they recommend rehabilitative and preventative treatments, etc. All of these measures are demonstratively effective in their own right, never mind the actual surgery. Therefore, surgeons could argue that the things surgeons do are demonstrably effective and helpful, even though surgery itself would be useless in this imagined scenario.

I am, of course, not for a minute claiming that surgery is rubbish, but I have used this rather extreme example to expose the flawed argument that is often used in alternative medicine for white-washing bogus treatments. The notion is that, because a particular alternative health care profession employs not just one but multiple forms of treatments, it should not be judged by the effectiveness of its signature-therapy, particularly if it happens to be ineffective.

This type of logic seems nowhere more prevalent than in the realm of chiropractic. Its founding father, D.D. Palmer, dreamt up the bizarre notion that all human disease is caused by ‘subluxations’ which require spinal manipulation for returning the ill person to good health. Consequently, most chiropractors see spinal manipulation as a panacea and use this type of treatment for almost 100% of their patients. In other words, spinal manipulation is as much the hallmark-therapy for chiropractic as surgery is for surgeons.

When someone points out that, for this or that condition, spinal manipulation is not of proven effectiveness or even of proven ineffectiveness, chiropractors have in recent years taken to answering as outlined above; they might say: WE DO ALL SORTS OF OTHER THINGS TOO, YOU KNOW. FOR INSTANCE, WE EMPLOY OTHER MANUAL TECHNIQUES, GIVE LIFE-STYLE ADVICE AND USE NO END OF PHYSIOTHERAPEUTIC INTERVENTIONS. YOU CANNOT SAY THAT THESE APPROACHES ARE BOGUS. THEREFORE CHIROPRACTIC IS FAR FROM USELESS.

To increase the chances of convincing us with this notion, they have, in recent months, produced dozens of ‘systematic reviews’ which allegedly prove their point. Here are some of the conclusions from these articles which usually get published in chiro-journals:

The use of manual techniques on children with respiratory diseases seems to be beneficial.

The majority of the included trials appeared to indicate that the parents of infants receiving manipulative therapies reported fewer hours crying per day than parents whose infants did not, based on contemporaneous crying diaries, and this difference was statistically significant.

A limited amount of research has been published that supports a role for manual therapy in improving postural stability and balance.

…a trial of chiropractic care for sufferers of autism is prudent and warranted.

This study found a level of B or fair evidence for manual manipulative therapy of the shoulder, shoulder girdle, and/or the FKC combined with multimodal or exercise therapy for rotator cuff injuries/disorders, disease, or dysfunction.

Chiropractic care is an alternative approach to the care of the child with colic.

There is a baseline of evidence that suggests chiropractic care improves cervical range of motion (cROM) and pain in the management of whiplash-associated disorders.

Results of the eight retrieved studies indicated that chiropractic care showed improvements [for asthma].

Personally, I find this kind of ‘logic’ irritatingly illogical. If we accept it as valid, the boundaries between sense and nonsense disappear, and our tools of differentiating between quackery and ethical health care become blunt.

The next step could then even be to claim that a homeopathic hospital must be a good thing because some of its clinicians occasionally also prescribe non-homeopathic treatments.

The efficacy or effectiveness of medical interventions is, of course, best tested in clinical trials. The principle of a clinical trial is fairly simple: typically, a group of patients is divided (preferably at random) into two subgroups, one (the ‘verum’ group) is treated with the experimental treatment and the other (the ‘control’ group) with another option (often a placebo), and the eventual outcomes of the two groups is compared. If done well, such studies are able to exclude biases and confounding factors such that their findings allow causal inference. In other words, they can tell us whether an outcome was caused by the intervention per se or by some other factor such as the natural history of the disease, regression towards the mean etc.

A clinical trial is a research tool for testing hypotheses; strictly speaking, it tests the ‘null-hypothesis’: “the experimental treatment generates the same outcomes as the treatment of the control group”. If the trial shows no difference between the outcomes of the two groups, the null-hypothesis is confirmed. In this case, we commonly speak of a negative result. If the experimental treatment was better than the control treatment, the null-hypothesis is rejected, and we commonly speak of a positive result. In other words, clinical trials can only generate positive or negative results, because the null-hypothesis must either be confirmed or rejected – there are no grey tones between the black of a negative and the white of a positive study.

