Could a Topical Cream Prevent Lymphedema? Study in Mice Suggests Yes

By Matthew Tontonoz,

Wednesday, February 15, 2017

Summary

Mounting evidence implicates inflammation as a cause of lymphedema, a common side effect of cancer treatment. Topical drugs that suppress this inflammation may hold promise as a therapy.

Highlights
  • Previous research has shown that immune cells promote the inflammation that leads to lymphedema.
  • Drugs that block the action of these cells may be one way to combat the condition.
  • In mice, an FDA-approved anti-inflammatory drug applied to the skin prevented lymphedema from developing and treated it once it occurred.

One of the most dreaded complications of cancer treatment is lymphedema — the uncomfortable and often disfiguring accumulation of fluid in the arms or legs. The condition is progressive and there are no known cures.

Lymphedema most commonly occurs following the removal of lymph nodes, a procedure that can injure the delicate vessels of the lymphatic system, which helps rid the body of toxins. About one in three people who undergo a lymph node dissection will develop the complication, which translates to roughly 50,000 new cases every year. Women with breast cancer are most at risk.

“A lot of patients describe it as worse than their actual cancer diagnosis,” says Babak Mehrara, Chief of the Plastic and Reconstructive Surgical Service at Memorial Sloan Kettering. “They wake up every day and they can’t do the things they want to do. They can’t wear their wedding ring.”

Previous research from Dr. Mehrara’s lab had suggested that lymphedema results from an uncontrolled inflammatory process promoted by certain immune cells. In a new paper, published on February 10 in the journal Nature Communications, he and his colleagues show that an FDA-approved drug that quells the actions of these inflammatory cells can reverse the debilitating condition, or prevent it from developing — at least in mice.

Whether the drug — which is applied directly to the skin — will have the same positive effects in humans is a question he and his team plan to explore in clinical trials.

Telling Tails

To study lymphedema and drugs that may fight it, Dr. Mehrara’s lab uses a mouse model that reproduces the hallmark features of the condition. Following a small injury to the lymphatic vessels in their tail, the mice reliably develop inflammation and swelling as well as a scarring process called fibrosis.

“The mouse model is very effective because it mimics the histological features of lymphedema very closely,” he says. “The inflammatory changes that we see are exactly the same as those we see in patients.”

When the team tested the drug, called tacrolimus, on the mice’s tails, they found that it could prevent lymphedema from developing when applied soon after the injury. It also greatly reduced the extent of lymphedema when applied later, after the condition had already developed.

Inflammation can impair the growth of new lymphatic vessels, but the topical treatment seemed to reverse that complication too. Treated mice showed growth of new, healthy lymphatic vessels, restoring function that had been lost due to the injury. 

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A Light Bulb Moment

Dr. Mehrara says the idea to test tacrolimus as a lymphedema treatment came from his experience as a plastic surgeon. Tacrolimus is commonly used to treat several skin disorders that are caused by inflammation, including psoriasis and eczema. It’s also used to prevent tissue rejection after an operation like a hand transplant. The drug works by suppressing the action of certain immune cells called CD4-positive T cells that provoke inflammation. These are the same cells that cause lymphedema.

I thought, well, if the goal is to deplete these T cells, why not just use this drug that's already commercially available and FDA approved?
Babak J. Mehrara
Babak J. Mehrara MSK plastic surgeon

“I thought, well, if the goal is to deplete these T cells, why not just use this drug that’s already commercially available and FDA approved? And so that’s what we did,” he says.

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Safety Concerns

It’s important to note that while tacrolimus is FDA approved to treat certain inflammatory conditions, it is not a drug to be used indiscriminately. And it cannot yet be recommended or prescribed for lymphedema. 

When prescribed for inflammatory skin conditions, it’s only meant to be applied over a very small area and for a limited period of time. The drug can cause kidney toxicity if too much is used.  

“If you have lymphedema of your arm, you can’t smear tacrolimus on your whole arm because you’d get too high a dose,” Dr. Mehrara says.

Moreover, lymphedema can sometimes take years to develop and it’s not possible to predict who will develop it. Nevertheless, the study provides a proof of concept that a topical treatment for lymphedema is possible. “That’s the real point of this research paper,” he notes. 

Dr. Mehrara says he plans to start applying in June for funds to conduct a clinical trial to test tacrolimus as a topical treatment for lymphedema in people. Because of the potential toxicity issues, the trial will only be for patients with very specialized cases of limited lymphedema. 

In addition to tacrolimus, his lab is also testing several other chemicals — some that may be less toxic to the kidneys — in the hopes of finding a safe, effective treatment for this damaging condition that currently affects 6 million people in the United States.

