MD, PhD, FMedSci, FSB, FRCP, FRCPEd

quality of life

There are dozens of observational studies of homeopathy which seem to suggest – at least to homeopaths – that homeopathic treatments generate health benefits. As these investigations lack a control group, their results can be all to easily invalidated by pointing out that factors like ‘regression towards the mean‘ (RTM, a statistical artefact caused by the phenomenon that a variable that is extreme on its first measurement tends to be closer to the average on its second measurement) might be the cause of the observed change. Thus the debate whether such observational data are reliable or not has been raging for decades. Now, German (pro-homeopathy) investigators have published a paper which potentially could resolve this dispute.

With this re-analysis of an observational study, the investigators wanted to evaluate whether the observed changes in previous cohort studies are due to RTM and to estimate RTM adjusted effects. SF-36 quality-of-life (QoL) data from a cohort of 2827 chronically diseased adults treated with homeopathy were reanalysed using a method described in 1991 by Mee and Chua’s. RTM adjusted effects, standardized by the respective standard deviation at baseline, were 0.12 (95% CI: 0.06-0.19, P < 0.001) in the mental and 0.25 (0.22-0.28, P < 0.001) in the physical summary score of the SF-36. Small-to-moderate effects were confirmed for most individual diagnoses in physical, but not in mental component scores. Under the assumption that the true population mean equals the mean of all actually diseased patients, RTM adjusted effects were confirmed for both scores in most diagnoses.

The authors reached the following conclusion: “In our paper we showed that the effects on quality of life observed in patients receiving homeopathic care in a usual care setting are small or moderate at maximum, but cannot be explained by RTM alone. Due to the uncontrolled study design they may, however, completely be due to nonspecific effects. All our analyses made a restrictive and conservative assumption, so the true treatment effects might be larger than shown.” 

Of course, the analysis heavily relies on the validity of Mee and Chua’s modified t-test. It requires the true mean in the target population to be known, a requirement that seldom can be fulfilled. The authors therefore took the SF-36 mean summary scores from the 1998 German health survey as proxies. I am not a statistician and therefore unable to tell how reliable this method might be (- if there is someone out there who can give us some guidance here, please post your comment).

In order to make sense of these data, we need to consider that, during the study period, about half of the patients admitted to have had additional visits to non-homeopathic doctors, and 27% also received conventional drugs. In addition, they would have benefitted from:

  • the benign history of the conditions they were suffering from,
  • a placebo-effect,
  • the care and attention they received
  • and all sorts of other non-specific effects.

So, considering these factors, what does this interesting re-analysis really tell us? My interpretation is as follows: the type of observational study that homeopaths are so fond of yields false-positive results. If we correct them – as the authors have done here for just one single factor, the RTM – the effect size gets significantly smaller. If we were able to correct them for some of the other factors mentioned above, the effect size would shrink more and more. And if we were able to correct them for all confounders, their results would almost certainly concur with those of rigorously controlled trials which demonstrate that homeopathic remedies are pure placebos.

I am quite sure that this interpretation is unpopular with homeopaths, but I am equally certain that it is correct.

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.

Rudolf Steiner was a weird guy by any stretch of imagination. He was the founding father of anthroposophy, an esoteric “philosophy” that created a new dimension of obtrusiveness. Not only that, he also dabbled in farming methods, devised an educational technique and created an entire school of health care, called anthroposophical medicine. The leading product in its range of homeopathy-inspired “drugs” is a mistletoe-extract which is, according to Steiner, a cure for cancer. His idea was simple: the mistletoe plant is a parasite that lives off host trees sapping its resources until, eventually, it might even kill its host - just like cancer threatening the life of a human being!!!

So, what is more logical than to postulate that extracts from mistletoe are a cure for cancer? Medicine seems simple – particularly, if  you do not understand the first thing about it!

But here comes the odd thing: some ingredients from mistletoe do actually have anti-cancer properties. So, was the old Steiner an intuitive genius who somehow sensed that mistletoe would be a life-saver for cancer patients? Or is all this just pure luck? Or was it perhaps predictable?

