MD, PhD, FMedSci, FRSB, FRCP, FRCPEd.

clinical trial

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Many experts doubt that acupuncture generates the many positive health effects that are being claimed by enthusiasts. Yet, few consider that acupuncture might not be merely useless but could even make things worse. Here is a trial that seems to suggest exactly that.

This study evaluated whether combining two so-called alternative medicines (SCAMs), acupuncture and massage, reduce postoperative stress, pain, anxiety, muscle tension, and fatigue more than massage alone.

Patients undergoing autologous tissue breast reconstruction were randomly assigned to one of two postoperative SCAMs for three consecutive days. All participants were observed for up to 3 months. Forty-two participants were recruited from January 29, 2016 to July 11, 2018. Twenty-one participants were randomly assigned to massage alone and 21 to massage and acupuncture. Stress, anxiety, relaxation, nausea, fatigue, pain, and mood (score 0-10) were measured at enrollment before surgery and postoperative days 1, 2, and 3 before and after the intervention. Patient satisfaction was evaluated.

Stress decreased from baseline for both Massage-Only Group and Massage+Acupuncture Group after each treatment intervention. Change in stress score from baseline decreased significantly more in the Massage-Only Group at pretreatment and posttreatment. After adjustment for baseline values, change in fatigue, anxiety, relaxation, nausea, pain, and mood scores did not differ between groups. When patients were asked whether they would recommend the study, 100% (19/19) of Massage-Only Group and 94% (17/18) of Massage+Acupuncture Group responded yes.

The authors concluded tha no additive beneficial effects were observed with addition of acupuncture to massage for pain, anxiety, relaxation, nausea, fatigue, and mood. Combined massage and acupuncture was not as effective in reducing stress as massage alone, although both groups had significant stress reduction. These findings indicate a need for larger studies to explore these therapies further.

I recently went to the supermarket to find out whether combining two bank notes (£10 + £5) can buy more goods than one £10 note alone. What I found was interesting: the former did indeed purchase more than the latter. Because I am a scientist, I did not stop there; I went to a total of 10 shops and my initial finding was confirmed each time: A+B results in more than A alone.

It stands to reason that the same thing happens with clinical trials. We even tested this hypothesis in a systematic review entitled ‘A trial design that generates only ”positive” results‘. Here is our abstract:

In this article, we test the hypothesis that randomized clinical trials of acupuncture for pain with certain design features (A + B versus B) are likely to generate false positive results. Based on electronic searches in six databases, 13 studies were found that met our inclusion criteria. They all suggested that acupuncture is effective (one only showing a positive trend, all others had significant results). We conclude that the ‘A + B versus B’ design is prone to false positive results and discuss the design features that might prevent or exacerbate this problem.

But why is this not so with the above-mentioned study?

Why is, in this instance, A even more that A+B?

There are, of course, several possible answers. To use my supermarket example again, the most obvious one is that B is not a £5 note but a negative amount, a dept note, in other words: A + B can only be less than A alone, if B is a minus number. In the context of the clinical trail, this means acupuncture must have caused a negative effect.

But is that possible? Evidently yes! Many patients don’t like needles and experience stress at the idea of a therapist sticking one into their body. Thus acupuncture would cause stress, and stress would have a negative effect on all the other parameters quantified in the study (pain, anxiety, muscle tension, and fatigue).

My conclusion: in certain situations, acupuncture is more than just useless; it makes things worse.

Melatonin is an indolamine hormone which is secreted from the human pineal gland during night-time acting as physiological regulator. In many countries, dietary supplements containing synthetically produced melatonin are available. Melatonin is being promoted as a treatment of a range of conditions, including virtually all types of cancer.

One website, for instance, states that the anti-cancer benefits of melatonin aren’t just indirect; this miracle molecule is also classified as a directly cytotoxic hormone and anti-cancer agent. Studies have referred to melatonin as a “full-service anti-cancer agent” due to its ability to inhibit the initiation of cell mutation and cancer growth, and to halt the progression and metastasis of cancer cell colonies.

