I have written previously about the rationale and evidence concerning the use of cranberry products to prevent or treat urinary tract infections. In my summary, I concluded:

There is weak theoretical justification for using cranberry products for urinary tract infections (UTI), though none of the supporting preclinical evidence involves dogs or cats. There is conflicting clinical trial evidence in humans, and no clinical studies in dogs and cats.  

A recent Cochrane review concerning the use of cranberry products to prevent UTIs in humans further undermines the already weak argument for the value of these products. This update of the previous review in 2008 includes an additional 14 clinical trials in a meta-analysis. The conclusion was that there is no evidence cranberry products are effective for preventing UTIs:

Data included in the meta-analyses showed that, compared with placebo, water or not [sic] treatment, cranberry products did not significantly reduce the occurrence of symptomatic UTI overall (RR 0.86, 95% CI 0.71 to 1.04) or for any the subgroups: women with recurrent UTIs (RR 0.74, 95% CI 0.42 to 1.31); older people (RR 0.75, 95% CI 0.39 to 1.44); pregnant women (RR 1.04, 95% CI 0.97 to 1.17); children with recurrent UTI (RR 0.48, 95% CI 0.19 to 1.22); cancer patients (RR 1.15 95% CI 0.75 to 1.77); or people with neuropathic bladder or spinal injury (RR 0.95, 95% CI: 0.75 to 1.20).

Prior to the current update it appeared there was some evidence that cranberry juice may decrease the number of symptomatic UTIs over a 12 month period, particularly for women with recurrent UTIs. The addition of 14 further studies suggests that cranberry juice is less effective than previously indicated….Given the large number of dropouts/withdrawals from studies (mainly attributed to the acceptability of consuming cranberry products particularly juice, over long periods), and the evidence that the benefit for preventing UTI is small, cranberry juice cannot currently be recommended for the prevention of UTIs. Other preparations (such as powders) need to be quantified using standardised [sic] methods to ensure the potency, and contain enough of the ‘active’ ingredient, before being evaluated in clinical studies or recommended for use.

Cranberry juice does not appear to have a significant benefit in preventing UTIs and may be unacceptable to consume in the long term. Cranberry products (such as tablets or capsules) were also ineffective (although had the same effect as taking antibiotics), possibly due to lack of potency of the ‘active ingredient’.

This review indicates pretty clearly that overall, cranberry juice is not effective in preventing UTIs despite theoretical reasons why it might be. This illustrates, yet again, why we cannot rely on extrapolation from pre-clinical or in vitro studies to tell us what will work in actual patients.

As always, one cannot completely rule out a subset of patients for whom these products might have benefits, but quite a variety of patient populations and different forms of cranberry have been investigated so far without any convincing evidence of value. And, of course, there is no clinical research at all in veterinary species to support using cranberry products to treat or prevent UTIs.

There is a recent study out which looks at the potential for a chemical derived from mushrooms to slow the progression of one type of cancer in dogs. It has both strengths and weaknesses, and it is a nice example of both good preliminary, exploratory research and why we shouldn’t put too much confidence in the findings of such research.

Dorothy Cimino Brown and Jennifer Reetz. Single Agent Polysaccharopeptide DelaysMetastases and Improves Survival in Naturally Occurring Hemangiosarcoma. Evidence-Based Complementary and Alternative Medicine. Volume 2012, Article ID 384301, 8 pages. doi:10.1155/2012/384301

The goal of the study was to see if a Chinese herbal medicine product, ImYunity, containing a standardized amount of a chemical called polysaccharopeptide (PSP), had an effect on the progression of the malignant blood vessel cancer hemangiosarcoma (HSA) in dogs. The dogs were those diagnosed with HSA after having surgery to remove their spleens, which were bleeding due to the presence of HSA. Typically, dogs with HSA who have a splenectomy and no other treatment only live a couple of months, though of course there is enough variation that the life expectancy of any individual patient cannot be accurately predicted. Given chemotherapy, these patients tend to live quite a bit longer, however most still do not survive to a year, and all will eventually die from metastatic HSA. Given this poor prognosis even with standard therapy, it is certainly reasonable to investigate alternative approaches.

PSP is believed to be the active compound in some mushrooms used for medicinal purposes, and there is a moderate amount of in vitro and laboratory animal research to suggest the compound may have some effects on the immune system and on cancer cells. I agree with the authors of this paper point out, however, when they say that “as with all other preclinical data, whether these reported findings of suppression of cell proliferation and induction of apoptosis in malignant cells from murine models have relevance in patient care is uncertain.”

