Capecitabine Could Greatly Lower Risk of New Breast Cancer, Recurrence or Death

Final results from the CREATE-X trial show capecitabine (Xeloda) could lower the risk of new breast cancer, recurrence or death by 30 percent or more. The randomized, phase III trial showed the most benefit in people with triple-negative breast cancer. Some oncologists have called the study “practice-changing.” LBBC first reported on early data from this trial in 2015.

Background

Breast cancer treatments are sometimes given before surgery, called neoadjuvant therapy, with the hope of shrinking the tumor, or causing it to disappear. At the time of surgery, doctors test whether any cancer cells were left behind in the breast or nearby lymph nodes. If invasive cancer cells are found after neoadjuvant therapy, researchers know that person has a higher risk of recurrence or death. Many clinical trials look at how to treat cancer that did not disappear entirely with neoadjuvant therapy.

Researchers with CREATE-X wondered if treatment after surgery, called adjuvant treatment, with the chemotherapy medicine capecitabine (Xeloda) could help people who still have cancer cells remaining despite neoadjuvant therapy. This chemotherapy works differently than others typically used for adjuvant treatment. So the researchers wondered if it would work against cancer cells left behind by pre-surgery treatment with other chemotherapy medicines.

The FDA approved capecitabine, a pill, to treat metastatic breast cancer in 1998. It is not currently approved to treat early-stage breast cancer.

Design

CREATE-X enrolled 910 women ages 20-74 with early-stage HER2-negative breast cancer in Japan and South Korea. All participants had remaining invasive cancer cells in the breast or lymph nodes at the time of surgery despite pre-surgery chemotherapy. The researchers did not include people with HER2-positive disease because of differences in the way HER2-positive and HER2-negative disease are treated.

After joining the trial, all participants had radiation therapy (if needed) and, if they had hormone receptor-positive breast cancer, hormonal therapy, both of which are standard treatments. For half the participants, treatment stopped there. The other half were assigned to treatment with capecitabine.

The original study plan was to give the capecitabine group treatment for 14 days on and 7 days off for 6 cycles. But the researchers later changed it to 8 cycles. Researchers sometimes do this if early trial information shows participants are handling side effects well, with the hope that more cycles will give better results. Six cycles of capecitabine were given to 159 of the participants and 8 cycles were given to 283 of the participants.

Results

The researchers found capecitabine significantly lowered the risk of new breast cancer, recurrence or death. The results were so significant that the researchers stopped the trial early.

This was true for everyone in the capecitabine group, whether they got six cycles or eight cycles.

After 5 years, more people in the capecitabine group were living without a new or recurring cancer than in the group that didn’t receive capecitabine:

• 74.1 percent of people in the capecitabine group were alive and free of recurrence or new invasive breast cancer
• 67.6 percent of people in the group that didn’t receive capecitabine were alive and free of recurrence or new invasive breast cancer

That means those who received capecitabine had a risk of new or recurring breast cancer or death that was 6.5 percentage points, or 30 percent, lower than those who didn’t get capecitabine.

People in the capecitabine group also lived longer, even if they had the cancer return. After 5 years:

• 89.2 percent of all people in the capecitabine group were still alive
• 83.6 percent of all people in the of the group that didn’t receive capecitabine were still alive

By Subtype

After 5 years of follow-up, all participants had better outcomes if they got capecitabine than if they didn’t. But researchers also compared the capecitabine and control groups by subtype, triple-negative and hormone receptor-positive, to see whether the treatment made a difference in outcomes.

In general, triple-negative breast cancer has a higher rate of recurrence and death in the first 5 years after diagnosis than hormone receptor-positive breast cancer. So whether they got capecitabine or not, participants with triple-negative breast cancer were more likely to face new breast cancer, recurrence or death in the first 5 years than those with hormone receptor-positive disease. This suggests people with triple-negative breast cancer had the greatest benefit from adding capecitabine when cancer remained after neoadjuvant therapy.

Among participants with triple-negative breast cancer, the capecitabine group did more than 8 percentage points better than the group that didn’t receive capecitabine:

• 69.8 percent of the capecitabine group was alive and free of recurrence or new invasive breast cancer, compared to 56.1 percent of the control group.
• 78.8 percent of the capecitabine group was still alive, versus 70.3 percent of the control group.

Among participants with hormone receptor-positive breast cancer, those who received capecitabine did about 3 percentage points better than those who didn’t get capecitabine:

• 76.4 percent of the capecitabine group was alive and free of recurrence or new invasive breast cancer, compared to 73.4 of the group that didn’t get capecitabine.
• 93.4 percent of the capecitabine group was still alive, versus 90 percent of the  group that didn’t get capecitabine.

Side Effects

Hand-foot syndrome, a skin reaction on the palms of the hands and soles of the feet, was the most common side effect of capecitabine, experienced by 73.4 percent of the group. More than 40 percent of the group experienced low blood counts, which can raise the risk of infection. More than 20 percent of the group experienced fatigue, nausea, diarrhea and inflammation of the mouth. Those who had eight treatment cycles were more likely to experience side effects than those who had six.

People in the group that didn’t get capecitabine experienced about four times fewer side effects related to low blood counts, and very few other side effects. In the group that received eight cycles of capecitabine, about one quarter had to stop treatment early due to side effects.

Limitations

Different people metabolize, or break down, medicines differently. Research shows Asians metabolize medicines like capecitabine differently than non-Asians. Since most participants in this study were Asian, results may not be the same in people who aren’t Asian.

What This Means for You

In the past, several trials of post-surgery capecitabine plus standard chemotherapy showed little success with the treatment.

This trial was different than earlier studies because it focused on giving capecitabine to people at higher risk of cancer returning because of cancer cells remaining after pre-surgery treatment. It’s possible cancer that did not respond well to pre-surgery chemotherapy will respond better to treatment with capecitabine for this group of people.

Many doctors say results of the CREATE-X trial are practice-changing. The results are especially exciting for those with triple-negative breast cancer, because it lessens the risk for recurrence and adds a new treatment option that can be taken as a pill.

Others say that it might be too early for capecitabine to become standard treatment for those with cancer cells left after neoadjuvant chemotherapy. They say more studies, particularly studies that include people of more ethnicities, are needed to confirm the results.

Because it can be taken as a pill, capecitabine may be more convenient than treatments that have to be given by a medical professional. Insurance may cover less of the cost of oral medicine than of infusions, though. Look at your policy or call your insurer to find out how much of the cost of each treatment you’d have to pay out of pocket.

Though it’s not yet FDA approved for early-stage breast cancer, some doctors are already recommending capecitabine off-label based on research like the CREATE-X study. It’s also possible treatment guidelines could change in the near future. If you have HER2-negative breast cancer and had pre-surgery chemotherapy that didn’t remove all the cancer in your breast or lymph nodes, post-surgery capecitabine could lower your risk of recurrence and death. Talk to your oncologist about whether capecitabine is a treatment option for you.

Masuda, N, Lee, S-J, Ohtani, S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017;376:2147-59;doi:10.1056/NEJMoa1612645.