For enthusiasts of alternative medicine, this can create a dilemma, particularly if there are lots of published studies with negative results. In this case, the totality of the available trial evidence is negative which means the treatment in question cannot be characterised as effective. It goes without saying that such an overall conclusion rubs the proponents of that therapy the wrong way. Consequently, they might look for ways to avoid this scenario.

One fairly obvious way of achieving this aim is to simply re-categorise the results. What, if we invented a new category? What, if we called some of the negative studies by a different name? What about NON-CONCLUSIVE?

That would be brilliant, wouldn’t it. We might end up with a simple statistic where the majority of the evidence is, after all, positive. And this, of course, would give the impression that the ineffective treatment in question is effective!

How exactly do we do this? We continue to call positive studies POSITIVE; we then call studies where the experimental treatment generated worst results than the control treatment (usually a placebo) NEGATIVE; and finally we call those studies where the experimental treatment created outcomes which were not different from placebo NON-CONCLUSIVE.

In the realm of alternative medicine, this ‘non-conclusive result’ method has recently become incredibly popular . Take homeopathy, for instance. The Faculty of Homeopathy proudly claim the following about clinical trials of homeopathy: Up to the end of 2011, there have been 164 peer-reviewed papers reporting randomised controlled trials (RCTs) in homeopathy. This represents research in 89 different medical conditions. Of those 164 RCT papers, 71 (43%) were positive, 9 (6%) negative and 80 (49%) non-conclusive.

This misleading nonsense was, of course, warmly received by homeopaths. The British Homeopathic Association, like many other organisations and individuals with an axe to grind lapped up the message and promptly repeated it: The body of evidence that exists shows that much more investigation is required – 43% of all the randomised controlled trials carried out have been positive, 6% negative and 49% inconclusive.

Let’s be clear what has happened here: the true percentage figures seem to show that 43% of studies (mostly of poor quality) suggest a positive result for homeopathy, while 57% of them (on average the ones of better quality) were negative. In other words, the majority of this evidence is negative. If we conducted a proper systematic review of this body of evidence, we would, of course, have to account for the quality of each study, and in this case we would have to conclude that homeopathy is not supported by sound evidence of effectiveness.

The little trick of applying the ‘NON-CONCLUSIVE’ method has thus turned this overall result upside down: black has become white! No wonder that it is so popular with proponents of all sorts of bogus treatments.

Cancer patients are bombarded with information about supplements which allegedly are effective for their condition. I estimate that 99.99% of this information is unreliable and much of it is outright dangerous. So, there is an urgent need for trustworthy, objective information. But which source can we trust?

The authors of a recent article in ‘INTEGRATIVE CANCER THARAPIES’ (the first journal to spearhead and focus on a new and growing movement in cancer treatment. The journal emphasizes scientific understanding of alternative medicine and traditional medicine therapies, and their responsible integration with conventional health care. Integrative care includes therapeutic interventions in diet, lifestyle, exercise, stress care, and nutritional supplements, as well as experimental vaccines, chrono-chemotherapy, and other advanced treatments) review the issue of dietary supplements in the treatment of cancer patients. They claim that the optimal approach is to discuss both the facts and the uncertainty with the patient, in order to reach a mutually informed decision. This sounds promising, and we might thus trust them to deliver something reliable.

In order to enable doctors and other health care professionals to have such discussion, the authors then report on the work of the ‘Clinical Practice Committee’ of ‘The Society of Integrative Oncology’. This panel undertook the challenge of providing basic information to physicians who wish to discuss these issues with their patients. A list of supplements that have the best suggestions of benefit was constructed by leading researchers and clinicians who have experience in using these supplements:

  1. curcumin,
  2. glutamine,
  3. vitamin D,
  4. maitake mushrooms,
  5. fish oil,
  6. green tea,
  7. milk thistle,
  8. astragalus,
  9. melatonin,
  10. probiotics.

The authors claim that their review includes basic information on each supplement, such as evidence on effectiveness and clinical trials, adverse effects, and interactions with medications. The information was constructed to provide an up-to-date base of knowledge, so that physicians and other health care providers would be aware of the supplements and be able to discuss realistic expectations and potential benefits and risks (my emphasis).

At first glance, this task looks ambitious but laudable; however, after studying the paper in some detail, I must admit that I have considerable problems taking it seriously – and here is why.

