Feature

Ketoprofen 'a huge step forward' for treatment of lymphedema symptoms

The anti-inflammatory drug ketoprofen appeared to effectively treat lymphedema symptoms and ease the burden of care, according to study results.

“Ketoprofen restores the health and elasticity of the skin. ... I believe it will reduce recurrent infection [and] can also reduce swelling,” Stanley G. Rockson, MD, professor of cardiovascular medicine at Stanford University School of Medicine, said in a press release. “This new treatment does not cure lymphedema, but our studies show it has the capacity to make the illness more livable and more workable.”

Lymphedema — a common condition that stems from a damaged lymphatic system — leads to swelling in one or more parts of the body. It typically affects the legs and arms.

Although lymphedema can be hereditary, it is common among patients with cancer who undergo lymph node-removing surgery.

Rockson and colleagues conducted two pilot trials to examine the safety and efficacy of ketoprofen among a small cohort of patients with lymphedema.

The first exploratory trial included 21 patients with primary or secondary lymphedema who received 75 mg ketoprofen three times daily. Researchers observed significant improvements in histopathology and skin thickness at 4 months compared with baseline.

Researchers then conducted a double-blind, placebo-controlled trial in which 34 patients with lymphedema received ketoprofen (n=16) or placebo (n=18). A change in skin thickness as measured by skin calipers served as the primary endpoint. Secondary endpoints included histopathology, limb volume, bioimpedance and systemic inflammatory mediators.

Results showed significant reductions in skin thickness with ketoprofen, as well as improvements in composite measures of histopathology, and decreases in plasma granulocyte-colony stimulating factor expression.

HemOnc Today spoke with Rockson about the trials, the clinical implications of the findings and next steps for research.

Question : Can you explain the rationale for these trials?

Answer: I began this work in animal models more than 15 years ago. I wanted to understand what it is in the body that characterizes an abnormal response and leads to the development of lymphedema. This is where the animal model came into play. This led us to identify conclusively for the first time that tissue in lymphedema is expressing a profound inflammatory reaction, and the molecular signature of this appeared to be quite specific. We identified a specific pathway that we thought may be uniquely involved in allowing the lymphedema to express itself. Subsequent work allowed us to substantiate this initial impression. We learned that the byproduct of this inflammatory response was to block the lymphatics’ ability to repair themselves, and this probably represented the difference between those who develop lymphedema and those who do not. It also allowed us to identify specific drugs that may block this pathway from being activated in a targeted way.

Q: How did you conduct the research and what did you find?

A: The human trial was performed in two phases. The first phase looked at open-label use of ketoprofen. We examined patients’ skin prior to treatment and after 16 weeks of treatment. We found that both the appearance of the skin under the microscope and the skin thickness had a tendency to normalize with treatment. We then conducted a second pilot study in which we randomly assigned patients to 16 weeks of either placebo or ketoprofen. At the end of 16 weeks, the study met its primary endpoint. Ketoprofen-treated patients demonstrated a reduction in the thickness of skin, whereas those who received placebo did not. We also saw that the appearance of the skin under the microscope normalized with ketoprofen but not with placebo.

Q: Did you observe any adverse events associated with this treatment ?

A: This study included a relatively small number of patients, but we had no significant adverse events reported during the trial. However, we know this class of nonsteroidal anti-inflammatory drugs is capable of causing significant side effects, such as gastrointestinal bleeding and effects on kidney function. After we finished this trial, the FDA placed a black box warning on all NSAIDs indicating they may confer cardiac toxicities, as well.

Q: What is next for research?

A: We have identified another drug that we think will be effective, based upon our animal work, that specifically targets the molecular culprit in lymphedema. We are concluding an initial clinical trial using this drug and, once we finish this, there will be some very specific downstream events related to this. As far as ketoprofen is concerned, I would like to look at the biology of the drug response a little more closely. I would like to understand a little better whether there are markers in the blood prior to treatment that will help us predict which patients will respond to this therapy.

Q: What are the clinical implications of the findings ?

A: Safety is already on the table to a significant degree because this drug, and NSAIDs in general, have been used in general medicine for 40 years. I think we can say they are relatively safe. On the other hand, lymphedema is a nontrivial medical problem that dramatically changes a person’s quality of life. This drug has demonstrated that it has efficacy for treatment response that we desire. For many, the balance of risk and benefit will be in favor of treatment.

Q: Is there anything else that you would like to mention?

A: I treat nearly 1,000 patients with lymphedema each year. I know what a horrible sentence it is for these patients, so to have a proven medication that can reverse the condition is a huge step forward. I suspect that the patient community will be avid for an opportunity to attempt this treatment. However, two things should be kept in mind. In our clinical trials, the responsiveness of the disease to drug therapy was not immediate. Also, any patient or practitioner contemplating this therapy needs to have a thorough assessment of the patient’s clinical presentation prior to deciding if this is appropriate. – by Jennifer Southall

Reference:

Rockson SG, et al. JCI Insight. 2018;doi:10.1172/jci.insight.123775.

For more information:

Stanley G. Rockson , MD, can be reached at Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Drive, Stanford, CA 94305; email: rockson@stanford.edu.

Disclosure : Rockson reports no relevant financial disclosures.

