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Ketoprofen for lymphedema? Proceed with Caution

By: Ryan Davey, PhD  
Last Updated: October 19, 2018
Editors: Ryan Davey, PhD and Lindsay Davey, MScPT, MSc, CDT

A new study published yesterday suggests that the anti-inflammatory drug known as ketoprofen may treat some symptoms of lymphedema. Is the hype justified?

Molecular structure of ketoprofen drug for treating lymphedema

Ketoprofen belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs). It is known to inhibit COX and 5-LO signaling pathways.

 

You can read the primary research article for yourself here (ref1), or read the accompanying press release from Stanford Medicine here. But don’t head off to read the press release without reading the below first. Like Stanford’s last press release on the related drug Ubenimex, this latest press release is demonstrably over-hyped. But unlike their last press release, this one might also be dangerously misleading for some patients.

The new ketoprofen data is really a look into the past

This latest research on ketoprofen for lymphedema isn’t really “new” per se, although it’s new to us. The authors performed the two small clinical studies described in this paper in 2010-2011 and 2011-2015, but didn’t publish the results until now. They were certainly busy in the interim.

In 2017 these same authors published a truly excellent study that advanced their understanding of how ketoprofen might work to help lymphedema patients (ref2). They concluded from this study that a related drug known as bestatin (Ubenimex) was a more promising therapeutic candidate than ketoprofen. This work prompted a Phase II clinical trial funded by Eiger BioPharmaceuticals.

Just this week, results of this Ubenimex clinical trial were also released. Unfortunately, Eiger BioPharmaceuticals concluded that Ubenimex failed to reduce swelling or skin hardening / thickness in patients with lymphedema. But we thought that this clinical trial was a long shot in the first place, so this result may not truly represent the potential of Ubenimex for treating lymphedema.

And now the earlier ketoprofen study data has finally been published along with a press release entitled “Anti-inflammatory drug effective for treating lymphedema symptoms” which hypes up the proposed benefits of ketoprofen. But didn’t the authors of this study previously conclude that they prefer Ubenimex over ketoprofen? Didn’t Ubenimex just fail to achieve significant benefit for lymphedema in a much larger clinical trial funded by a drug company? In light of this, should we believe that ketoprofen is as big of a breakthrough as the Stanford press release suggests?

Ubenimex or ketoprofen – which looks more promising according to the authors?

Sure, Eiger BioPharmaceuticals has backed away from pursuing Ubenimex, but we don’t think the story of Ubenimex should end there. The scientific story is compelling, and the data backing it up is interesting, but the clinical trial as designed was a bit of a long-shot. Now we finally have the ketoprofen data accompanied by a press release hyping it up. Let’s dig into why the authors actually prefer Ubenimex over ketoprofen.

Their research

In their foundational 2017 paper the authors of this body of work discovered that when lymphatic vessels in a mouse are damaged the resulting inflammation helps promote healing – but only up to a point. They found that a naturally occurring pro-inflammatory factor known as LTB4 (leukotriene B4) helps the healing process when a small amount is present, but begins to prevent healing as too much LTB4 accumulates in the wound. Amazingly, when they blocked LTB4 at the right time they found that healing occurred more completely, thereby reducing or eliminating entirely the onset of lymphedema in these mice.

So what did they use to block LTB4 and promote lymphatic repair? The anti-inflammatory drugs ketoprofen and bestatin (Ubenimex). They further demonstrated that LTB4 is also elevated in human lymphedema patients (not just in mice with experimental lymphedema), and when human lymphatic cells are grown in a lab, high concentrations of LTB4 stop them from growing. You can read our more detailed analysis of this fascinating work here.

Their conclusion

Importantly, the authors concluded that:

“bestatin [Ubenimex] was as effective as ketoprofen and with significantly less adverse effects”

In fact, they go on to say:

“Unfortunately, ketoprofen has gastrointestinal, cardiac, nervous system, renal, and hepatic toxicities, which potentially limit its long-term use, and safer, more targeted therapies will be necessary for amelioration and stabilization of this chronic disease.”

Why would ketoprofen have more side effects than Ubenimex?

Ketoprofen has two well-known targets, it inhibits both the 5-LO and COX pathways, whereas Ubenimex has more selective action against just the 5-LO pathway (LTB4). Many of the side effects mentioned above are likely a result of COX inhibition.

Since the authors’ found that the benefit of ketoprofen for lymphedema was likely entirely attributable to LTB4 inhibition, and that Ubenimex was at least as effective as ketoprofen at inhibiting LTB4 but with more selective action, Ubenimex appeared to be the better choice. As a result, Eiger BioPharmaceuticals initiated a Phase II clinical trial for Ubenimex.