Methodologically, the study was of mixed quality. There were only 15 subjects, which is a very small number, and this can lead to random individual variations having a significant effect on any differences seen between groups of subjects. The dogs were selected on the basis of having been diagnosed with HSA and having had their spleens removed. Some had metastases elsewhere in their abdomen at the time of diagnosis and others did not. The dogs were randomly assigned to three different dosage levels of PSP. The investigators and owners were blinded to which dose each dog was getting. However, there was no control group receiving either a placebo or standard therapy.

The two main outcomes studied were time to progression of metastatic disease in the abdomen and survival. While survival is a fairly clear outcome, it is influenced by factors other than the just the progression of the disease since most dogs with cancer are euthanized at their owners’ request. The factors that lead an owner to be ready to do this are many and varied, and not all hinge on the stage of disease in the pet. Still, this is a useful measure in the real world since presumably an effective therapy which slows the progress of disease will be an important factor in determining how long it is before an owner feels it is time to let the pet go.

The second outcome measure is a little less clearly described. An abdominal ultrasound was done on all patients at the time of their enrollment in the study and them monthly thereafter. It isn’t perfectly clear from the report, but it appears that the radiologists performing these examinations were unaware of the treatment each dog was receiving. According to the paper, “Based on this comparison, the board certified radiologist made the determination of progression of metastatic disease.” It’s also not entirely clear what criteria were used to determine progression. How many new lesions or how much growth in established lesions counted as “progression,” and how standardized and consistent was this determination between different radiologists? Such a subjective measure can complicate interpretation of the effect of a therapy.

The results were relatively unimpressive, though some could be consistent with a therapeutic benefit. There was no difference in the median survival among the three groups. However, dogs in the middle and high dose groups lived longer than has previously been reported for dogs with HAS treated only with surgery. This could be consistent with the theory that PSP had some effect on survival.

However, in the absence of an untreated control group, it is at least as likely that this group of dogs differed from those for which survival has previously been reported in some way other than the use of PSP. For example, dogs treated with surgery and not chemotherapy are typically not given any other treatment, and they are certainly not extensively evaluated monthly at a university veterinary hospital. Perhaps the owners who were willing to be a part of this trial were likely to take longer to choose euthanasia than those owners not interested in having their dogs take part for psychological reasons. Or perhaps they generally took better care of their dogs than owners not interested in participating. And it is well know that, for a variety of reasons, people who participate in a research study have better outcomes than those who don’t even if the participants are only getting a placebo, for a variety of reasons. So this result cannot reliable establish that the PSP had any effect on how long these dogs lived.

The other outcome measure, time to progression of abdominal metastases, only showed a statistically significant difference between the high-dose group and the low-dose group. There was no detectable difference between the middle group and either of the others. And the p-value, which establishes how likely this difference was to be due to chance (though not that the difference was due to the treatment), was 0.046. The usual cutoff value for significance is 0.05, so this value was only marginally significant. The difference might be due to an effect of treatment, but it might also be due to chance, especially given the small number of dogs in the trial and the lack of any control groups.

A reasonable interpretation of these results is that this small pilot study found a marginal difference between progression in the high dose group and the low dose, and this could suggest an effect of the drug or could be due to chance, measurement variability, bias, or some other factor. And the survival of the high dose group, which was roughly 6 ½ months compared to the previously reported 3 months for dogs treated with surgery alone (and 6-9 months with chemotherapy), could represent a small benefit from the PSP. Or it could simply be due to random variation or some other, undetected difference between this group of dogs and those studied previously.

Not surprisingly, the authors take a somewhat more positive position on the significance of the results.

While it is necessary to now document more robust and statistically significant differences in an appropriately powered definitive placebo controlled study, it is encouraging that clear patterns and an obvious dose choice emerged from the pilot program.

Based on this data, one could hypothesize that PSP has the potential to have effects on survival similar to that which is seen with standard of care chemotherapy.

Proving, in a biologically aggressive animal model, that PSP delivers antitumor and survival effects in a magnitude similar to that which is seen in standard chemotherapy could have significant implications for shifts in standard of care from current cytotoxic therapies to complementary compounds, such as PSP, that have little to no negative documented effects on normal cells. Most importantly, for those cancer patients throughout the world for whom advanced treatments and cytotoxic therapies are not accessible, CAM, such as PSP as a single agent, could offer benefits to survival and quality of life that are not yet imagined for those populations.