The anti-inflammatory drug ketoprofen appeared to effectively treat lymphedema symptoms and ease the burden of care, according to study results.

“Ketoprofen restores the health and elasticity of the skin. ... I believe it will reduce recurrent infection [and] can also reduce swelling,” Stanley G. Rockson, MD, professor of cardiovascular medicine at Stanford University School of Medicine, said in a press release. “This new treatment does not cure lymphedema, but our studies show it has the capacity to make the illness more livable and more workable.”

Lymphedema — a common condition that stems from a damaged lymphatic system — leads to swelling in one or more parts of the body. It typically affects the legs and arms.

Although lymphedema can be hereditary, it is common among patients with cancer who undergo lymph node-removing surgery.

Rockson and colleagues conducted two pilot trials to examine the safety and efficacy of ketoprofen among a small cohort of patients with lymphedema.

The first exploratory trial included 21 patients with primary or secondary lymphedema who received 75 mg ketoprofen three times daily. Researchers observed significant improvements in histopathology and skin thickness at 4 months compared with baseline.

Researchers then conducted a double-blind, placebo-controlled trial in which 34 patients with lymphedema received ketoprofen (n=16) or placebo (n=18). A change in skin thickness as measured by skin calipers served as the primary endpoint. Secondary endpoints included histopathology, limb volume, bioimpedance and systemic inflammatory mediators.

Results showed significant reductions in skin thickness with ketoprofen, as well as improvements in composite measures of histopathology, and decreases in plasma granulocyte-colony stimulating factor expression.

HemOnc Today spoke with Rockson about the trials, the clinical implications of the findings and next steps for research.

Question : Can you explain the rationale for these trials?

Answer: I began this work in animal models more than 15 years ago. I wanted to understand what it is in the body that characterizes an abnormal response and leads to the development of lymphedema. This is where the animal model came into play. This led us to identify conclusively for the first time that tissue in lymphedema is expressing a profound inflammatory reaction, and the molecular signature of this appeared to be quite specific. We identified a specific pathway that we thought may be uniquely involved in allowing the lymphedema to express itself. Subsequent work allowed us to substantiate this initial impression. We learned that the byproduct of this inflammatory response was to block the lymphatics’ ability to repair themselves, and this probably represented the difference between those who develop lymphedema and those who do not. It also allowed us to identify specific drugs that may block this pathway from being activated in a targeted way.

PAGE BREAK

Q: How did you conduct the research and what did you find?

A: The human trial was performed in two phases. The first phase looked at open-label use of ketoprofen. We examined patients’ skin prior to treatment and after 16 weeks of treatment. We found that both the appearance of the skin under the microscope and the skin thickness had a tendency to normalize with treatment. We then conducted a second pilot study in which we randomly assigned patients to 16 weeks of either placebo or ketoprofen. At the end of 16 weeks, the study met its primary endpoint. Ketoprofen-treated patients demonstrated a reduction in the thickness of skin, whereas those who received placebo did not. We also saw that the appearance of the skin under the microscope normalized with ketoprofen but not with placebo.

Q: Did you observe any adverse events associated with this treatment ?

A: This study included a relatively small number of patients, but we had no significant adverse events reported during the trial. However, we know this class of nonsteroidal anti-inflammatory drugs is capable of causing significant side effects, such as gastrointestinal bleeding and effects on kidney function. After we finished this trial, the FDA placed a black box warning on all NSAIDs indicating they may confer cardiac toxicities, as well.

Q: What is next for research?

A: We have identified another drug that we think will be effective, based upon our animal work, that specifically targets the molecular culprit in lymphedema. We are concluding an initial clinical trial using this drug and, once we finish this, there will be some very specific downstream events related to this. As far as ketoprofen is concerned, I would like to look at the biology of the drug response a little more closely. I would like to understand a little better whether there are markers in the blood prior to treatment that will help us predict which patients will respond to this therapy.

Q: What are the clinical implications of the findings ?

A: Safety is already on the table to a significant degree because this drug, and NSAIDs in general, have been used in general medicine for 40 years. I think we can say they are relatively safe. On the other hand, lymphedema is a nontrivial medical problem that dramatically changes a person’s quality of life. This drug has demonstrated that it has efficacy for treatment response that we desire. For many, the balance of risk and benefit will be in favor of treatment.

PAGE BREAK

Q: Is there anything else that you would like to mention?

A: I treat nearly 1,000 patients with lymphedema each year. I know what a horrible sentence it is for these patients, so to have a proven medication that can reverse the condition is a huge step forward. I suspect that the patient community will be avid for an opportunity to attempt this treatment. However, two things should be kept in mind. In our clinical trials, the responsiveness of the disease to drug therapy was not immediate. Also, any patient or practitioner contemplating this therapy needs to have a thorough assessment of the patient’s clinical presentation prior to deciding if this is appropriate. – by Jennifer Southall

Reference:

Rockson SG, et al. JCI Insight. 2018;doi:10.1172/jci.insight.123775.

For more information:

Stanley G. Rockson , MD, can be reached at Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Drive, Stanford, CA 94305; email: rockson@stanford.edu.

Disclosure : Rockson reports no relevant financial disclosures.