Such statements sound far too good to be true. So, let’s have a look and find out what the evidence tells us. Test-tube experiments suggest that melatonin has anti-cancer effects.[1] Its actions include the advancement of apoptosis, the arrest of the cell cycle, inhibition of metastasis, and antioxidant activity.[2]

A review of 21 clinical trials of melatonin for cancer found positive effects for complete response, partial response, and stable disease. In trials combining melatonin with chemotherapy, adjuvant melatonin therapy decreased 1-year mortality and improved outcomes of complete response, partial response, and stable disease. In these studies, melatonin also significantly reduced asthenia, leukopenia, nausea and vomiting, hypotension, and thrombocytopenia. The authors concluded that melatonin may benefit cancer patients who are also receiving chemotherapy, radiotherapy, supportive therapy, or palliative therapy by improving survival and ameliorating the side effects of chemotherapy.[3]

A further systematic review of RCTs of melatonin in solid tumour cancer patients evaluated its effect on one-year survival. Ten trials were included of melatonin as either sole treatment or as adjunct treatment. Melatonin reduced the risk of death at 1 year. Effects were consistent across melatonin dose, and type of cancer. No severe adverse events were reported.[4]

A 2012 systematic review confirmed these findings by concluding that Melatonin as an adjuvant therapy for cancer led to substantial improvements in tumor remission, 1-year survival, and alleviation of radiochemotherapy-related side effects.[5]

Finally, a 2020 review concluded that melatonin in combination with anticancer agents may improve the efficacy of routine medicine and survival rate of patients with cancer. [6] Apart from its direct anticancer potential, melatonin also seems to reduce chemotherapy toxicity, while improving its therapeutic efficacy.[7]

So, is this evidence compelling? While all this does indeed sound encouraging, it is necessary to mention several important caveats:

  • The primary studies of melatonin suffer from several methodological shortcomings.
  • Their vast majority originate from one single research group.
  • In recent years, there have been no further clinical studies trying to replicate the initial findings.

This means that definitive trials are still missing, and it would seem wise to interpret the existing evidence with great caution.

References

[1] Kong X, Gao R, Wang Z, Wang X, Fang Y, Gao J, Reiter RJ, Wang J. Melatonin: A Potential Therapeutic Option for Breast Cancer. Trends Endocrinol Metab. 2020 Sep 3:S1043-2760(20)30155-7. doi: 10.1016/j.tem.2020.08.001. Epub ahead of print. PMID: 32893084.

[2] Samanta S. Melatonin: an endogenous miraculous indolamine, fights against cancer progression. J Cancer Res Clin Oncol. 2020 Aug;146(8):1893-1922. doi: 10.1007/s00432-020-03292-w. Epub 2020 Jun 24. PMID: 32583237.

[3] Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, Mills E. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2012 Dec;11(4):293-303. doi: 10.1177/1534735411425484. Epub 2011 Oct 21. PMID: 22019490.

[4] Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005 Nov;39(4):360-6. doi: 10.1111/j.1600-079X.2005.00258.x. PMID: 16207291.

[5] Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012 May;69(5):1213-20. doi: 10.1007/s00280-012-1828-8. Epub 2012 Jan 24. PMID: 22271210.

[6] Pourhanifeh MH, Mehrzadi S, Kamali M, Hosseinzadeh A. Melatonin and gastrointestinal cancers: Current evidence based on underlying signaling pathways. Eur J Pharmacol. 2020 Nov 5;886:173471. doi: 10.1016/j.ejphar.2020.173471. Epub 2020 Aug 30. PMID: 32877658.

[7] Iravani S, Eslami P, Dooghaie Moghadam A, Moazzami B, Mehrvar A, Hashemi MR, Mansour-Ghanaei F, Mansour-Ghanaei A, Majidzadeh-A K. The Role of Melatonin in Colorectal Cancer. J Gastrointest Cancer. 2020 Sep;51(3):748-753. doi: 10.1007/s12029-019-00336-4. PMID: 31792737.

Alzheimer is a devastating condition. Despite much research, we are still far from being able to effectively prevent or treat it. Some claim that relatively simple dietary interventions might work. What does the evidence tell us?

The aim of this systematic review was to evaluate the effect of dietary interventions on the cognitive performance of individuals with Alzheimer’s disease (AD).  Thirty-two RCT could be included.

The findings show that a wide range of supplements have been submitted to testing in RCTs. Most of the supplements seem to be less than useful. However, some seem to show some promise:

  • Omega-3 fatty acid has positive effects at different doses.
  • ‘Fortasyn Connect’ (a multi-nutrient mixture) seems to be effective in the early stages of the disease.
  • Probiotic, Ginseng, Inositol and specialized nutritional formulas seem to have a positive effect on cognition.

Most of the primary studies had poor methodological quality, included patients with mild AD, small samples, and did not obtain significative results for all the cognitive outcomes.

The authors concluded that the effect of most dietary interventions on cognition in AD patients remains inconclusive, however, several nutrients, isolated or not, show potential to improve cognitive function in AD, especially in its early stages.