Many plants produce molecules that are so toxic that they can kill (cancer) cells, and many conventional cancer drugs were originally derived from plants; the fact that mistletoe has some anti-cancer activity therefore comes as a surprise only to those who have little or no knowledge of phyto-pharmacology.

Ok, mistletoe might have some ingredients which possess pharmacological activity. But to claim that it is a cancer cure is still a huge leap of faith. This fact did not stop promoters of anthroposophical medicine to do just that.

Due to decades of clever promotion, it is now hard in many countries (including for instance Germany) to find cancer patients who have not tried mistletoe; indeed, selling mistletoe preparations to desperate cancer patients has become a mega-business.

But does it actually work?  Do these extracts achieve what proponents advertise?

The claims for mistletoe are essentially twofold:

1) Mistletoe cures cancer.

2) Mistletoe improves the quality of life (QoL) of cancer patients.

The crucial question clearly is: are these claims based on good evidence?

According to our own systematic review, the answer is NO. In 2003, we looked at all the clinical trials and demonstrated that some of the weaker studies implied benefits of mistletoe extracts, particularly in terms of quality of life. None of the methodologically stronger trials exhibited efficacy in terms of quality of life, survival or other outcome measures. The current Cochrane review (of which I am not a co-author) concluded similarly : The evidence from RCTs to support the view that the application of mistletoe extracts has impact on survival or leads to an improved ability to fight cancer or to withstand anticancer treatments is weak.

But both reviews have one major weakness: they included all of the many available extracts of mistletoe - and one cannot deny that there are considerable differences between them. The market leader in this area is Weleda (avid readers of science blogs might remember that this firm has been mentioned before); they produce ISCADOR, the mistletoe extract that has been tested more than any other such preparation.

Perhaps it would be informative to focus specifically on this product then? A German team from the “Center for Integrative Medicine, Faculty of Health, University of Witten/Herdecke” has done just that; despite the fact that these authors are not really known for their critical analyses of anthroposophical medicine, their conclusion is also cautious: The analyzed studies give some evidence that Iscador treatment might have beneficial short-time effects on QoL-associated dimensions and psychosomatic self-regulation.

So, what is the bottom line? Sceptics would say that almost a century of research without a solid proof of efficacy is well and truly enough; one should now call it a day. Proponents of mistletoe treatment, however, insist: we need more and better studies. Well, there is more! A new RCT of Iscador has just been published.

It included chemotherapy-naive advanced non-small-cell lung cancer (NSCLC) patients to assess Iscador’s influence on chemotherapy-related adverse-effects and QoL. Patients with advanced NSCLC were randomised to receive chemotherapy alone or chemotherapy plus Iscador thrice weekly until tumour progression. Chemotherapy consisted of 21-day cycles of carboplatin combined with gemcitabine or pemetrexed. Seventy-two patients were enrolled of whom 65% were in stage IV, and 62% had squamous histology. Median overall survival in both groups was 11 months. Median time to tumour progression was not significantly different between the two groups. Differences in grade 3-4 haematological toxicity were not significant, but more control patients had chemotherapy dose reductions, grade 3-4 non-haematological toxicities, and hospitalisations.

The authors’ conclusion: No effect of Iscador could be found on quality of life or total adverse events. Nevertheless, chemotherapy dose reductions, severe non-haematological side-effects and hospitalisations were less frequent in patients treated with Iscador, warranting further investigation of Iscador as a modifier of chemotherapy-related toxicity.

So, does Steiner’s notion based on the weirdest of intuitions contain some kernel of truth? I am not sure. But for once I do agree with the proponents of mistletoe: we need more and better research to find out.

Lymph oedema in the arms or legs is a frequent complication after lymph-node dissections for cancer. Treatment or prevention can be difficult, and the results  are often unsatisfactory. Consequently, the burden of suffering of cancer patients affected by this problem is immense.

Amongst several options, a little-known massage technique, called lymph-drainage (or lymphatic drainage, LD), is sometimes recommended. It consists of gentle manual movements which lightly push the lymph fluid through the lymphatic vessels that eventually enter into the blood circulation. During a session of lymph-drainage, a specially trained massage therapist lightly moves his or her hands along the lymph vessels to facilitate the lymph flow. The treatment is agreeable and relaxing, but does it really reduce the oedema?

