Carboplatin Shows Promise, but Adding Avastin to Standard Chemo Before Surgery Adds More Severe Side Effects in Women Diagnosed With Triple-Negative Disease

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Doctors hoped Avastin (chemical name: bevacizumab) would be an effective breast cancer treatment when the U.S. Food and Drug Administration conditionally approved it for this use in 2008. The targeted therapy, which is also used to treat advanced-stage cancers of the lung, colon, and rectum, stops the growth of blood vessels that help tumors grow.

In late 2011, the FDA removed the breast cancer indication from Avastin, saying that follow-up studies hadn’t proven the drug was effective and safe for breast cancer.

Still, many doctors continue to use it off-label, prescribing it to women diagnosed with breast cancer if they think the medicine will offer benefits. Most commonly, Avastin is used in combination with chemotherapy to treat metastatic breast cancer. Metastatic breast cancer is cancer that has spread to parts of the body away from the breast, such as the bones or liver.

But new research has continued to be disappointing. The latest results found that adding Avastin to a standard chemotherapy regimen before surgery increased the number of severe side effects in women diagnosed with early-stage triple-negative breast cancer. The researchers felt these risks outweighed any benefits Avastin offered. Still, the study did suggest that adding carboplatin to the standard regimen offers benefits.

The study, “Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance),” was presented on December 13, 2013 at the 2013 San Antonio Breast Cancer Symposium.

Treatment given before surgery to weaken or shrink the cancer is called neoadjuvant treatment. Neoadjuvant treatment often is recommended when the breast cancer is large, aggressive, and/or has spread beyond the breast to surrounding tissue.

Triple-negative breast cancer is:

  • estrogen-receptor-negative
  • progesterone-receptor-negative
  • HER2-negative

About 15% to 20% of breast cancers are triple-negative. Triple-negative cancers usually are more aggressive, harder to treat, and more likely to come back than cancers that are hormone-receptor-positive and/or HER2-positive. Hormonal therapy and the targeted therapies Herceptin (chemical name: trastuzumab), Tykerb (chemical name: lapatinib), and Perjeta (chemical name: pertuzumab) usually don't work on triple-negative breast cancer.

Because triple-negative breast cancer is aggressive and there are a limited number of treatment choices, doctors are looking for new ways to treat it, especially early-stage triple-negative disease.

Carboplatin is the only platinum-based chemotherapy medicine approved by the U.S. Food and Drug Administration (FDA) to treat breast cancer. Platinum-based chemotherapy weakens or destroys breast cancer cells by damaging the genetic material in the cells and making it hard for cells to repair any genetic damage. Carboplatin is used to treat advanced-stage breast cancer and is usually given in combination with other chemotherapy medicines.

In this study, called the CALGB 40603 study, the researchers randomly assigned 454 women diagnosed with early-stage triple-negative breast cancer to get one of four neoadjuvant treatment regimens:

  • the first group received 12 weeks of Taxol (chemical name: paclitaxel), followed by four rounds of Doxil (chemical name: doxorubicin) and Cytoxan (chemical name: cyclophosphamide)
  • the second group received 12 weeks of Taxol plus carboplatin, followed by four rounds of Doxil and Cytoxan
  • the third group received 12 weeks of Taxol plus Avastin, followed by four rounds of Doxil and Cytoxan
  • the fourth group received 12 weeks of Taxol plus carboplatin and Avastin, followed by four rounds of Doxil and Cytoxan

After neoadjuvant treatment, the women had surgery to remove the breast cancer. A pathologist examined the removed tissue to see if there were signs of cancer cell activity. One way doctors judge the effectiveness of treatment given before surgery is to look at the tissue removed during surgery to see if any active cancer cells are present. If no active cancer cells are there, doctors call it a “pathologic complete response.” Many doctors believe that a pathologic complete response to neoadjuvant treatment means the cancer is less likely to come back.

The researchers looked at pathologic complete response rates in the breast:

  • 60% of the women who got carboplatin had a pathologic complete response compared to 46% of women who didn’t get carboplatin
  • 59% of women who got Avastin had a pathologic complete response compared to 48% of women who didn’t get Avastin

These results were significant, which means they were likely due to the difference in medicine and not just to chance.

The researchers also looked at pathologic complete response rates in both the breast and the lymph nodes:

  • 54% of women who got carboplatin had a pathologic complete response compared to 41% of women who didn’t get carboplatin; this result was significant
  • 52% of women who got Avastin had a pathologic complete response compared to 44% of women who didn’t get Avastin; this difference wasn’t significant, which means that it could have been due to chance and not because of the difference in medicines

When the researchers compared serious side effects among the four groups of women, they found that women who got Avastin were more likely to have:

  • bleeding
  • high blood pressure
  • infection
  • blood clots, especially blood clots in the lungs

Based on the results, the researchers said they would recommend adding carboplatin to the standard neoadjuvant treatment regimen for early-stage triple-negative breast cancer, but not Avastin.

“It clearly is an active drug,” lead researcher William Sikov, M.D., associate professor of medicine at the Warren Alpert Medical School of Brown University said in an interview. “But if you have to balance benefit and risk, I think the side effects -- some of which are serious and life-threatening with bevacizumab -- would argue against it being routinely used.”

If you’ve been diagnosed with triple-negative breast cancer, you and your doctor will develop a treatment plan that will likely include chemotherapy and possibly targeted therapy medicines. No matter which treatments are recommended for you, you may want to talk to your doctor about:

  • why each treatment is recommended (including any combinations)
  • treatment timing and sequence
  • the expected benefits, risks, and side effects of each treatment

If you’ll be getting neoadjuvant treatment and carboplatin isn’t part of the regimen, you may want to talk to you doctor about this study and ask if including carboplatin makes sense for your unique situation.

For more information, visit the Breastcancer.org pages on Triple-Negative Breast Cancer.


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