I am relieved that the authors of this thoroughly-researched review phrased their conclusions as cautiously as they did. The thing is, most of the primary trials are truly not worth writing home about. Some are just 4 weeks long, others include merely 30 odd patients. Many look more like marketing excercises than science.

The authors also stated that better quality studies are urgently needed to confirm the therapeutic potential of the diet so that a dietary recommendation in AD that contributes to the quality of life of patients and relatives can be established. This has become almost a standard sentence for ending a scientific paper. In this instance, however, it seems very true.

Some of us got used to the idea that acupuncture might be effective for pain. But could it work for infections? Unlikely! Well, let’s not rely on gut feelings; let’s have a fair and critical look at the evidence.

This systematic review assessed the evidence for acupuncture for uncomplicated recurrent urinary tract infections (rUTI) women. Five randomised controlled trials (RCTs) evaluating the effects of acupuncture and related therapies for prophylaxis or treatment of uncomplicated rUTI in women were included. The methodological quality of the studies and the strength of the evidence were low to moderate. The chance of achieving a composite cure with acupuncture therapies was greater than that with antibiotics (three studies, 170 participants, RR 1.92, 95% CI 1.31‐2.81, I2 = 38%). The risk of UTI recurrence was lower with acupuncture than with no treatment (two studies, 135 participants, RR 0.39, 95% CI 0.26–0.58, I2 = 0%) and sham acupuncture (one study, 53 participants, RR 0.45, 95% CI 0.22–0.92).

The authors concluded that acupuncture showed promising results compared to no treatment and sham acupuncture in reducing recurrence, based on low to moderate certainty evidence. Low certainty evidence found acupuncture increased the chance of achieving a composite cure compared to antibiotics. Findings from this review should be interpreted with caution, taking into consideration the biases identified and small sample size of the included trials. Included studies suggest acupuncture has a good safety profile for women with UTI, and may be considered as a therapeutic option in the treatment and prevention of rUTI in women, particularly those who are unresponsive to, or intolerant of, antibiotics. Rigorously designed research is needed to inform clinical decisionmaking about the use of acupuncture for women with UTIs.

The authors of this review are affiliated to the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangdong Provincial Academy of Chinese Medical Sciences and The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China and the China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia. The review was funded by the China-Australia International Research Centre for Chinese Medicine (CAIRCCM) (International Cooperation Project, Grant Number 2012DFA31760), and the National Natural Science Foundation of China (NSFC) (Grant Number 81873261). In view of these facts, it is strange, I think, that the authors declared no conflicts of interest.

The 5 primary studies included in this review are the following:

    1. Alraek T, Soedal LI, Fagerheim SU, Digranes A, Baerheim A. Acupuncture treatment in the
      prevention of uncomplicated recurrent lower urinary tract infections in adult women. American journal of
      public health. 2002;92(10):1609-11.
    2. Aune A, Alraek T, LiHua H, Baerheim A. Acupuncture in the prophylaxis of recurrent lower urinary
      tract infection in adult women. Scandinavian journal of primary health care. 1998;16(1):37-9.
    3. Hong JY, Li F, Liang XQ, Hou Z. [Efficacy observation on female chronic pyelonephritis treated with
      abdominal cluster-needling therapy]. Zhongguo zhen jiu = Chinese acupuncture & moxibustion.
      2013;33(4):303-5.
    4. Yu SM, Guo DD. Moxibustion combined with antibiotics was used to treat 30 cases of chronic
      urinary tract infection in adult women. Shandong Journal of Traditional Chinese Medicine.
      2010;29(09):621-2.
    5. Liu JL, Luo Q, Liu XH, Lin L. Observation on the clinical effect of external treatment of strong renal
      moxibustion on recurrent urinary tract infection. China Modern Doctor. 2018;56(29):116-8.

As always, it is worth checking these studies for reliability.

In the trial by Alraek et al patients were randomised patients to receive either acupuncture or no treatment. Is anyone surprised that the former group fared better than the latter? (I am not!)

The trial by Aune et al is the only study that attempted to control for placebo effects by using a sham control group. This is what they used as a sham treatment: Sham acupuncture was given using six needles superficially inserted in the calves, thighs or abdomen outside known acupuncture points or meridians. Needles were not manipulated in the sham group. Sham controls have the purpose of rendering patients unaware whether they receive the real or the sham treatment. The method used here cannot achieve this aim; patients were easily able to determine that they were in the control group.