A recent systematic review and meta-analysis of RCTs evaluated the effectiveness of LD in the prevention and treatment of breast-cancer related lymph-oedema. The primary outcome for prevention was the incidence of postoperative lymph-oedema. The outcome for management of  was a reduction in oedema volume.

In total, 10 RCTs with altogether 566 patients were identified. Two studies evaluating the preventive outcome of LD found no significant difference in the incidence of lymph-oedema between the LD and standard treatments. Seven studies assessed the reduction in arm volume, and found no significant difference between the LD and standard treatments.

The authors conclusion was negative about the value of LD: The current evidence from RCTs does not support the use of LD in preventing or treating lymph-oedema. However, clinical and statistical inconsistencies between the various studies confounded our evaluation of the effect of LD on breast-cancer-related lymph-oedema.

Perhaps a brand-new clinical trial which had not been included in the above assessment would have persuaded the authors to be a little more optimistic. This study evaluated the effectiveness of LD in the prevention of lymph-oedema after treatment of breast cancer. The study-population consisted of 67 women, who had undergone surgery for breast cancer. From the second day of surgery, 33 randomly chosen women were given LD. The control group consisted of 34 women who did not receive LD. Measurements of the volumes of both arms were taken before surgery and on days 2, 7, 14, and at 3 and 6 months after surgery.

Among the women who did not have LD, a significant increase in the arm volume on the operated side was observed after 6 month. There was no statistically significant  increase in the volume of the upper limb on the operated side in women who underwent LD.

The authors conclude that regardless of the surgery type and the number of the lymph nodes removed, LD effectively prevented lymph-oedema of the arm on the operated side. Even in high risk breast cancer treatments (operation plus irradiation), LD was demonstrated to be effective against arm volume increase. Even though confirmatory studies are needed, this study demonstrates that LD administered early after operation for breast cancer should be considered for the prevention of lymph-oedema.

So, does LD reduce oedema or not? This does not seem to be such a difficult question that it should take decades to resolve! And who would doubt that it is an important one? Lymph-oedema has the potential to seriously impede the quality of life of many patients, and it can even contribute to unnecessary mortality. The fact that the few available studies are too small and too weak to generate reliable results is disappointing and shines a dim light on the supposedly patient-centred research in oncology, in my view.

The concept of LD is plausible, at least some of the findings from clinical trials are encouraging, and the problem of lymph-oedema is both prevalent and relevant. So what is stopping us from funding a large, well-designed and definitive study?

Where I live, some of the old-fashioned, privately-owned shops that used to dominate our high streets have survived the onslaught of the supermarkets. Our bakery is such a quaint remnant from the past. Surprisingly, it also is more holistic and more therapeutic than any alternative health centre I have come across.

The first thing that strikes anyone who enters the premises is the irresistible smell. Customers’ well being hits the ceiling, and the local aromatherapists are in danger of going out of business. The intense stimulation of the customers’ olfactory system relaxes their mind and puts them into a meditative state as they patiently wait to be served. Everyone in the queue has a little word with the baker’s wife, and progress is therefore slow – but we don’t mind: the chat is holistic counselling at its best, and our slow movements towards the counter are healthier than tai chi.

“You are looking well today,” says the baker’s wife, thereby gently arousing me from my aroma-induced meditation and indicating that she is about to focus her shaman healing-energy on me. Her diagnosis is spot on; the alternative therapies I enjoyed while waiting have re-balanced my chakras and got my qi flowing nicely – no wonder I am looking well!

The whole-wheat scones are finely balanced and nutritious; so I order three—one for the walk home and two for tea later. Prices have gone up a bit but, as with all holistic therapies, the more you pay, the more it’s worth. “Here you are,” she says, handing me her dietary delights. As I pay, our hands touch ever so briefly, just long enough for me to experience the instant transfer of healing energy that is so characteristic of Therapeutic Touch.

“Take care now, and God bless”, she says. As I walk out of her aura, I contemplate her words full of empathetic spiritual guidance and ancient wisdom. “That was expensive”, my wife mutters back home. I beg to differ: not only did I get the most wholesome food for my physical body, but I received holistic and patient-centred aromatherapy, counselling, meditation, tai chi and energy healing for my emotional, psychological and spiritual needs.

