Low-dose Chemotherapy Plus Antiangiogenesis Drug Has Activity In Advanced Breast Cancer

In a pilot study of 55 patients, the combination of low-dose chemotherapy and the anti-VEGF antibody, bevacizumab (Avastin; Genentech) delayed the breast cancer's progression by an average of 5 ½ months, compared to two months with the low-dose chemotherapy alone, said Harold Burstein, MD, PhD, a medical oncologist at Dana-Farber. He will present the results in a General Session at the annual San Antonio Breast Cancer Symposium on Thursday, Dec. 8.

"Pairing metronomic therapy with a dedicated angiogenesis inhibitor showed clinical activity, and was quite well tolerated," said Burstein. "We think this is a combination worth pursuing and are exploring this treatment concept further in a Phase II study, which extends these treatments into early stage breast cancer therapy."

The current study is one of the first rigorous tests of a treatment strategy that was proposed several years ago as a means of improving the results of chemotherapy for breast cancer, said Burstein, who is also an assistant professor of medicine at Harvard Medical School.

Historically, high doses of chemotherapy are given at intervals of two to three weeks, with time off the drug to recover from side effects. However, laboratory researchers have suggested that this rest period also allows the blood vessels feeding the tumor to re-form after they had been destroyed by the chemotherapy. They proposed giving smaller, almost constant doses of the drug – as regular as the ticking of a metronome – as a way to hamper angiogenesis (the growth of new blood vessels).

In the Dana-Farber study, the chemotherapy drugs cyclophosphamide and methotrexate were given in a metronomic regimen to 21 patients with advanced, metastatic breast cancer. In another 34 patients, the chemotherapy was paired with the angiogenesis inhibitor bevacizumab, or Avastin, given intravenously every 14 days. None of the patients had been previously heavily treated for their advanced cancer.

The metronomic-alone therapy led to two partial responses (10 percent of the patients), while in another eight patients the cancer remained stable. Results seemed better in the combination group, in which 10 patients (29 percent) had partial responses, while 14 (41 percent) experienced stable disease. There were still some side effects in both groups, including fatigue, but Burstein said the therapies were generally well tolerated and lacked the major side effects of traditional chemotherapy such as gastrointestinal and hair loss.

The researchers concluded that the metronomic therapy by itself had limited clinical activity, but the activity seen when the antiangiogenesis drug was added suggests "further investigation of this novel treatment study is warranted."

Support for the trial came from a National Cancer Institute-Avon Partners for Progress Award, a breast cancer SPORE (Specialized Program of Research Excellence) grant to the Dana-Farber/Harvard Cancer Center, and from Genentech, Inc., manufacturer of Avastin.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School, and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive care center the National Cancer Institute.