The last three trials are all not Medline-listed studies authored by Chinese investigators published in inaccessible journals in Chinese. We know that such studies invariably report positive outcomes which are often fabricated and thus have a reliability close to zero. But even if we ignore these facts for a moment, from what I see in the results table of the review, these studies are invalid. All three are equivalence trials of acupuncture versus antibiotics; with a sample size of merely around 30, they must be woefully underpowered and thus unable to generate a reliable result.

The authors of this review claim that the risk of bias of trials was generally high or unclear. This is an understatement to put it mildly. In fact, the quality of the studies was mostly dismal.

In view of all this, I take the liberty to re-formulate the conclusions drawn by the review authors as follows:

Due to the lack of reliable RCTs, the effectiveness of acupuncture as a treatment or prevention of rUTIs remains unproven. Due to the implausibility of the therapy, its effectiveness seems highly unlikely.

PS

The BJOG should never have published such a deeply misleading paper.

Vitamin D and Omega-3 supplements help the elderly avoid Covid-19 infection by boosting their immune systems, study claims. Yes, that was the headline in the DAILY MAIL on 11/11/2020. Naturally, I found this interesting. So, I looked up the original paper. Here is its abstract:

Importance: The benefits of vitamin D, omega-3 fatty acids, and exercise in disease prevention remain unclear.

Objective: To test whether vitamin D, omega-3s, and a strength-training exercise program, alone or in combination, improved 6 health outcomes among older adults.

Design, setting, and participants: Double-blind, placebo-controlled, 2 × 2 × 2 factorial randomized clinical trial among 2157 adults aged 70 years or older who had no major health events in the 5 years prior to enrollment and had sufficient mobility and good cognitive status. Patients were recruited between December 2012 and November 2014, and final follow-up was in November 2017.

Interventions: Participants were randomized to 3 years of intervention in 1 of the following 8 groups: 2000 IU/d of vitamin D3, 1 g/d of omega-3s, and a strength-training exercise program (n = 264); vitamin D3 and omega-3s (n = 265); vitamin D3 and exercise (n = 275); vitamin D3 alone (n = 272); omega-3s and exercise (n = 275); omega-3s alone (n = 269); exercise alone (n = 267); or placebo (n = 270).

Main outcomes and measures: The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary end points, 99% confidence intervals are presented and P < .01 was required for statistical significance.

Results: Among 2157 randomized participants (mean age, 74.9 years; 61.7% women), 1900 (88%) completed the study. Median follow-up was 2.99 years. Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years. For instance, the differences in mean change in systolic BP with vitamin D vs no vitamin D and with omega-3s vs no omega-3s were both -0.8 (99% CI, -2.1 to 0.5) mm Hg, with P < .13 and P < .11, respectively; the difference in mean change in diastolic BP with omega-3s vs no omega-3s was -0.5 (99% CI, -1.2 to 0.2) mm Hg; P = .06); and the difference in mean change in IR of infections with omega-3s vs no omega-3s was -0.13 (99% CI, -0.23 to -0.03), with an IR ratio of 0.89 (99% CI, 0.78-1.01; P = .02). No effects were found on the outcomes of SPPB, MoCA, and incidence of nonvertebral fractures). A total of 25 deaths were reported, with similar numbers in all treatment groups.

Conclusions and relevance: Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes.

Speachless?

Me too!

The study has noting to do with COVID-19 and very little with infections. The bit about infections shows almost the opposite of what the MAIL claims. So, where does the notion stipulated in the headline come from?

The MAIL article gives the answer: Professor Heike Bischoff-Ferrari from Zurich University in Switzerland, who led the latest study, said: ‘Our findings suggest supplementation of vitamin D and omega-3s in adults aged 70 or older who lead an active lifestyle and have no pre-existing conditions does not provide any benefits when it comes to bone health, memory and muscle function. ‘However, we believe there is an effect on infections – such as Covid-19.’  

I would not be surprised, if the last sentence in the quote was taken out of context.

I would not be surprised, if this is the worst health related article in the DAIL MAIL this year.

And, by Jove, there are plenty to choose from.

And why do I report all this?

As I have pointed out before, I believe that journalists have a lot to answer for when it comes to misleading the public about so-called alternative medicine (SCAM):

My hope is that, by reminding them of their ‘errors’ every now and then, I might contribute to some progress.

Yes, I know, I am an incurable optimist!