The first question I ask myself when reading the abstract is: Who are these “leading researchers and clinicians”? Surely such a consensus exercise crucially depends on who is being consulted. The article itself does not reveal who these experts are, merely that they are all members of the ‘Society of Integrative Oncology’. A little research reveals this organisation to be devoted to integrating all sorts of alternative therapies into cancer care. If we assume that the experts are identical with the authors of the review; one should point out that most of them are proponents of alternative medicine. This lack of critical input seems more than a little disconcerting.

My next questions are: How did they identify the 10 supplements and how did they evaluate the evidence for or against them? The article informs us that a 5-step procedure was employed:

1. Each clinician in this project was requested to construct a list of supplements that they tend to use frequently in their practice.

2. An initial list of close to 25 supplements was constructed. This list included supplements that have suggestions of some possible benefit and likely to carry minimal risk in cancer care.

3. From that long list, the group agreed on the 10 leading supplements that have the best suggestions of benefit.

4. Each participant selected 1 to 2 supplements that they have interest and experience in their use and wrote a manuscript related to the selected supplement in a uniformed and agreed format. The agreed format was constructed to provide a base of knowledge, so physicians and other health care providers would be able to discuss realistic expectations and potential benefits and risks with patients and families that seek that kind of information.

5. The revised document was circulated among participants for revisions and comments.

This method might look fine to proponents of alternative medicine, but from a scientific point of view, it is seriously wanting. Essentially, they asked those experts who are in favour of a given supplement to write a report to justify his/her preference. This method is not just open bias, it formally invites bias.

Predictably then, the reviews of the 10 chosen supplements are woefully inadequate. These is no evidence of a systematic approach; the cited evidence is demonstrably cherry-picked; there is a complete lack of critical analysis; for several supplements, clinical data are virtually absent without the authors finding this embarrassing void a reason for concern; dosage recommendations are often vague and naïve, to say the least (for instance, for milk thistle: 200 to 400 mg per day – without indication of what the named weight range refers to, the fresh plant, dried powder, extract…?); safety data are incomplete and nobody seems to mind that supplements are not subject to systematic post-marketing surveillance; the text is full of naïve thinking and contradictions (e.g.”There are no reported side effects of the mushroom extracts or the Maitake D-fraction. As Maitake may lower blood sugar, it should be used with caution in patients with diabetes“); evidence suggesting that a given supplement might reduce the risk of cancer is presented as though this means it is an effective treatment for an existing cancer; cancer is usually treated as though it is one disease entity without any differentiation of different cancer types.

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. But I do wonder, isn’t being in favour of integrating half-baked nonsense into cancer care and being selected for one’s favourable attitude towards certain supplements already a conflict of interest?

In any case, the review is in my view not of sufficient rigor to form the basis for well-informed discussions with patients. The authors of the review cite a guideline by the ‘Society of Integrative Oncology’ for the use of supplements in cancer care which states: For cancer patients who wish to use nutritional supplements, including botanicals for purported antitumor effects, it is recommended that they consult a trained professional. During the consultation, the professional should provide support, discuss realistic expectations, and explore potential benefits and risks. It is recommended that use of those agents occur only in the context of clinical trials, recognized nutritional guidelines, clinical evaluation of the risk/benefit ratio based on available evidence, and close monitoring of adverse effects. It seems to me that, with this review, the authors have not adhered to their own guideline.

Criticising the work of others is perhaps not very difficult, however, doing a better job usually is. So, can I offer anything that is better than the above criticised review? The answer is YES. Our initiative ‘CAM cancer’ provides up-to-date, concise and evidence-based systematic reviews of many supplements and other alternative treatments that cancer patients are likely to hear about. Their conclusions are not nearly as uncritically positive as those of the article in ‘INTEGRATIVE CANCER THERAPIES’.

I happen to believe that it is important for cancer patients to have access to reliable information and that it is unethical to mislead them with biased accounts about the value of any treatment.

I am sure, we have all heard it hundreds of times: THERE ARE IMPORTANT LINKS BETWEEN OUR DIET AND CERTAIN CANCERS. The evidence for this statement seems fairly compelling. Yet it also is complex and often confusing.