If only our Health Secretary knew about this traditional, yet integrated and therefore cutting-edge approach to cost-effective health and holistic well-being. We could all have it for free, and it might even save the NHS from its current crisis!

Some national and international guidelines advise physicians to use spinal manipulation for patients suffering from acute (and chronic) low back pain. Many experts have been concerned about the validity of this advice. Now an up-date of the Cochrane review on this subject seems to provide clarity on this rather important matter.

Its aim was to assess the effectiveness of spinal manipulative therapy (SMT) as a treatment of acute low back pain. Randomized controlled trials (RCTs) testing manipulation/mobilization in adults with  low back pain of less than 6-weeks duration were included. The primary outcome measures were pain, functional status and perceived recovery. Secondary endpoints were return-to-work and quality of life. Two authors independently conducted the study selection, risk of bias assessment and data extraction. The effects were examined for SMT versus  inert interventions, sham SMT,  other interventions, and for SMT as an adjunct to other forms of treatment.

The researchers identified 20 RCTs with a total number of 2674 participants, 12 (60%) RCTs had not been included in the previous version of this review. Only 6 of the 20 studies had a low risk of bias. For pain and functional status, there was low- to very low-quality evidence suggesting no difference in effectiveness of SMT compared with inert interventions, sham SMT or as adjunct therapy. There was varying quality of evidence suggesting no difference in effectiveness of SMT compared with other interventions. Data were sparse for recovery, return-to-work, quality of life, and costs of care.

The authors draw the following conclusion: “SMT is no more effective for acute low back pain than inert interventions, sham SMT or as adjunct therapy. SMT also seems to be no better than other recommended therapies. Our evaluation is limited by the few numbers of studies; therefore, future research is likely to have an important impact on these estimates. Future RCTs should examine specific subgroups and include an economic evaluation.”

In other words, guidelines that recommend SMT for acute low back pain are not based on the current best evidence. But perhaps the situation is different for chronic low back pain? The current Cochrane review of 26 RCTs is equally negative: “High quality evidence suggests that there is no clinically relevant difference between SMT and other interventions for reducing pain and improving function in patients with chronic low-back pain. Determining cost-effectiveness of care has high priority. Further research is likely to have an important impact on our confidence in the estimate of effect in relation to inert interventions and sham SMT, and data related to recovery.”

This clearly begs the question why many of the current guidelines seem to mislead us. I am not sure I know the answer to this one; however I suspect that the panels writing the guidelines might have been dominated by chiropractors and osteopaths or their supporters who have not exactly made a name for themselves for being impartial. Whatever the reason, I think it is time for a re-think and for up-dating guidelines which are out of date and misleading.

Similarly, it might be time to question for what conditions chiropractors and osteopaths, the two professions who use spinal manipulation/mobilisation most, do actually offer anything of real value at all. Back pain and SMT are clearly their domains; if it turns out that SMT is not evidence-based for back pain, what is left? There is no good evidence for anything else, as far as I can see. To make matters worse, there are quite undeniable risks associated with SMT. The conclusion of such considerations is, I fear, obvious: the value of and need for these two professions should be re-assessed.

Many cancer patients use some form of complementary and alternative medicine (CAM), mostly as an adjunct to conventional cancer therapies to improve the symptoms of the disease or to alleviate the side-effects of the often harsh cancer-therapy. The hope is that this approach leads to less suffering and perhaps even longer survival – but is this really so?

In a recently published study, Korean researchers evaluated whether CAM-use influenced the survival and health-related quality of life (HRQOL) of terminal cancer patients. From July 2005 to October 2006, they prospectively studied a cohort study of 481 cancer patients. During a follow-up of 163.8 person-years, they identified 466 deceased patients. Their multivariate analyses of these data showed that, compared with non-users, CAM-users did not have better survival. Using mind-body interventions or prayer was even associated with significantly worse survival. CAM users reported significantly worse cognitive functioning and more fatigue than nonusers. In sub-group analyses, users of alternative medical treatments, prayer, vitamin supplements, mushrooms, or rice and cereal reported significantly worse HRQOL. The authors conclude that “CAM did not provide any definite survival benefit, CAM users reported clinically significant worse HRQOLs.”