Reflexology (originally called ‘zone therapy’ by its inventor) is a manual technique where pressure is applied to the sole of the patient’s foot. Reflexology is said to have its roots in ancient cultures. Its current popularity goes back to the US doctor William Fitzgerald (1872-1942) who did some research in the early 1900s and thought to have discovered that the human body is divided into 10 zones each of which is represented on the sole of the foot. Reflexologists thus drew maps of the sole of the foot where all the body’s organs are depicted. Numerous such maps have been published and, embarrassingly, they do not all agree with each other as to the location of our organs on the sole of our feet. By massaging specific zones which are assumed to be connected to specific organs, reflexologists believe to positively influence the function of these organs.

So, does reflexology do more good than harm?

The aim of this review was to conduct a systematic review, meta-analysis, and metaregression to determine the current best available evidence of the efficacy and safety of foot reflexology for adult depression, anxiety, and sleep quality.

Twenty-six studies could be included. The meta-analyses showed that foot reflexology intervention significantly improved adult depression, anxiety, and sleep quality. Metaregression revealed that an increase in total foot reflexology time and duration can significantly improve sleep quality.

The authors concluded that foot reflexology may provide additional nonpharmacotherapy intervention for adults suffering from depression, anxiety, or sleep disturbance. However, high quality and rigorous design RCTs in specific population, along with an increase in participants, and a long-term follow-up are recommended in the future.

Sounds good!

Finally a so-called alternative medicine (SCAM) that is backed by soild evidence!

Or perhaps not?

Here are a few concerns that lead me to doubt these conclusions:

  • Most of the primary studies were of poor methodological quality.
  • Most studies failed to mention adverse effects.
  • Very few studies controlled for placebo effects.
  • There was evidence of publication bias (negative studies tended to remain unpublished).
  • Studies published in languages other than English were not considered.
  • The authors fail to point out that a foot massage is, of course, agreeable (and thus may relieve a range of symptoms), but reflexology with all its weird assumptions is less than plausible.
  • Many of the studies located by the authors were excluded for reasons that are less than clear.

The last point seems particularly puzzling. Our own trial, for instance, was excluded because, according to the review authors, it did not include relevant outcomes. However, our method secion makes it clear that the primary focus for this study was the subscores for anxiety and depression, which comprise four and seven items, respectively. As it happens, our study was negative.

Also cuirous is the fact that the authors did not mention our own 2011 systematic review of reflexology:

Reflexology is a popular form of complementary and alternative medicine (CAM). The aim of this update is to critically evaluate the evidence for or against the effectiveness of reflexology in patients with any type of medical condition. Six electronic databases were searched to identify all relevant randomised clinical trials (RCTs). Their methodological quality was assessed independently by the two reviewers using the Jadad score. Overall, 23 studies met all inclusion criteria. They related to a wide range of medical conditions. The methodological quality of the RCTs was often poor. Nine high quality RCTs generated negative findings; and five generated positive findings. Eight RCTs suggested that reflexology is effective for the following conditions: diabetes, premenstrual syndrome, cancer patients, multiple sclerosis, symptomatic idiopathic detrusor over-activity and dementia yet important caveats remain. It is concluded that the best clinical evidence does not demonstrate convincingly reflexology to be an effective treatment for any medical condition.

I wonder why!

I know of one patient who turned to the Gerson Therapy having been told that she was suffering from terminal cancer and would not survive another course of chemotherapy. Happily, seven years later she is alive and well. So therefore it is vital that, rather than dismissing such experiences, we should further investigate the beneficial nature of these treatments.

HRH The Prince of Wales (2004)

I was reminded of this embarrassing (because displaying profound ignorance) quote when I looked at the website of the ‘GERSON SUPPORT GROUP UK‘ where it is prominently cited. Under the heading ‘SCIENCE & CLINICAL RATIONAL’ the site offers a long article about the Gerson therapy (GT). Allow me to show you a few quotes from it:

Dr Max Gerson’s therapy is based on the belief that insufficient nutrients within the cells and an accumulation of toxins in the tissues lead to a breakdown in healthy cellular function which, if left unchecked, can trigger cancer.

That is interesting, I find, because the statement clearly admits that the GT is not an evidence-based therapy but a belief-based treatment.

The therapy that he developed uses a restrictive, plant-based diet and specific supplements to boost healthy cellular function; and various detoxification procedures, including coffee enemas, to eliminate waste products.

The claims hidden in this sentence remain unproven. There is no evidence that cellular fuction is boosted, nor that the procedures eliminate toxins.

… we only need to look at communities across the globe which exist in a pre-industrialised state to see that, whilst they might be more likely to die from pneumonia or tuberculosis, rates of degenerative illness are a fraction of those in the ‘developed‘ world. The age-adjusted death rate from breast cancer is less than 2 per 100,000 of the population in Thailand, Sri Lanka and El Salvador and around 33 per 100,000 in the UK, US, The Netherlands and numerous other affluent, Western countries.