One could hypothesize that PSP is as good as standard chemotherapy for this disease, but that’s only a guess, and this study does little to support that hypothesis. The authors are correct to acknowledge that additional work is needed to demonstrate this is actually true, but they strike a tone that is just a touch more optimistic than these data would seem to justify. Such is inevitable when a researcher has a lot invested in their hypothesis, and it is understandable that the authors would try to put as positive a spin on the results as possible.

However, the suggestion that this therapy, or other alternative therapies, might potentially replace chemotherapy for cancer care is thoroughly unwarranted. For one thing, it has been shown repeatedly than avoiding conventional care in favor of alternative therapies, or even adding these therapies to conventional care, more commonly worsens outcome and quality of life. (see the studies below for a few examples). So it would take a much stronger result than that shown in this paper to even begin to justify the suggestion that alternative therapies could ever be considered a replacement for conventional care.

And the authors also seem to suggest one advantage of PSP as a cancer therapy is the absence of any side effects. No truly effective therapy for a serious disease has ever been found that is free of side effects, so this is an extraordinary hypothesis, which will require extraordinary evidence to prove. Given how unlikely the idea is, it deserves great skepticism and it is ethically questionable to put it forward as an appropriate expectation.

Finally, the authors justify their study partly on the principle that many people cannot afford conventional cancer therapy and that cheaper, possibly safer alternatives should be sought.

A large percentage of [cancer patients] will live in countries that lack the resources for cancer control. The dramatic technological changes that will continue in surgery, radiotherapy, and chemotherapy will lead to increased cure rates; however, these anticipated advances come at a price usually beyond the means of most cancer patients. It is imperative that affordable complementary and alternative treatment strategies, that could considerably reduce the global disease burden at manageable costs, are developed.

There is clear evidence that health and longevity have improved since the advent of a science-based approach to health, and that the benefits of scientific medicine have been greatest in countries which are affluent enough for people to have access to this kind of care (Fig. 1). In poorer countries, people often are forced to rely on traditional folk medicine practices that have not been scientifically validated, and they frequently have poorer health. So there is no question that there is a need to provide better healthcare to people in these countries. There is not, however, any justification for suggesting that alternative medicine, even if rigorously investigated scientifically, will meet this need.

This figure shows how life expectancy, one measure of health, has increased as the scientific approac to health has replaced traditional medicine, and how lack of access to scientific medicine is associated with lower life expectancy.

For one thing, the reason conventional care is so expensive is largely because tremendous resources are needed to properly develop and research therapies to ensure they are safe and effective. Alternative therapies are largely cheaper because this rigorous scientific study has not been carried out and such therapies are not subject to meaningful regulation requiring evidence of safety and efficacy or verifiable quality control in production and distribution. There is no reason to suppose that if alternative therapies were subject to the same standards of evidence and the same regulatory oversight as conventional medicine that they would be any cheaper.

And it strikes me as ethically questionable to suggest that the proper answer to the healthcare needs of people without access to the best scientific medicine available should be met by putting resources into developing alternative medical therapies for them. These resources would likely be better spent reducing the cost and increasing the availability of therapies already established to be effective. It is perfectly fine to look for additional or better treatments in alternative medicine (subject to reasonable use of plausibility and pre-clinical research to target limited resources efficiently), but the suggestion that such therapies can or should replace conventional care for economically disadvantaged people is not reasonable. There is no good evidence these therapies will be as safe or effective as conventional care or cheaper, so this is a weak justification for research efforts directed at alternative interventions.

Bottom Line
This paper provides an intriguing suggestion that there might be benefit to mushroom-derived PSP for patients with hemangiosarcoma. It is by no means adequate in size or design to demonstrate this to be true, and the results are actually quite weak and as likely to be due to chance or bias as to an actual effect of PSP on this cancer. However, further research into this therapy is certainly justified.

The suggestion that alternative medicine is likely to provide therapies that are as effective as conventional therapy with no side effects is implausible and contradicted by existing evidence. The idea that the proper response to the inadequate availability of proven cancer therapies for economically disadvantaged people is to put resources into investigating alternative medicine and developing a separate set of therapies for these people is an ethically dubious proposition. While investigating such therapies may be appropriate given sufficient evidence to suggest they will prove useful, it would be more appropriate to address healthcare inequities directly rather than justifying such investigation with the goal of developing separate treatments for people with different socioeconomic status.

1. Han E, Johnson N, Delamelena T, Glissmeyer M, Steinbock K. Alternative therapy used as primary treatment for breast cancer negatively impacts outcomes. Ann Surg Oncol 2011;Jan 12 [Epub ahead of print].
   