A recent review, for instance, suggested that fruits (particularly citrus) and vegetable consumption may be beneficial in the primary prevention of pancreatic cancer, the consumption of whole grains has been shown to reduce the risk and fortification of whole grains with folate may confer further protection. Red meat, cooked at high temperatures, should be avoided, and replaced with poultry or fish. Total fat should be reduced. The use of curcumin and other flavonoids should be encouraged in the diet. Another equally recent review, however, indicated that there is no conclusive evidence as an independent risk factor for isolated nutrients versus adoption of dietary patterns for cancer risk. Cancer colon risk derived from meat intake is influenced by both total intake and its frequency. The interaction of phenolic compounds on metabolic and signalling pathways seems to exert an inhibitory effect on cell proliferation and tumor metastasis and induces apoptosis in various types of cancer cells, including colon, lung, prostate, hepatocellular or breast cancer. A third recent review concluded that cruciferous vegetable intake protects against cancer of the colon, while a forth review suggested that the Mediterranean dietary pattern and diets composed largely of vegetables, fruit, fish, and soy are associated with a decreased risk of breast cancer. There was no evidence of an association between traditional dietary patterns and risk of breast cancer.

Not least based on these mixed messages from the scientific literature, an entire industry has developed selling uncounted alternative cancer-diets and dietary supplements to desperate patients and consumers. They promise much more than just cancer prevention, in fact, leave little doubt about the notion that cancer might be curable by diet. Here are just a few quotes from the thousands of websites promoting alternative cancer diets:

  • The Ketogenic Diet is believed capable of starving cancer cells to death, and thus capable of restricting tumour development.
  • a more alkaline body makes it difficult for tumors to grow.
  • Budwig diet: This diet was developed by Dr. Johanna Budwig who was nominated for the noble Prize sixth times. The diet is intended as a preventative as well as an alternative cancer treatment.
  • the Gerson Therapy naturally reactivates your body’s magnificent ability to heal itself – with no damaging side effects. This a powerful, natural treatment boosts the body’s own immune system to heal cancer, arthritis, heart disease, allergies, and many other degenerative diseases. Dr. Max Gerson developed the Gerson Therapy in the 1930s, initially as a treatment for his own debilitating migraines, and eventually as a treatment for degenerative diseases such as skin tuberculosis, diabetes and, most famously, cancer.
  • the concept of macrobiotics is much more than an alternative diet for cancer, or any other illness, but rather the ancient Chinese belief that all life, indeed the whole universe, is a balance of two opposing forces Yin and Yang.

Confused? Yes, I do worry how many cancer patients listen to these claims and pin their hopes on one of these diets. But what exactly does the evidence tell us about them?

A German team of researchers evaluated the following alternative cancer-diets: raw vegetables and fruits, alkaline diet, macrobiotics, Gerson’s regime, Budwig’s and low carbohydrate or ketogenic diet. Their extensive searches of the published literature failed to find clinical evidence supporting any of the diets. Furthermore, case reports and pre-clinical data pointed to the potential harm of some of these diets. The authors concluded that considering the lack of evidence of benefits from cancer diets and potential harm by malnutrition, oncologists should engage more in counselling cancer patients on such diets.

In other words, alternative cancer diets – and I mean not just the ones mentioned above, but all of them – are not supported by good evidence for efficacy as a treatment or prevention of any type of cancer. In addition, they might also cause harm.

What follows is obvious: cancer patients should take sound nutritional advice and adopt a healthy general life-style. But they should run a mile as soon as anyone suggests an alternative dietary cure for their disease.

There is not a discussion about homeopathy where an apologist would eventually state: HOMEOPATHY CANNOT BE A PLACEBO, BECAUSE IT WORKS IN ANIMALS!!! Those who are not well-versed in this subject tend to be impressed, and the argument has won many consumers over to the dark side, I am sure. But is it really correct?

The short answer to this question is NO.

Pavlov discovered the phenomenon of ‘conditioning’ in animals, and ‘conditioning’ is considered to be a major part of the placebo-response. So, depending on the circumstances, animals do respond to placebo (my dog, for instance, used to go into a distinct depressive mood when he saw me packing a suitcase).

Then there is the fact that the animal’s response might be less important than the owner’s reaction to homeopathic treatment. This is particularly important with pets, of course. Homeopathy-believing pet owners might over-interpret the pet’s response and report that the homeopathic remedy has worked wonders when, in fact, it has made no difference.

Finally, there may be some situations where neither of the above two phenomena can play a decisive role. Homeopaths like to cite studies where entire herds of cows were treated homeopathically to prevent mastitis, a common problem in milk-cows. It is unlikely that conditioning or wishful thinking of the owner are decisive in such a study. Let’s see whether homeopathy-promoters will also be fond of this new study of exactly this subject.

