Rehab Science Blog » Lymphedema » Can Selenium Supplements Treat Lymphedema?

Can Selenium Supplements Treat Lymphedema?

By: Ryan Davey, PhD  
June 27, 2016
Editors: Ryan Davey, PhD and Lindsay Davey, MScPT, MSc, CDT

It was with great interest that I downloaded a recent review article on the topic of selenium supplements and cancer-related lymphedema (ref 1), and when I saw the authors’ summary of their findings, I had to read it right away.

Here’s what it says:

Table showing hypothesized roles for selenium supplements in lymphedema

Fig 1: Summary of the relationship between selenium and lymphedema from ref 1. Figure reproduced from ref 1 which you can find in full here:  http://www.sciencedirect.com/science/article/pii/S0946672X1630075X

 

Not only does it say that selenium supplements (in the form of sodium selenite) reduce lymphedema volume and increase the efficacy of physical therapy, it even offers a snazzy rationale for it: patients with lymphedema have reduced selenium levels, and these levels further decrease with lymphedema progression.

I found myself feeling a bit out of the loop. Why haven’t I heard about the wondrous effects of this trace mineral before? It was time to dig into the data to see what I’ve been missing.

What is selenium and why might it help treat lymphedema?

Selenium is an essential mineral found in our bodies and in various foods we eat. It is needed for the normal function of a variety of enzymes, including ones that play a role in protecting us from damaging oxygen free radicals (also known as reactive oxygen species).

These unwanted free radicals occur naturally in our bodies, but can also be created by radiation treatment, chemotherapy treatment, and as a result of poor oxygen delivery to tissues – such as that which occurs during lymphedema. These free radicals can damage cells and promote inflammatory processes, which can therefore exacerbate lymphedema.

Not surprisingly, selenium is a commonly used supplement by cancer patients. It is hoped by the many users of selenium that large doses of it may help reduce some of the side effects of cancer therapy, including nausea, diarrhea and perhaps even lymphedema.

So far it seems like a compelling story, so where’s the clinical data?

Does clinical data support a role for selenium in lymphedema?

A 2006 review in the esteemed Cochrane Database of Systematic Reviews (which was updated in 2009 with new data) concluded that evidence for the efficacy of selenium is lacking (ref 2). They reported that the available clinical data was insufficient to show that selenium supplementation decreases the side effects of cancer therapy, including decreased quality of life and secondary lymphedema.  So the authors couldn’t make a recommendation either for or against the use of selenium supplementation.

So what new information does this latest review uncover, to support their summary “highlights” in Fig. 1 above?

As it turns out, not much. The new review basically takes another look at the studies published in 2005 and prior. Their arguments appear to rest primarily on the conclusions of three underwhelming studies. One consisted merely of anectdotal evidence, a second lacked statistical rigor and focused on early postoperative swelling (which may not have been lymphedema), and the third was a review article that contained clinical data rather than a dedicated clinical study (but which I unfortunately couldn’t access to properly evaluate).

In addition to their rehash of earlier studies, the authors of this latest review added a bit of their own data to help rationalize why selenium supplementation could be beneficial for lymphedema. In short, if they could show that selenium levels were abnormally low in lymphedema patients, this might provide a rationale for why selenium supplements could be beneficial. Their study consisted of measuring selenium levels in the blood of a population of 234 people with lymphedema of various types and stages, as well as patients with lipedema.

They concluded from their study that:

  1. People with secondary lymphedema display reduced blood selenium levels. Unfortunately their data simply does not show this. This is because their study didn’t include participants without lymphedema (or lipedema), so they frankly never tested this hypothesis. Furthermore, their data showed no difference in selenium levels between patients with lymphedema and those with lipedema. So patients with secondary lymphedema show reduced selenium levels compared to whom?
  2. Blood selenium levels decrease with increasing lymphedema stage. Unfortunately their data simply does not show this. They present a figure (reproduced as Figure 2 below) that shows by their statistical analysis that Stage III lymphedema patients have less blood selenium levels than Stage I or Stage II patients, but not that Stage II patients have less than Stage I. So use of the word “increasing” is incorrect. Moreover, I think their conclusion that Stage III patients have less blood selenium levels than Stage I and Stage II patients is also very questionable because of the statistical method they used. – NERD ALERT – Only read the remainder of this paragraph if you happen to enjoy statistics. Without getting too technical, the authors used a non-parametric Mann-Whitney U test. I don’t think most of my fellow biologists would reach for this type of test in this case. To use this test you need to first do a test to show that the data is not normally distributed (which they didn’t describe nor show) and you also need to perform a correction when looking at the differences between multiple conditions (which they didn’t describe). Furthermore, take a look at the error bars in Figure 2. Conventional statistical methods such as ANOVA would rule these reported differences to be non-significant. Perhaps not surprisingly then, the authors’ statistical approach also generated the inexplicable conclusion that selenium levels differ between patients with primary and secondary lymphedema.
Figure of selenium levels in blood vs stage of lymphedema

Fig 2: Mean selenium concentration in the blood of patients at different stages of lymphedema. Statistical significance p-values were calculated by the authors using the non-parametric Mann-Whitney U test. Figure was reproduced from ref 1 which you can find in full here: http://www.sciencedirect.com/science/article/pii/S0946672X1630075X

 

One last point of interest with respect to this new review article: two of the three authors on the paper have a potential conflict of interest in that they work for a German pharmaceutical company that manufactures high-concentration selenium supplements. This of course doesn’t mean that there are any integrity concerns with respect to this study, but it should be noted.