2. John A. Chabot, Wei-Yann Tsai, Robert L. Fine, Chunxia Chen, Carolyn K. Kumah, Karen A. Antman, and Victor R. Grann. Pancreatic Proteolytic Enzyme Therapy Compared with Gemcitabbine-based Chemotherapy for the Treatment of Pancreatic Cancer. Journal of Clinical Oncology. 2010;28(12):2058-63.
   
3. Kurian Joseph, Sebastian Vrouwe, Anmmd Kamruzzaman, Ali Balbaid, David Fenton, Richard Berendt, Edward Yu and Patricia Tai. Outcome analysis of breast cancer patients who declined evidence-based treatment.World Journal of Surgical Oncology 2012, 10:118.
   
4. Risberg T, Vickers A, Bremnes RM, Wist EA, Kaasa S, Cassileth BR. Does use of alternative medicine predict survival from cancer? Eur J Cancer. 2003 Feb;39(3):372-7.

I’ve written extensively about herbal remedies and dietary supplements both because these seem among the most likely to be useful of CAM therapies and also because they are widely used despite the lack of good evidence that they are safe and effective in most cases. The success of pharmaceutical medicines and vitamin supplements to treat deficiency diseases has created an expectation that taking a pill can have beneficial effects. When combined with the naturalistic fallacy (that we can identify some things as “natural” and then trust that these are safe) this predisposes people to believe dietary supplements and herbal medicines are good for them.

At least one NIH study suggests that about 18% of adults in the U.S. take some form of “natural product,” that is an herb or remedy that is not a vitamin of mineral. These consist mostly of herbal remedies, with Echinacea, Gingko biloba, garlic, glucosamine, St. John’s Wort, Ginseng, and fish oil being among the most popular. However, there is growing research evidence that these popular products don’t have the health benefits for which most people take them.

Echineacea does not appear to have consistently demonstrable benefits for cold and flu sufferers (1, 2), and there is even less evidence to support other purported benefits (3). The strongest evidence of benefit for Gingko biloba initially was for Alzheimer’s and dementia (4), however two large, long-term clinical trials have failed to support this hoped-for effect (5, 6). I’ve already written repeatedly about the consistent failure of glucosamine to perform better than placebo, and about the equivocal findings for garlic. Ginseng doesn’t perform much better, with mixed results in generally small and not high-quality research studies. (7)

Among the strongest cases for herbal or other “natural” supplements are those made for St. John’s Wort and fish oil. St. John’s Wort does appear to have some benefit for mild depression, though no greater and with no fewer risks than conventional pharmaceuticals, which aren’t themselves always consistently better than placebo (8). Not exactly a ringing endorsement for one of the most intensively studies herbal remedies, to say that it works about as well as the lousy conventional therapies it is meant to replace or complement.

The evidence is better for fish oils, which have shown some consistent, repeatable benefits in clinical studies (9). However, additional recent work has called into question even this widely accepted conclusion (10). I myself have taken fish oil supplements for years, though I have recently decided to skip the capsules and just eat more fish since, as seems to be turning out to be true most of the time, the health benefits associated with eating particular foods don’t necessarily translate into benefits from supplements based on those foods. (For what it’s worth, I also took glucosamine for a while, with no obvious effects, until the evidence against a real benefit became strong enough to convince me I was wasting my money. The key to an evidence-based approach to healthcare is both being open to new ideas and willing to abandon ideas that fail to live up to their early promise). 

So while there is support for using some popular herbal remedies and other supplements, generally the evidence is far weaker than most people suppose. And the Decline Effect is readily apparent in the research on such remedies, with pre-clinical evidence and small, low-quality early trials showing apparent benefit which then gets progressively smaller and often disappears entirely and the amount and quality of the research grows. Promising ideas are worth investigating, but most fail to live up to their promise, so jumping on a new supplement bandwagon early is usually a mistake.

Vitamin and mineral supplements are the other major piece of the supplement market. Unquestionably, there is a real benefit for these in preventing specific nutritional deficiencies. However, the optimal intake of most vitamins and minerals for most individuals isn’t known. Age, sex, lifestyle, health, and many other variables affect how much of what we need to be as healthy as possible, and almost all recommendations to take more of these products than needed to prevent a deficiency are simply made up. General and irrational use of vitamin and mineral supplements not based on specific scientific evidence has consistently proved not only to not be beneficial but in some cases to be actively harmful (11, 12, 13, 14, 15, 16).

Of course, it is a given that people will continue to take supplements even based on flimsy evidence or even when the evidence is clear that benefits are lacking and there is real risk. The desire to control our health through therapeutic rituals, to believe what we wish were true even if it may not be, and the cognitive dissonance involved in letting go of deeply held beliefs when there is strong evidence against them are all factors that make it hard to give up behaviors that we feel, even mistakenly, are beneficial for us. So what should doctors do about our patients’ supplement use?