The best data available suggests that Ubenimex may be the safer and potentially more effective therapeutic option. The problem is that unlike ketoprofen, Ubenimex is not approved by the FDA even though it has been approved as a chemotherapy adjuvant in Japan for 35 years. So let’s put Ubenimex aside for a minute since your doctor likely can’t give you a prescription for it.

What does this “new” ketoprofen data say?

First off, please disregard what the Stanford press release says, there are issues with how they represented this research. Instead, let’s focus on the actual research paper itself.

Participants in the two small pilot studies reported in the ketoprofen paper received 75 mg of ketoprofen (or placebo control in one arm of the study) orally 3 times a day for 4 months.

The authors found that ketoprofen usage did not improve limb volume (by limb circumference measurements) nor reduce levels of extracellular fluid (as measured by bioimpedance) in either their “open-label” pilot study (a weak study design) or their placebo-controlled pilot study (a stronger design).

However, both pilot studies did suggest that ketoprofen may have positive effects on the skin. In the placebo-controlled pilot study the authors found that skin thickness was statistically significantly reduced (as measured by calipers), and that the skin looked more normal (by histopathology) – although inexplicably the histopathology of some members of the placebo group also improved.

If you are curious, in the ketoprofen group skin thickness reduced from 49.4 mm (+/-5.7) to 41.4 mm (+/-5.8), which was found to be statistically significant. Thickness also reduced in the placebo control group from 49.7 mm (+/-7.0) to 47.4 mm (+/-7.7), although this was not found to be a statistically significant improvement.

The authors concluded:

“While favorable responses to ketoprofen are encouraging, the widespread, chronic use of ketoprofen is limited, as are all NSAIDs, by a black box warning regarding cardiovascular toxicity. This warning was issued by the US Food and Drug Administration (FDA) after our last subject was enrolled in the study.”

Conclusion

The available data taken as a whole suggests that chronic use of ketoprofen might help reduce inflammation in the skin of lymphedema patients, and thereby reduce skin thickness and improve skin elasticity.

There are lymphedema patients currently taking ketoprofen to help treat their skin. For some patients this may be effective, but the available studies are too small for us to recommend it broadly, in particular when considering the heterogeneity of lymphedema patients with respect to stage and symptoms.

Importantly, even if you find ketoprofen to be effective for you, the decision to consume it over the long-term needs to be balanced against the well-known (and for some individuals, potentially severe) cardiovascular and other side effects.

It’s also not yet clear if the beneficial skin effects reported are due to ketoprofen’s ability to inhibit the COX pathway or the 5-LO pathway. If its actions are due to the COX pathway then presumably other NSAIDs could be equally effective. Alternatively, if the proposed benefits of ketoprofen are due to inhibition of the 5-LO pathway, Ubenimex appears to be a more promising drug candidate. In addition, as per the 2017 study, Ubenimex (and to a lesser extent ketoprofen) may have a potentially more significant role in preventing lymphedema onset or progressive lymphatic damage by relieving inflammatory barriers to natural healing. However, this potential benefit has yet to be demonstrated in humans.

References

  1. Rockson SG, Tian W, Jiang X, et al. Pilot studies demonstrate the potential benefits of anti-inflammatory therapy in human lymphedema. JCI Insight. 2018;3(20). https://insight.jci.org/articles/view/123775
  1. Tian W., Rockson S.G., Jiang X., Kim J., et al. Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci Transl Med. 2017 May 10;9(389). http://stm.sciencemag.org/content/9/389/eaal3920

 

8 Comments

  1. Canada MALE Canada MALE says:

    Timely & thoughtful perspective, Doctor – helpful, too, for the lay patients. Your medicalese-to-English translation is appreciated by this “Lympho” (male living with LE). Please, do continue with the efforts. As with us advocates, we all need to ‘fight the good fight’ with our respective strengths & talents. All members of the “Lymphedema (LE) Community” need to become engaged…for any hopeful future in the fight vs this progressive, chronic scourge for which there is (yet!) no cure.
    Good health!
    Canada MALE (Male Advocate for LymphEdema) | FB: Lymphedema – LE Nexus Canada ✌️

  2. I agree, thanks so much Steve!

  3. Louise Louise says:

    Thank you so much for sharing your expertise in research with
    those of us wtih LE. One of my hopes for a cure has been the work of Dr.Rockson at Stanford. I need to know the current status of success with drug treatment and just as importantly its side effects. I will never knowlingly take a drug that might increase my risk for a second cancer. 