New Zealand vets compared clinical and bacteriological cure rates of clinical mastitis following treatment with either antimicrobials or homeopathic preparations. They used 7 spring-calving herds from the Waikato region of New Zealand to source cases of clinical mastitis (n=263 glands) during the first 90 days following calving. Duplicate milk samples were collected for bacteriology from each clinically infected gland at diagnosis and 25 (SD 5.3) days after the initial treatment. Affected glands were treated with either an antimicrobial formulation or a homeopathic remedy. Generalised linear models with binomial error distribution and logit link were used to analyse the proportion of cows that presented clinical treatment cures and the proportion of glands that were classified as bacteriological cures, based on initial and post-treatment milk samples.

The results show that the mean cumulative incidence of clinical mastitis was 7% (range 2-13% across herds) of cows. Streptococcus uberis was the most common pathogen isolated from culture-positive samples from affected glands (140/209; 67%). The clinical cure rate was higher for cows treated with antimicrobials (107/113; 95%) than for cows treated with homeopathic remedies (72/114; 63%) (p<0.001) based on the observance of clinical signs following initial treatment. Across all pathogen types bacteriological cure rate at gland level was higher for those cows treated with antimicrobials (75/102; 74%) than for those treated with a homeopathic preparation (39/107; 36%) (p<0.001).

The authors conclude that homeopathic remedies had significantly lower clinical and bacteriological cure rates compared with antimicrobials when used to treat post-calving clinical mastitis where S. uberis was the most common pathogen. The proportion of cows that needed retreatment was significantly higher for the homeopathic treated cows. This, combined with lower bacteriological cure rates, has implications for duration of infection, individual cow somatic cell count, costs associated with treatment and animal welfare.

Yes, I know, this is just one single study, and we need to consider the totality of the reliable evidence. Currently, there are 203 clinical trials of homeopathic treatments of animals; and they are being reviewed at the very moment (unfortunately by a team that is not known for its objective stance on homeopathy). So, we will have to wait and see. When, in 1999, A. Vickers reviewed all per-clinical studies, including those on animals, he concluded that there is a lack of independent replication of any pre-clinical research in homoeopathy. In the few instances where a research team has set out to replicate the work of another, either the results were negative or the methodology was questionable.

All this is to say that, until truly convincing evidence to the contrary is available, the homeopaths’ argument ‘HOMEOPATHY CANNOT BE A PLACEBO, BECAUSE IT WORKS IN ANIMALS!!!’ is, in my view, as weak as the dilution of their remedies.

One of the questions I hear regularly is ‘HOW DO THE EFFECTS OF THIS ALTERNATIVE TREATMENT COMPARE TO THOSE OF CONVENTIONAL OPTIONS’? Take acupuncture in the management of osteoarthritis, for instance. There is some encouraging evidence suggesting it might help. The most recent systematic review that I know of concluded that “acupuncture provided significantly better relief from knee osteoarthritis pain and a larger improvement in function than sham acupuncture, standard care treatment, or waiting for further treatment.” However, in order to estimate its value in practice, we ought to know whether it is as good as or perhaps even better than standard treatments. In other words, what we really want to know is its relative effectiveness.

Data to evaluate the relative effectiveness of acupuncture or other alternative therapies are hard to come by. Ideally, one would require clinical trials which provide direct comparisons between the alternative and the conventional therapy. Sadly, such studies are scarce or even non-existent. Therefore we might have to rely on more indirect evidence. A new paper could be a step in the right direction.

The aim of this systematic review was to critically evaluate existing osteoarthritis (OA) management guidelines to better understand potential issues and barriers.

A systematic review of the literature in MEDLINE published from January 1, 2000 to April 1, 2013 was performed and supplemented by bibliographic reviews, following PRISMA guidelines and a written protocol. Following initial title and abstract screening, two authors independently reviewed full-text articles; a third settled disagreements. Two independent reviewers extracted data into a standardized form. Two authors independently assessed guideline quality; three generated summary recommendations based on the extracted guideline data.