There is a lack of consistent and coherent policies among regulators and healthcare institutions to help doctors and patients manage the use of supplements concurrently with conventional medical therapies. Many patients (or veterinary clients) don’t tell their doctors about supplement use. Given that these products can interact in dangerous ways with conventional medicines, this present a real risk. So there are a number of things doctors should do, regardless of how favorably or skeptically they view herbal remedies and supplements, to minimize the risks to their patients associated with these products. 

1. Know What Your Patient is Taking

Doctors should ask their patients or clients about supplement use at every visit. I always ask my clients if their pets are on any medications. If they say “No,” I then ask about vitamins, supplements, herbal remedies, or other healthcare products, and they very often then reveal a whole host of things they are giving their pet.

Despite their belief that these products treat or prevent disease in their pets, these owners don’t think of the products as medicine since that word is generally associated with pharmaceutical products. Only specific and detailed questioning is likely to yield a true picture of what chemicals an owner is putting into their pet’s body. 

2. Understand the Evidence

We cannot counsel our clients effectively without being knowledgeable about the products they are interested in using. If a supplement or herbal remedy is truly beneficial, we should know this and know how to use it to help our patients. And if such a product presents a danger to our patients, or is simply a waste of our clients’ money, we should know that as well.

Obviously, I am skeptical about the value of many supplements. But I own quite a few references and textbooks about such products which I consult regularly, I maintain a subscription to the Natural Medicines Comprehensive Database, and I make the effort to be informed about the current scientific evidence regarding herbs and supplements (and to make that information available to others through this blog when I can). This seems a crucial part of being a truly useful resource for my clients and patients, even if often I end up having to tell that that the evidence is inconclusive and what they are giving their pets may or may not be in their best interests.

This is not to say that all veterinarians or veterinary students should undergo specialized training in herbal medicine or the use of supplements. All too often, such training is produced by individuals with firm beliefs about the value of such products who recommend them on the basis of historical use, personal experience, or kinds of evidence weaker than, and often in conflict with, the evidence of scientific research. To have an educated, informed, and science-based understanding of supplements does not require one to be trained in their use by practitioners already committed to their worth any more than being an educated, informed, and science-based critic of astrology or homeopathy requires one to train as an astrologer or homeopath.

3. Communicate Effectively

I see educating and informing my clients as a crucial part of my job. I cannot care for my patients effectively if I cannot communicate effectively with their owners. This means presenting the facts as I understand them, and my informed opinions (which, after all, is what the client is paying me for), clearly and in a way my clients can understand. This also means not taking an adversarial position against the values and beliefs my clients hold. I see it as an ethical duty to tell my clients when I believe they are treating their pets in a way that is useless or harmful, but this message cannot be heard unless it originates from a position of respect for their intentions and their feelings and a shared desire to do what is best for the animal.

My critics would likely be surprised at how many of my clients, with whom I have long-standing relationships of trust and cooperation, utilize therapies that I actively recommend they not use. Disagreement need not lead to personal antipathy, and my clients understand that even when I tell them something they don’t believe or don’t want to hear, I am not challenging their commitment to their pets’ wellbeing or their own competence as an owner.

Veterinarians need to be honest and explicit with their clients about the evidence concerning the therapies we offer and those we recommend against, and we need to not only share what we know but also admit what we do not know. When it comes to counseling clients about the use of supplements, making clear the uncertainty about these products, and that this uncertainty applies to their safety as much as to their purported benefits, is a necessary part of helping our clients make rational, informed decisions about their pets’ care. The biggest problem with the promotion and advertising of such supplements is that they make confident claims well beyond anything even remotely justified by real evidence.

Bottom Line

Overall, there is some reason to hope that some herbal remedies and nutritional supplements will one day be a useful tool in treating our patients. However, even the best-studied of such remedies currently have only weak evidence to support safety and efficacy, and most have nearly nothing but wishful thinking to justify their widespread use, especially in veterinary medicine where good quality clinical trials of such products are almost non-existent.

This means that we need to be aware of the evidence that does exist and explicit with our clients about what it does and does not tell us. And we need to be vigilant in watching out for harm from products that are often mistakenly assumed to be inherently safe. Clearly, such products will continue to be in fairly widespread use until the political climate changes to allow meaningful regulation of them and requirements that they be validated through proper, rigorous scientific study. Until then, veterinarians need to make the effort to be a source of reliable and honest information for our clients in order to protect and care for our patients.