So in conclusion, the Cochrane study summarizes the data to date nicely:

“Research findings do not provide a basis for any recommendation in favour or against selenium supplementation in cancer patients”.

Taking all of the above into consideration, it looks like Figure 1 above should be modified as follows:

Table showing a corrected summary of the relationship between selenium and lymphedema

Fig 3: Summary of the relationship between selenium and lymphedema from ref 1. Reproduced from ref 1 and modified by Ryan to better reflect the available data.

 

The real issue with selenium supplementation for lymphedema

Let’s pretend for a moment that the selenium supplementation studies showed conclusively that selenium improves lymphedema symptoms. Who knows, some good clinical data might some day support this. If so, should you start taking selenium supplements to treat lymphedema?

Probably not, and here’s why:

  1. Lymphedema is a chronic condition. Selenium supplementation as described in the few clinical studies to date use high (perhaps very high?) doses of selenium (1000 ug per day) over a few weeks, although with the expectation that levels would be reduced, perhaps to as low as 300 ug per day for the long term. While 1000 ug per day appears in these studies to be safe in the short-term, long term selenium intake studies in China saw selenosis toxicity appearing above 910 ug per day, and 400 ug per day was considered the maximum safe dose (ref 3). Selenium side effects include nail discolouration and loss, hair loss, diarrhea, fatigue, joint pain, and nausea.
  2. Lymphedema is caused by a mechanical failure to adequately clear lymph fluid. If selenium does turn out to be effective at relieving free radical induced inflammatory processes in lymphedema, this might reduce symptoms for a subset of lymphedema patients who have a selenium deficiency. But selenium supplements can’t repair the underlying lymphatic issue, or prevent the progressive tissue changes that accompany it.

So should I consider taking selenium supplements?

You should discuss with your doctor before deciding to take any dietary supplements.

If you are currently receiving cancer treatment, or will be soon, ask your doctor about selenium. Short-term supplementation of high doses of selenium immediately following (or during) cancer therapy might help with some of the side effects of cancer treatment.

Even though the above mentioned Cochrane review concluded that sufficient evidence is lacking to support the use of selenium to treat the side effects of cancer therapy, it sets a high bar for clinical evidence. Since its publication, various researchers have continued to investigate and argue that selenium may decrease various side effects, in particular those caused by radiation therapy (ref 4). Nevertheless, most researchers would agree that more studies are needed to confirm the possible benefits of selenium supplementation, and to determine an optimal dosing level and schedule.

But don’t expect selenium supplements to decrease your chances of developing secondary lymphedema, as no evidence supports this. There is also no evidence (or physiological basis) to suggest that selenium supplementation can cure lymphedema.

At best, current proponents of selenium supplementation point to low quality studies that appear to suggest that very high doses of selenium may help reduce lymphedema swelling and/or decrease the risk of bacterial infection in the short term.

Even if this proves to be true (and it may not) there is no clinical data supporting long-term selenium supplementation for managing the symptoms of lymphedema. In fact, the long-term intake of high doses of selenium is likely to be hazardous to your health (see discussion above). While dietary recommendations for selenium are sparse, the US Food and Nutrition Board, Institute of Medicine, recommends a dietary allowance of only 55ug/day (ref 5).

Rather than experimenting with supplements, lymphedema can be effectively managed through self-care and self-monitoring practices including self-massage, compression garments, and skin care. A lymphedema therapist trained in complex decongestive therapy (CDT) can help you get your symptoms under control, and educate you about tried and true self-care practices.

While the benefits of selenium seem overhyped, It may be heartening for you to know that  a variety of drug candidates are currently under investigation as potential treatments for the symptoms of lymphedema. The most promising of which may be Ubenimex.

References

  1. Pfister C., Dawzcynski H., Schingale F.J. Sodium selenite and cancer related lymphedema: Biological and pharmacological effects. J Trace Elem Med Biol. 2016 May 24 [Epub ahead of print].
  2. Dennert G., Horneber M. Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD005037.
  3. Yang G.Q., Wang S.Z, Zhou R.H. et al. Endemic selenium intoxication of humans in China. Am J Clin Nutr. 1983 May;37(5):872-81.
  4. Puspitasari I.M., Abdulah R., Yamazaki C., et al. Updates on clinical studies of selenium supplementation in radiotherapy. Radiat Oncol. 2014 May 29;9:125.
  5. Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of DRIs, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. DRI Dietary Referece Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington D.C: National Academy Press; 2000.