Overall, 16 articles were included in the final review. There was broad agreement on recommendations by the various organizations. For non-pharmacologic modalities, education/self-management, exercise, weight loss if overweight, walking aids as indicated, and thermal modalities were widely recommended. For appropriate patients, joint replacement was recommended; arthroscopy with debridement was not recommended for symptomatic knee OA. Pharmacologic modalities most recommended included acetaminophen/paracetamol for first line treatment and oral or topical NSAIDs for second line therapy. Intra-articular corticosteroids were generally recommended for hip and knee OA. Controversy remains about the use of acupuncture, knee braces, heel wedges, intra-articular hyaluronans, and glucosamine/chondroitin.

I think that this tells us fairly clearly that, compared to other options, acupuncture is not considered to be an overwhelmingly effective treatment for osteoarthritis by those who understand that condition best. Several other therapies seem to be preferable because the evidence is clearer and stronger and their effect sizes is larger. This, I think begs the question whether it is in the best interest of patients or indeed ethical to ignore this knowledge and recommend acupuncture as a treatment of osteoarthritis.

More generally speaking, we should always bear in mind that it is not enough proving a therapy to be effective; we usually also need to consider what else is on offer. And if you think that this is rather complex, you are, of course, correct – but wait until someone mentions issues such as safety and cost of all the relevant therapeutic options.

Cancer patients are understandably desperate and leave no stone unturned to improve their prognosis. Thus they become easy prey of charlatans who claim that this or that alternative therapy will cure them or improve their outlook. One of the most popular alternative cancer therapies is mistletoe, a treatment dreamt up by Rudolf Steiner on the basis of the ‘like cures like’ principle: the mistletoe plant grows on a host tree like a cancer in the human body. One of many websites on this subject, for instance, states:

Mistletoe therapy

  • integrates with conventional cancer treatments
  • can be used for a wide range of cancers
  • may be started at any stage of the illness….

potential benefits…include:

  • Improved quality of life
  • generally feeling better
  • increased appetite and weight
  • less tired/more energy
  • reduced pain
  • better sleep pattern
  • felling more hopeful and motivated
  • reduced adverse effects from chemo and radiotherapy
  • reduced risk of cancer spread and recurrence
  • increased life expectancy.

Mistletoe extracts have been shown in studies to:

  • stimulate the immune system
  • cause cancer cell death
  • protect healthy cells against harmful effects of radiation and chemotherapy.

In fact, the debate about the efficacy of mistletoe either as a cancer cure, a supportive therapy, or a palliative measure is often less than rational and seems never-ending.

The latest contribution to this saga comes from US oncologists who published a phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC). The trial was aimed at evaluating: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM.

A total of 44 study participants were enrolled; 20 were treated in stage I (mistletoe dose escalation phase) and 24 in stage II (gemcitabine dose escalation phase). All patients had stage IV disease; the majority had received previous chemo-, hormonal, immunological, or radiation therapy, and 23% were chemotherapy-naïve.

Patients were treated with increasing doses of a mistletoe-extract (HELIXOR Apis (A), growing on fir trees) plus a fixed GEM dose in stage I, and with increasing doses of GEM plus a fixed dose of mistletoe in stage II. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery.

The results show that dose-limiting toxicities were neutropenia, thrombocytopenia, acute renal failure, and cellulitis, attributed to mistletoe. GEM 1380 mg/m2 and mistletoe 250 mg combined were the MTD. Of the 44 patients, 24 developed non-neutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation.

6% of patients showed a partial response, and 42% had stable disease. Of the 44 study participants, three died during the study, 10 participants requested to terminate the study, 23 participants progressed while on study, one terminated the study due to a dose limiting toxicity, 6 left due to complicating disease issues which may be tied to progression, and one voluntarily withdrew.

An attempt was made to follow study subjects once they terminated study treatment until death. At the last attempt to contact former participants, three were still alive and five others were lost to follow-up. The median time to death of any cause was approximately 200 days. Compliance with mistletoe injections was high.

The authors explain that a partial response rate of 6% is comparable to what would be expected from single agent gemcitabine in this population of patients with advanced, mostly heavily pretreated carcinomas. The median survival from study enrollment of about 200 days is within the range of what would be expected from single agent gemcitabine.

The authors concluded that GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response  is similar to GEM alone.

These results are hardly encouraging but they originate from just one (not particularly rigorous) study and might thus not be reliable. So, what does the totality of the reliable evidence tell us? Our 2003 systematic review of 10 RCTs found that none of the methodologically stronger trials exhibited efficacy in terms of quality of life, survival or other outcome measures. Rigorous trials of mistletoe extracts fail to demonstrate efficacy of this therapy.