Correlation is not causation! Pre-industrial societies also watch less TV, eat less ice-cream, read less fashion magazines, etc., etc. Are these habits also the cause of cancer?

… migrant studies show that within two generations the cancer rates of migrants increase rapidly towards Western rates, again underlining the assertion that cancer is caused primarily by diet and lifestyle rather than ‘faulty’ genes.

In no way is this an argument for eating raw vegetable and taking your coffee via the rectum.

In the German scientific golden age of the 1920s and 30s…

Golden age for what, for fascists?

Gerson had used a restricted diet to cure himself of migraines. He then helped another patient to reverse tuberculosis, and many others to reverse a variety of degenerative illnesses, all by similar means. He later developed his therapy to the point where he was able to help individuals reverse cancer. 

In this case, Max Gerson was ignorant of the fact that experience and evidence are two fundamentally different things.

Max Gerson developed his therapy in an iterative way, starting with a restrictive plant-based diet, adding vitamins, minerals and enzymes to encourage the oxygenation of the cells and then introducing the coffee enemas to aid detoxification of waste products. What is fascinating is that science has subsequently explained the mechanism of action behind some of his theories. (See Biochemical Basis to the Therapy).

Science has not explained the mechanism of action, not least because the action has never been verified. There are no robust clinical trials of Gerson’s therapy. Evidently, 100 years were not enough to conduct any – or perhaps the proponents know only too well that they would not generate the results they hoped?

Equally interesting is that in 2012 Dr Thomas Seyfried published the results of many years research in Cancer as a Metabolic Disease. 

Really? On Medline, I find only two cancer-related papers for Seyfried T. 2012:

Thus, nearly a century after their original proposition that the fundamental cause of cancer was faulty cellular metabolism, it seems that doctors Otto Warburg and Max Gerson might be vindicated.

No, to ‘vindicate’ a therapeutic suggestion one needs several rigorous clinical trials. And for the GT, they remain absent.

_______________________________

So, what does the GT amount to?

  • proponents had ~100 years to produce evidence;
  • they failed to do so;
  • thus the therapy is at best unproven;
  • it is also biologically implausible;
  • moreover, it is expensive;
  • crucially it is not free of serious adverse effects;
  • it is promoted only by those who seem to make money from it.

The only controlled clinical trial of a Gerson-like therapy that I know of is this one (rarely cited by Gerson fans):

Conventional medicine has had little to offer patients with inoperable pancreatic adenocarcinoma; thus, many patients seek alternative treatments. The National Cancer Institute, in 1998, sponsored a randomized, phase III, controlled trial of proteolytic enzyme therapy versus chemotherapy. Because most eligible patients refused random assignment, the trial was changed in 2001 to a controlled, observational study.

METHODS

All patients were seen by one of the investigators at Columbia University, and patients who received enzyme therapy were seen by the participating alternative practitioner. Of 55 patients who had inoperable pancreatic cancer, 23 elected gemcitabine-based chemotherapy, and 32 elected enzyme treatment, which included pancreatic enzymes, nutritional supplements, detoxification, and an organic diet. Primary and secondary outcomes were overall survival and quality of life, respectively.

RESULTS

At enrollment, the treatment groups had no statistically significant differences in patient characteristics, pathology, quality of life, or clinically meaningful laboratory values. Kaplan-Meier analysis found a 9.7-month difference in median survival between the chemotherapy group (median survival, 14 months) and enzyme treatment groups (median survival, 4.3 months) and found an adjusted-mortality hazard ratio of the enzyme group compared with the chemotherapy group of 6.96 (P < .001). At 1 year, 56% of chemotherapy-group patients were alive, and 16% of enzyme-therapy patients were alive. The quality of life ratings were better in the chemotherapy group than in the enzyme-treated group (P < .01).

CONCLUSION

Among patients who have pancreatic cancer, those who chose gemcitabine-based chemotherapy survived more than three times as long (14.0 v 4.3 months) and had better quality of life than those who chose proteolytic enzyme treatment.

Considering all this, I believe, it would be hard to name a cancer quackery that is less credible than the GT.

If you thought that lousy research in so-called alternative medicine (SCAM) is confined to human medicine, you were wrong. The papers published in veterinary medicine is just one of many examples to suggest that it is, in fact, even worse. Take, for instance, this study of homeopathy.