4 Comments

  1. Helen Maleh Helen Maleh says:

    I found your review of the selenium/lymphedema question very interesting. I do go by the Cochrane review meta-analysis. However, where is the evidence done by the Cochrane review that recommends Total Decongestive therapy? Can you provide the links please? From what I read the Cochrane meta-analysis does not show any evidence for Total Decongestive therapy. Also, I think the drug you refer to eubinex is currently being studied in a trial However I think it is also important to note that the drug company that is making the drug is also supporting this clinical trial. Thanks for your information. 

  2. Ryan Davey Ryan Davey says:

    Hi Helen,

    I support taking a skeptic view, and I also value Cochrane Systematic Reviews. Good for you :)

    Regarding clinical evidence supporting combined (or total) decongestive therapy (CDT) for lymphedema, there is a good amount of clinical data, but which usually takes the form of evaluating the primary components of CDT, that being: compression garments, manual lymphatic drainage, skin care, etc. Broadly speaking, this body of clinical evidence supports it’s use, and accordingly, it is currently the gold-standard conservative treatment recommended by the Lymphology Association. In terms of Cochrane reviews, there aren’t Cochrane reveiws of every medical intervention available (many common health interventions have very little clinical data supporting them), but off hand, here’s a link to one Cochrane review that evaluates manual lymphatic drainage for breast cancer related lymphedema, and concludes (with caveats – there are always caveats when you’re dealing with combining data from many small trials that were performed with different protocols) that “MLD is safe and may offer additional benefit to compression bandaging for swelling reduction.” https://www.ncbi.nlm.nih.gov/pubmed/25994425. It’s important to also keep in mind that there is a different burden of evidence required before we can confidently recommend different clinical interventions. For example, very little clinical evidence is required to support the practice of using compression garments because: (1) there is a very clear physical and biological mechanism underlying why it helps reduce limb swelling, (2) it is a relatively safe and easy practice, (3) receiving compression does not exclude the patient from doing other recommended treatments, (4) there is a long history of anecdotal evidence supporting it’s use, (5) there is a very clear and demonstrable effect – limbs reduce in size when you compress them. I’m anticipating you wondering if a “clear physical or biological mechanism” underpins manual lymphatic drainage. Here’s a link to a recent neat infrared imaging examination of how MLD stimulates lymph flow in healthy people (https://www.ncbi.nlm.nih.gov/pubmed/28749744). In contrast, pharmacological interventions should require SUBSTANTIALLY more clinical evidence because they don’t typically benefit from the five conditions listed above.

    In terms of ubenimex, you are correct. There is a clinical trail ongoing that is funded by a drug company. You can see more information on my article about it here: https://torontophysiotherapy.ca/ubenimex-bestatin-for-treating-lymphedema/ Unfortunately, public health agencies around the world are unable to independently evaluate treatments, so these studies are instead sponsored by those who will benefit financially from it being approved. That said, health agencies (in particular the FDA), do a good job setting the standards for such studies, and reviewing and evaluating the quality of the results. So the result is that very few drugs get pulled off the market.

    I hope this gives you additional food for thought :)

  3. Christina Pfister Christina Pfister says:

    Thanks for reading and discussing my review in depth. Naturally I have a different opinion on several points you mentioned. It would be a rather long text, if I explained my points in detail, but there are a few points I’d like to add for clarification: First: It is not about treating lymphedema with food supplements. The trials used approved pharmaceuticals in form of sodium selenite, which is for example approved in Germany and have to be prescribed. Therefore, it is clear that a high-dosed therapy with sodium selenite should only be used under supervision. Second: The review states exactly how long the high–dosed sodium selenite therapy was used, which was depending on the trial up to three month without side effects. You mentioned the daily lifelong selenium dose of 400 microgram a person can take in without any side effects. The 1000 microgram in the trials is only the initial dose and is after a short time reduced to 500 microgram and then 300 microgram. This makes clear that a long-term usage would contain of 300 microgram selenium as sodium selenite per day, which is below 400 microgram. Third: As you might noticed I say sodium selenite not selenium. As described in the review there is a direct pharmacological effect of sodium selenite, which has not been shown for other selenium forms. Fourth: As you correctly mentioned, I am a little bit biased. i work for biosyn, a small pharma company from Germany, which is specialized in selenium pharmaceuticals. We would be happy, if independent researches would be more active in the research for lymphedema. But the reality is different. Therefore, we decided to work together with doctors, who are specialized in this field and want to do research, but don’t have the time to do it on their own.

  4. Hi Christina,

    Thank you for taking the time to comment, and for the clarifications on your work. I’ve corrected the above to make it clear to the reader that the expectation would be to gradually reduce supplementation levels to 300 ug for the long term, rather than to keep it at a presumably much more toxic 1000 ug.

    The lymphedema community is very thankful when anyone, commercial or academic, takes up a pipette and tries to help. So thank you for your interest in lymphedema, and I hope that any future work you are involved with is successful!

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