  4. That’s an understandable position to take. I should clarify that the relationship between NSAID use and cancer risk is unclear, and some studies suggest that NSAID use might REDUCE the risk of metastasis. But the effects of NSAIDs on cancer promotion will certainly depend on the type of tumor as well as the particular NSAID used, along with how much, for how long, and when it is initiated (for example before a diagnosis is made vs after treatment is initiated). So on second thought, I have decided to remove any discussion of NSAID use with respect to cancer from the above. More clinical data is needed, in particular with respect to ketoprofen, and this topic deserves a more nuanced treatment. Thanks, Ryan

  5. Deb Deb says:

    Ryan, thank you again for a timely and necessary blog response to these recent publications.

    With all of this research, we need to come to accept that there is definitely an inflammatory component that is a large component of this incurable condition, and that varies, along a spectrum of lymphedema states.

    To that end, more research to focus on particular molecules as drug targets to improve inflammatory skin changes and inflammatory damage to the tissues related to recurrent cellulitis need to be considered.  For example should an “anti-inflammatory” type of drug with a low side effect track record be used in an intermittent fashion along with antibiotics if there is active infection in order to improve recovery or reduce frequency of infection when recurrent cellulitis is a problem? Which class of those drugs are the “right” ones to target the “right” molecules? More basic research is needed!

    Secondly, if these particular “anti-inflammatory” drugs are not significantly improving lymphatic circulation when lymph is congested in the tissues (ie reducing the swelling), what processes are really at work, and how much do we understand what happens during the “normal” physiological circulation of lymph fluid?  Once all these “normal” circulatory physiological factors are understood, then perhaps a more suitable pharmaceutical intervention could be tested on the impaired process creating the swelling itself. For example, I realize “damaged plumbing” is a problem, but can a drug actually enhance the circulation that remains or that has grown to circumvent the “damaged plumbing” by way of aiding the “normal” processes that facilitate lymph circulation in a given region, even when there has been damage?

    So this research, even if announced in an exaggerated way favouring its success, has revealed extremely important knowledge that will only improve the chances of finding the “right” combination of factors to target with a pharmaceutical intervention in the future.  For this reason, I am remain thankful for it.

    In the meantime….we need to realize and speak about the importance of consistent management of the swelling with all the physical management means those of us with the condition can participate in. Sadly this therapy is unaffordable for so many. It also may not be recognized as important, when lymphedema occurs along with other co-existing medical conditions.  But we must recognize that there is an underlying inflammatory process that will seriously damage the tissues in the affected regions (or perhaps beyond, when there are other systems affected by poor lymphatic circulation), if not adequately managed.  

    And this is why we need more well researched medical intervention, in my opinion.  These underlying factors of the condition itself should not be ignored when physical management alone is too difficult or too expensive for those affected.

  6. Really great comments Deb, I think I agree with everything you’ve said. Thanks so much for contributing :)

  7. Sue Hansard Sue Hansard says:

    A really interesting analysis of research presented as proven fact. It’s sobering and a timely reminder NOT to simply accept this type of claim, but to read between the lines . I found it fascinating that skin change values were deemed statistically significant in the the lymphoedema group but very similar values in the control group were deemed insignificant! Shows how stats can be manipulated to massage the facts.Thankyou.

  8. Thanks Sue, reading beyond the headlines or between the lines is definitely important. Yes, interesting that the placebo group also saw a decrease in skin thickness that wasn’t all that different (although deemed non-significant). If the correct statistical test is used (ie the underlying assumptions of that test are met by the study population and design) then statistical significance can help us separate true differences from spurious ones. In this case, it looks like the difference for the treatment group was significant, and so it likely was. But what should we infer from the observation that the placebo group also appeared to demonstrate a small improvement but that didn’t achieve statistical significance? It likely means that the placebo group did not experience a significant decrease in skin thickness, but it could also mean that they also experienced a significant decrease in skin thickness but that the clinical trial wasn’t powerful enough (large enough) to prove it. I think it’s instructive that the authors decided to comment on the possibility that the improvement in the placebo group WAS real and hypothesized that if it were that it might be explainable by greater care and attention these patients received after becoming part of the study. If this is true there are larger repercussions on their conclusions: perhaps the skin thickness improvements in the ketoprofen group require that a patient ALSO receive adequate care, and that in the absence of proper management ketoprofen could be entirely ineffective… Again, it’s interesting :)

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