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Monday, August 25, 2014

ONLINE FIRST: More Evidence that Tamoxifen Gels May Work as Well as Oral Medication but with Fewer Side Effects



Presurgical application of a gel containing an active metabolite of tamoxifen was just as effective in inhibiting cell proliferation as oral tamoxifen in women with estrogen receptor-positive ductal carcinoma in situ (DCIS), but with lower levels in the blood and hence potentially fewer serious side effects, according to a small Phase II trial.


In the study, published in Clinical Cancer Research (2014;20:3672-3682), researchers tested the gel, which contains the breakdown product 4-hydroxytamoxifen (4-OHT), in 26 patients enrolled in the randomized, double-blind, placebo-controlled study, 12 of whom used the gel. After six to 10 weeks, the gel was found to reduce Ki-67, a key marker of cell proliferation in the breast, at rates comparable to those achieved with oral tamoxifen over a similar period of time.


The team, led by senior author Seema A. Khan, MD, Professor of Surgery at Northwestern University Feinberg School of Medicine, found equal amounts of 4-OHT in the breast tissue of patients in both the gel and oral arms (5.8 versus 5.4 ng/g, respectively) collected during surgery, but the level of 4-OHT in the blood of patients from the gel arm was 5.5-fold lower than in those in the oral tamoxifen arm (0.2 versus 1.1 ng/ml, respectively).


Oral tamoxifen decreases the risk of cancer recurrence in the same breast and secondary primary cancer in the other breast. Studies have shown, however, that as many as half of eligible women decline or fail to adhere to treatment out of concern for side effects, which can include an increased risk of thromboembolism, endometrial and uterine cancers, hot flashes, vaginal, and other symptoms.


Oral tamoxifen must be broken down by the liver into its active components, which include 4-OHT, but it then enters the bloodstream. Because of this, harmful side effects can arise, such as the activation of certain proteins that cause blood clots and increased risk of endometrial and uterine cancers.


“We found that applying the gel to the skin resulted in high drug levels in the breast but not in the blood, which mean that it maintains the effectiveness of the drug but should minimize serious side effects,” she said in an interview. “When the 4-OHT gel is applied directly to breast skin it is not directly metabolized by the liver, which should eliminate the risk of blood clots.”


Unfortunately, though, the trial had to end before the researchers could accrue their full target of subjects because the shelf-life of 4-OHT gel expired and the manufacturer had made a decision to stop making it. “Until then we had worked up a good head of steam, so it was back to the drawing board,” Khan said.


She noted, though, that other tamoxifen breakdown metabolites are either available or in development and the team is planning a study using a similar gel, endoxifen, another tamoxifen breakdown metabolite.  At the most recent San Antonio Breast Cancer Symposium, Matthew P. Goetz, MD, Deputy Director of the Mayo Clinic Breast Cancer Specialized Program of Research Excellence, reported encouraging anti-tumor results using the oral form of endoxifen in a Phase I trial involving 22 women with estrogen receptor (ER)-positive breast cancer (Abstract  PD3-4)


Study Details

In the Northwestern trial (first author is Oukseub Lee, PhD), all the patients had ER-positive ductal carcinoma in situ and were between the ages of 45 and 86. Starting six to 10 weeks before surgery, half of the women applied 1 ml of the gel to the skin of each breast every morning. Patients in the oral tamoxifen group took a 20 mg tamoxifen capsule every day. One ml of the gel contains 2 mg of 4-OHT.


Each patient provided blood samples at the beginning and end of the trial and completed the Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire at 15 days, at the end of the study, and at a post-surgery visit.


Responses to the questionnaire showed that the women who applied tamoxifen gel had no significant improvement over those in the oral medication arm in vaginal or gastrointestinal symptoms, hot flashes, or night sweats. Khan noted that such side effects, although not serious, may be responsible for the less than optimal adherence rates to oral tamoxifen.


‘Intrigued, but Still Early’

Asked for her opinion for this article, Anees Chagpar MD, Director of the Breast Center at Smilow Cancer Hospital of Yale University School of Medicine, said, “I am not sure we are quite ready to switch to the gel yet. This was a small study, with just 12 women in the tamoxifen-gel arm. While I am encouraged that Ki-67 was reduced to the same degree in both oral and topical gel arms, and that both resulted in similar side effects like vaginal drying and hot flashes, it may be premature to draw any conclusions from differences in clotting profile because the study was not powered for this endpoint, and actual thromboembolic events were not quantitated.


“Even so, I am intrigued,” she continued. “The study was well thought out, and I like the presurgical window design. While the authors wondered whether the study accrued slowly as patients did not want to delay surgery, it allowed for pre- and post-Ki67 measurements that were critical for discovering that perhaps transdermal tamoxifen therapies deserve more research.”


Chagpar noted that transdermal approaches for hormonal therapy have so far not generated much interest. “This study, however, suggests that such an approach might be beneficial. I wonder if a patch might be more conducive for patients rather than the gel, and perhaps a larger randomized trial with longer follow-up would provide greater insight into whether the changes noted in coagulation parameters will translate into a meaningful difference in thromboembolic events.”


Khan said that there is interest in a transdermal patch of tamoxifen breakdown, including one study of an NSAID patch used for pain relief by athletes that might also provide some anti-inflammatory benefits in breast cancer. The researchers, though, found that distribution of the active agent was uneven with the patch. Moreover, it was deemed more intrusive by trial subjects.


“We have a study of a gel containing an anti-progesterone agent and endoxifen gel that we expect to be ready to start this fall. It should take about two year to complete and another year for the data to be analyzed. In terms of timing, realistically the likelihood of widespread availability of some type of tamoxifen gel is probably seven to eight years away.”