This Indian study was conducted to evaluate the ameliorative potential of homeopathic drugs in combination (Sulfur 30C, Thuja 30C, Graphites 30C, and Psorinum 30C) in 16 dogs affected with oral papillomatosis which had not undergone any previous treatment. Papillomas are benign epithelial tumours caused by infection with species-specific DNA papilloma-viruses. They tend to disappear within 6-12 months.

Dogs affected with oral papillomatosiswere randomly divided into two groups, namely, homeopathic treatment group (n=8) and placebo control group (n=8). The homeopathic combination of drugs and placebo drug (distilled water) was administered orally twice daily for 15 days. The 4 homeopathy drugs were used in the 30C potency and given orally at 2 drops per 5 kg body weight. The clinical evaluation in both groups of dogs was performed by the same investigator throughout the period of study (12 months). All  dogs were clinically scored for oral lesions on days 0, 5, 7, 10, 15, 20, 25, 30, 45, 60, 90, 120, and 150 after initiation of treatment.

The homeopathic treatment group showed early recovery with a significant reduction in oral lesions reflected by a clinical score in comparison to placebo-treated group. Oral papillomatous lesions regressed in the homeopathic group between 7 and 15 days, whereas regression of papilloma in the placebo group occurred between 90 and 150 days. The homeopathic treated group was observed for 12 months post-treatment period and no recurrence of oral papilloma was observed.

The authors concluded that the result of this investigation proves that the combination of homeopathic drugs (Sulfur 30+Thuja 30+Graphites 30+Psorinum 30) offers an attractive, non-invasive and most economical way of treating COP. A combination of homeopathic drugs is a novel approach for treating canine oral papilloma and further studies are needed to elucidate the use of homeopathic combination as a veterinary oncological therapeutics and to explore the mechanism of action of these homeopathic drugs in ameliorating oral papilloma.

The graph says it all. Very rarely is any medical treatment as effective as to produce such impressive results.

So, are we witnessing a scientific sensation?

Is this the breakthrough homeopaths have been waiting for?

Should the Nobel committee be informed?

Perhaps not!

A group size of 8 is underwhelming, to say the least. It is not sufficient to generate a reliable result. The results, even if true, ‘prove‘ nothing other than the authors’ ignorance of research methodology.

The HOMEOPATHY RESEARCH INSTITUTE (HRI) – yes we did discuss its activities before – has just published an ‘update’ on clinical trials of homeopathy. Let me show it to you:

We are pleased to share the results of a recent collaboration with Dr Robert Mathie to update his analysis of randomised controlled trials of homeopathy.

The findings from the 5-year update from 2014-2019 are as follows:

Total number of randomised controlled trials

2014: 189 trials of homeopathic treatment for 100 medical conditions
2019: 221 trials of homeopathic treatment for 115 medical conditions

Placebo-controlled trials only

2014: 104 trials on 63 medical conditions
2019: 129 trials on 77 medical conditions

When considering the balance of positive, negative and inconclusive studies, it is interesting to observe the following shifts in the evidence base for homeopathy over this 5 year period:

Positive trials                Up from 41% to 45%
Negative trials              Down from 5% to 4%
Inconclusive trials        Down from 54% to 51%

__________________________________________________

Impressed?

Me too (but only about the profound ignorance of the HRI)!

One could now point out that the ‘pee counting’ method of reviewing clinical trial evidence is nonsense and leads almost invariably to irrelevant findings. All the positive trials could, for instance, be methodologically invalid, while the negative are rigorous. But this is not even necessary. The triumphant update can be invalidated much more easily.

All we need to do is to remind ourselves of what clinical trials are.

Simply put, they are experiments that test a hypothesis, to be precise, they test the ‘null-hypothesis’: the experimental therapy generates results that are not different from those in the control group. Depending on the data, the null-hypothesis must then be either rejected or accepted by the results of the clinical trial. If it is rejected, the therapy seems to be better than placebo. If it is accepted, the therapy seems to perform just like a placebo.

THERE IS NO SUCH THING AS NEITHER REJECTING NOR ACCEPTING!

The results can not say: “We like the null-hypothesis just as much as we dislike it.” Clinical trials always give a YES or NO answer.

This means the category of ‘inconclusive trials’ is entirely an invention of homeopaths and similar wishful thinkers. In their interpretation, it covers those trials where the null-hypothesis was accepted, while the ‘negative trials’ are studies where the control group had better results than the patients treated homeopathically. But trials that accept the null-hypothesis are negative!

So, what does the HRI’s ‘pee-counting’ update really show?