Will this stop the highly lucrative trade in mistletoe extracts? will it prevent desperate cancer patients being misled about the value of mistletoe treatment? I fear not.

Times of celebration are often also times of over-indulgence and subsequent suffering. Who would not know, for instance, how a hangover can spoil one’s pleasure at the start of a new year? But where is the research that addresses this problem? Scientists seem to be cynically devoid of sympathy for the hangover-victim – well, not all scientists.

During the course of my research-career, I must have conducted well over 60 clinical trials, but none was remotely as entertaining as the one my Exeter-team did several years ago to test whether an artichoke extract is effective in preventing the signs and symptoms of alcohol-induced hangover.

We recruited healthy adult volunteers from our own ranks to participate in a randomized double-blind crossover trial. Participants received either 3 capsules of commercially available standardized artichoke extract or indistinguishable, inert placebo capsules immediately before and after alcohol exposure. After a 1-week washout period the volunteers received the opposite treatment. Each participant predefined the type and amount of alcoholic beverage that would give him/her a hangover and ate the same meal before commencing alcohol consumption on the two study days. The primary outcome measure was the difference in hangover severity scores between the artichoke extract and placebo interventions. Secondary outcome measures were differences between the interventions in scores using a mood profile questionnaire and cognitive performance tests administered 1 hour before and 10 hours after alcohol exposure.

The mean number of alcohol units consumed per person during treatment with artichoke extract and placebo were  10.7 and 10.5 respectively, equivalent to 1.2 g of alcohol per kilogram body weight. The volume of non-alcoholic drink consumed and the duration of sleep after the binge were similar during the artichoke extract and placebo interventions. The hangovers we experienced the mornings after our alcohol exposure were monumental but unaffected by the treatments. None of the outcome measures differed significantly between interventions. Adverse events of the treatment were rare and were mild and transient. Our results therefore suggested that artichoke extract is not effective in preventing the signs and symptoms of alcohol-induced hangover.

While it was great fun to obtain ethic’s approval and run this trial, the results of our two binges in the name of science were, of course, a disappointment. As diligent researchers we felt we had to do a little more for the poor victims of over-indulgence.

We thus decided to conduct a systematic review aimed at assessing the clinical evidence on the effectiveness of any medical intervention for preventing or treating alcohol hangover. We conducted systematic searches to identify all RCTs of any medical intervention for preventing or treating alcohol hangover. Fifteen potentially relevant trials were found. Seven publications failed to meet all inclusion criteria. Eight RCTs assessing 8 different interventions were reviewed. The agents tested were propranolol, tropisetron, tolfenamic acid, fructose or glucose as well as the dietary supplements Borago officinalis (borage), Cynara scolymus (artichoke), Opuntia ficus-indica (prickly pear), and a yeast based preparation. All studies were double blind. Significant intergroup differences for overall symptom scores and individual symptoms were reported only for tolfenamic acid, gamma linolenic acid from borage, and a yeast based preparation.

We concluded that the most effective way to avoid the symptoms of alcohol induced hangover is to practise abstinence or moderation.

WISE WORDS PERHAPS, BUT EASIER SAID THAN DONE, I’M SURE.

Many dietary supplements are heavily promoted for the prevention of chronic diseases, including cardiovascular disease (CVD) and cancer. But do they actually work or are they just raising false hopes? The evidence on this subject is confusing and proponents of both camps produce data which seemingly support their claims. In this situation, we need an independent analysis of the totality of the evidence to guide us. And one such review has just become available

The purpose of this article was to systematically review evidence for the use of multivitamins or single nutrients and functionally related nutrient pairs for the primary prevention of CVD and cancer in the general population.

The authors searched 5 databases to identify literature that was published between 2005 and January 29, 2013. They also examined the references from the previous reviews and other relevant articles to identify additional studies. In addition, they searched Web sites of government agencies and other organizations for grey literature. Two investigators independently reviewed identified abstracts and full-text articles against a set of a priori inclusion and quality criteria. One investigator abstracted data into an evidence table and a second investigator checked these data. The researchers then qualitatively and quantitatively synthesized the results for 4 key questions and grouped the included studies by study supplement. Finally, they conducted meta-analyses using Mantel-Haenzel fixed effects models for overall cancer incidence, CVD incidence, and all-cause mortality.