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Comments

Could this cream be used on the leg?

Very interested in this treatment. I have lymphadema in my leg from hip to knee. Had lymph nodes removed in groin after removal of Melanoma tumor. Had spread to sentinel node. Control condition by wearing compression stockings.

Just wondered if you are studying anyone with primary Lymphedema or only those who have had cancer. I have primary and was wondering if the results would be the same.

Dear Janet, the research described in this study is still being done only in laboratory mice. It's too early to know if it will be effective in patients, and if so, which ones. Thank you for your comment, and best wishes to you.

I would be interested in being a part of your study. It's my left arm that is swollen for at least 3 or 4 years due to breast cancer 23 years ago. I do what i need to due daily to keep swelling down.

Dear Teri, these studies are still in the planning stages, and it's too early to know which patients will be helped by this treatment, if any. We suggest that you discuss how to deal with your lymphedema now with your current healthcare team. Thank you for your comment, and best wishes to you.

I am a Certified Lymphedema Therapist. I have worked with Lymphedema for almost 20 years and would love to know where to refer my clients...And what topical drugs you are using.
Paula

Dear Paula,
This treatment is still experimental and must be tested in clinical trials to determine whether it is safe and effective for people with lymphedema. If your clients are interested in learning about clinical trials at MSK, they are encouraged to visit: https://www.mskcc.org/cancer-care/clinical-trials. Thank you for your comment.

Is this on the market now? Does it need a prescription from my oncologist? How long could I use it? If I couldn't use it the length of my affected leg, do I just used it in more affected parts and by doing so, will it be absorbed and improve the rest of my leg? My whole leg is affected after three cancer surgeries...the last on was at MSK about four years ago for leiomyosarcoma. My third one. I am very diligent about self care. Creams each day, self massage, compression stockings all day, and a leg garment all night. Any other ideas would be appreciated.

Dear Ellen,
Tacrolimus is a drug that must be prescribed by a doctor. It is not yet approved for use as a treatment for lymphedema and cannot be recommended until clinical trials are done. You should talk to your doctor about the best ways to manage lymphedema in your particular case, but Dr. Mehrara did say that exercise is very good for people with lymphedema and those at risk for it. Thank you for your comment.

This give me hope that maybe there is some chance for help with this. I am newly diagnosed and am dismayed that with 50.000 new cases a year, it's not discussed with cancer patients. I never heard of it until now. I was diagnosed with Fallopian tube cancer in 2008. It's hard to believe this could come about 9 years later.

Interesting work. It reminds me of the cream: Unguentum Lymphaticum, made in Germany and used by many lymphoedema therapists in the past. We know that promoting growth of new vessels is vital, however this treatment will not promote re growth of lymph nodes and lymphoedema post cancer treatment is a consequence of node depletion not simply vessel impairment. So this is possibly another adjuvent treatment, not cure.

I have lymphedema in my right leg due to endometrial cancer. Originally it was below my knee but after a reoccurence and more aggressive radiation my entire leg is now affected severely. Have to have all my pants altered. Would love to hear of a break through treatment

Dear Maureen, we're sorry to hear that you've experienced this. Thank you for your comment, and best wishes to you.

Love to know of any trials of this used

I've never had cancer. I've developed Lymphedema in 2012 then got rid of it with therapy. Then in 2015 it came back full force. Now it's all over. Nothing I've tried has helped me this time. I am huge. My mobility is very limited. I pray everyday for some relief.
Hope someone finds a cure soon.

I have had Lymphadema for 6 years now in my leg. I have found giving up sugar and alcohol do help . I have a tarred riding a bike and this has been my biggest releif. Whether it is outside or a stationary bike. It really help my leg from feeling heavy and does help control the swelling.

20 years ago in Australia was developed Coumarin cream and powder. Due to some damages to patients it was removed from the market. Did you hear about the coumarin?

Can I use this on my legs ? I have it in both legs from hip to knee is worse. Is there any open treatments going on at this time to have the experiment done on my legs?

Dear Peggy, we're sorry to hear that you have this problem. The cream discussed on this article is not yet being tested in clinical trials. As reported in the story, it's not clear whether this treatment would be effective in patients, and it's too toxic to be used in its current form. Researchers hope to begin testing it in patients soon.

Thank you for your comment and best wishes to you.

Read your article with interest. I've just been diagnosed with lymphedema after removal of lymph nodes two years ago. Are there any clinical trials in Boston or the MA area?
I was surprised to see tacrolimus as a possible cure. My cat gets this drug as eye drops for a vision impairment. I'm going to ask the veterinarian about side effects to my cats kidneys. Thank you for talking about this.

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