It reveals that, of the 221 RCTs of homeopathy, 45% are positive, i.e. they suggest that homeopathy was better than the control intervention. That is a sizable percentage, but we might ask how reliable these studies were, what control treatments they employed, and whether they all truly used homeopathy (I know, some used isopathy and some employ homotoxicology, for instance).

The majority of the 221 RCTs, however, are trials where the null-hypothesis had to be accepted. These are the studies failing to show that homeopathy works. In other words, the HRI’s triumphant ‘pee-counting’ update confirms what we have pointed out as nauseam for years:

THE MAJORITY OF THE EVIDENCE ON HOMEOPATHY IS NEGATIVE.

The aim of this RCT was to examine symptom responses resulting from a home-based reflexology intervention delivered by a friend/family caregiver to women with advanced breast cancer undergoing chemotherapy, targeted, and/or hormonal therapy.

Patient-caregiver dyads (N = 256) were randomized to 4 weekly reflexology sessions or attention control. Caregivers in the intervention group were trained by a reflexology practitioner in a 30-min protocol. During the 4 weeks, both groups completed telephone symptom assessments using the M. D. Anderson Symptom Inventory. Those who completed at least one weekly call were included in this secondary analysis (N = 209). Each symptom was categorized as mild, moderate, or severe using established interference-based cut-points. Symptom response meant an improvement by at least one category or remaining mild. Symptom responses were treated as multiple events within patients and analysed using generalized estimating equations technique.

Reflexology was more successful than attention control in producing responses for pain with no significant differences for other symptoms. In the reflexology group, greater probability of response across all symptoms was associated with lower number of comorbid condition and lower depressive symptomatology at baseline. Compared to odds of responses on pain (chosen as a referent symptom), greater odds of symptom response were found for disturbed sleep and difficulty remembering with older aged participants.

Adjusted odds ratios (ORs) of symptom responses for reflexology arm versus control (adjusted for age, number of comorbid conditions, depressive symptoms at baseline, and treatment type: chemotherapy with or without hormonal therapy versus hormonal therapy alone)
Symptom                                 OR      (95% CI)        p value
Fatigue                                    1.76      (0.99, 3.12)       0.06
Pain                                         1.84      (1.05, 3.23)       0.03
Disturbed sleep                         1.45      (0.76, 2.77)       0.26
Shortness of breath                   0.58      (0.26, 1.30)       0.19
Remembering                           0.96      (0.51, 1.78)       0.89
Lack of appetite                        1.05      (0.45, 2.49)       0.91
Dry mouth                               1.84      (0.86, 3.94)       0.12
Numbness and tingling              1.40     (0.75, 2.64)        0.29
Depression                              1.38      (0.78, 2.43)       0.27

The authors concluded that home-based caregiver-delivered reflexology was helpful in decreasing patient-reported pain. Age, comorbid conditions, and depression are potentially important tailoring factors for future research and can be used to identify patients who may benefit from reflexology.

This is certainly one of the more rigorous studies of reflexology. It is well designed and reported. How valid are its findings? To a large degree, this seems to depend on the somewhat unusual statistical approach the investigators employed:

Baseline characteristics were summarized by study group for outcome values and potential covariates. The unit of analysis was patient symptom; multiple symptoms were treated as nested within the patient being analyzed, using methodology described by Given et al. [24] and Sikorskii et al. [17]. Patient symptom responses were treated as multiple events, and associations among responses to multiple symptoms within patients were accounted for by specifying the exchangeable correlation structure in the generalized estimating equations (GEE) model. The GEE model was fitted using the GENMOD procedure in SAS 9.4 [25]. A dummy symptom variable with 9 levels was included in the interaction with the trial arm to differentiate potentially different effects of reflexology on different symptoms. Patient-level covariates included age, number of comorbid conditions, type of treatment (chemotherapy or targeted therapy with or without
hormonal therapy versus hormonal therapy only), and the CES-D score at baseline. Odds ratios (ORs) and their 95% confidence intervals (CIs) were obtained for the essential parameter of study group for each symptom.

Another concern is the fact that the study crucially depended on the reliability of the 256 carers. It is conceivable, even likely, I think, that many carers from both groups were less than strict in adhering to the prescribed protocol. This might have distorted the results in either direction.

Finally, the study was unable to control for the possibly substantial placebo response that a reflexology massage unquestionably provokes. Therefore, we are not able to tell whether the observed effect is due to the agreeable, non-specific effects of touch and foot massages, or to the postulated specific effects of reflexology.

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