103 articles representing 26 unique studies met the inclusion criteria. Very few studies examined the use of multivitamin supplements. Two trials showed a protective effect against cancer in men; only one of these trials included women and found no effect. No effects of treatment were seen on CVD or all-cause mortality.

Beta-carotene showed a negative effect on lung cancer incidence and mortality among individuals at high risk for lung cancer at baseline (i.e., smokers and asbestos-exposed workers); this effect was persistent even when combined with vitamin A or E. Trials of vitamin E supplementation showed mixed results and altogether had no overall effect on cancer, CVD, or all-cause mortality. Only one of two studies included selenium trials showed a beneficial effect for colorectal and prostate cancer; however, this trial had a small sample size. The few studies addressing folic acid, vitamin C, and vitamin A showed no effect on CVD, cancer, and mortality. Vitamin D and/or calcium supplementation also showed no overall effect on CVD, cancer, and mortality. Harms were infrequently reported and aside from limited paradoxical effects for some supplements, were not considered serious.

The authors’ conclusion are less than encouraging: there are a limited number of trials examining the effects of dietary supplements on the primary prevention of CVD and cancer; the majority showed no effect in healthy populations. Clinical heterogeneity of included studies limits generalizability of results to the general primary care population. Results from trials in at-risk populations discourage additional studies for particular supplements (e.g., beta-carotene); however, future research in general primary care populations and on other supplements is required to address research gaps.

A brand-new RCT provides further information, specifically on the question whether oral multivitamins are effective for the secondary prevention of cardiovascular events. In total, 1708 patients aged 50 years or older who had myocardial infarction (MI) at least 6 weeks earlier with elevated serum creatinine levels were randomly assigned to an oral, 28-component, high-dose multivitamin and multi-mineral mixture or placebo. The primary end point was time to death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. Median follow-up was 55 months. Patients received treatments for a median of 31 months in the vitamin group and 35 months in the placebo group. 76% and 76% patients in the vitamin and placebo groups completed at least 1 year of oral therapy, and 47% and 50% patients completed at least 3 years. Totals of 46% and 46% patients in both groups discontinued the vitamin regimen, and 17% of patients withdrew from the study.

The primary end point occurred in 27% patients in the vitamin group and 30% in the placebo group. No evidence suggested harm from vitamin therapy in any category of adverse events. The authors of this RCT concluded that high-dose oral multivitamins and multiminerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. However, this conclusion is tempered by the nonadherence rate.

These findings are sobering and in stark contrast to what the multi-billion dollar supplement industry promotes. The misinformation in this area is monumental. Here is what one site advertises for heart disease:

Vitamin C could be helpful, limit dosage to 100 to 500 mg a day.

Vitamin E works better with CoQ10 to reduce inflammation in heart disease. Limit vitamin E to maximum 30 to 200 units a few times a week. Use a natural vitamin E complex rather than synthetic products.

CoQ10 may be helpful in heart disease, especially in combination with vitamin E. I would recommend limiting the dosage of Coenzyme Q10 to 30 mg daily or 50 mg three or four times a week.

B complex vitamins reduce levels of homocysteine. Keep the vitamin B dosages low, perhaps one or two times the RDA. Taking higher amounts may not necessary be a healthier approach.

Curcumin protects rat heart tissue against damage from low oxygen supply, and the protective effect could be attributed to its antioxidant properties. Curcumin is derived from turmeric, which is often used in curries.

Garlic could be an effective treatment for lowering cholesterol and triglyceride levels for patients with a history or risk of cardiovascular disease, especially as a long term strategy.

Terminalia arjuna, an Indian medicinal plant, has been reported to have beneficial effects in patients with ischemic heart disease in a number of small studies. Arjuna has been tested in angina and could help reduce chest pain.
Magnesium is a mineral that could help some individuals. It is reasonable to encourage diets high in magnesium as a potential means to lower the risk of coronary heart disease.

Danshen used in China for heart conditions.

And in the area of cancer, the choice is even more wide and audacious as this web-site for example demonstrates.

So, the picture that emerges from all this seems fairly clear. Despite thousands of claims to the contrary, dietary supplements are useless in preventing cardiovascular diseases or cancer. All they do produce, I am afraid, is rather expensive urine.

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