Most proponents of CAM would find this result counter-intuitive and might think it is a one-off coincidental result or a fluke. But, in fact, it is not; similar data have been reported before. For instance, a Norwegian study from 2003 examined the association between CAM-use and cancer survival. Survival data were obtained with a follow-up of 8 years for 515 cancer patients. A total of 112 patients used CAM. During the follow-up period, 350 patients died. Death rates were higher in CAM-users (79%) than in those who did not use CAM (65%). The hazard ratio of death for CAM-use compared with no use was 1.30. The authors of this paper concluded that “use of CAM seems to predict a shorter survival from cancer.”

I imagine that, had the results been the opposite (i.e. showing that CAM-users live longer and have a better quality of life), most CAM-enthusiasts would not have hesitated in claiming a cause effect relationship (i.e. that the result was due to the use of alternative medicine). Critical thinkers, however, are more careful, after all, correlation is not causation! So, how can these findings be explained?

There are, of course, several possibilities, for example:

1) Some patients might use ineffective alternative therapies instead of effective cancer treatments thus shortening their life and reducing their quality of life.

2) Other patients might employ alternative treatments which cause direct harm; for this, there are numerous options; for instance, if they self-medicate St John’s Wort, they would decrease the effectiveness of many mainstream medications, including some cancer drugs.

3) Patients who elect to use alternative medicine as an adjunct to their conventional cancer treatment might, on average, be more sick than those who stay clear of alternative medicine.

The available data do not allow us to say which explanation applies. But things are rarely black or white, and I would not be surprised, if a complex combination of all three possibilities came closest to the truth.

Chiropractors have become (in)famous for making claims which  contradict the known facts. One claim that we find with unfailing regularity is that “regular chiropractic treatments will improve your quality of life“. There are uncounted websites advertising this notion, and most books on the subject promote it as well, some are even entirely dedicated to the theme. Here is a quote from a typical quote from one site chosen at random: “Quality of life chiropractic care is the pinnacle of chiropractic care within the chiropractic paradigm.  It does not solely rely on pain or postural findings, but rather on how a persons life can be positively influenced through regular adjustments… A series of regular adjustments is programmed and continual advice on life improvement is given.  It is designed as a long term approach and gains its strength from the regularity of its delivery.”

Given the ubiquitous nature of such claims, and given the fact that many chiropractic clients have back problems which reduce their quality of life, and given that back pain is just about the only condition for which chiropractors might have something to offer, it seems relevant to ask the following question: what is the evidence that chiropractic interventions affect the quality of life of back pain sufferers?

Some time ago, an Italian randomised clinical trial compared chiropractic spinal manipulations with sham-manipulations in patients affected by back pain and sciatica. Its results were disappointing and showed “no significant differences in quality of life and psychosocial scores.” But this is just one (potentially cherry-picked) study, I hear my chiropractic friends object. What we quite clearly need, is someone who takes the trouble to evaluate the totality of the available evidence.

Recently, Australian researchers published a review which did just that. Its authors conducted thorough literature searches to find all relevant studies on the subject. Of the 1,165 articles they located, 12 investigations of varying quality were retained, representing 6 studies, 4 randomised clinical trial and two observational studies. There was a high degree of inconsistency and lack of standardisation in measurement instruments and outcome measures. Three studies reported reduced use of additional treatments as a positive outcome; two studies reported a positive effect of chiropractic interventions on pain, and two studies reported a positive effect on disability. The 6 studies reviewed concentrated on the impact of chiropractic care on physical health and disability, rather than the wider holistic view which was the focus of the review. On the basis of this evidence, the authors conclude that “it is difficult… to defend any conclusion about the impact of chiropractic intervention on the quality of life, lifestyle, health and economic impact on chiropractic patients presenting with back pain.”

So….

What should we make of all this? I don’t know about you, but I fear the notion that chiropractic improves the quality of life of back pain patients is just another of these many bogus assumptions which chiropractors across the globe seem to promote, advertise and make a living from.

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