Single-agent or combination chemo for breast ca mets?

SAN FRANCISCO—The decision to treat metastatic breast cancer with combination or single-agent chemotherapy may depend on the patient's and the clinician's perception and definition of the goals of such therapy, according to speakers at the 3rd Annual Oncology Congress.

"All therapy for metastatic breast cancer is palliative, and median survival depends mostly on the tempo of the patient's disease, defined by its biology, rather than the therapy we give," said Hyman B. Muss, MD, of the Vermont Cancer Center at the University of Vermont. "Once you've exhausted hormonal therapy in hormone-receptor positive patients, the average survival is only about 2 years. So the goal of treatment is to control disease and symptoms and to maximize quality of life."

In a debate session at the congress, Dr. Muss presented the argument for single-agent therapy for most patients with metastatic breast cancer.

Although Dr. Muss argued that "kindler, gentler" single-agent sequential therapy is generally the more appropriate choice, he cited possible exceptions: combination therapy with biologics such as bevacizumab (Avastin), trastuzumab (Herceptin), lapatinib (Tykerb), and ixabepilone (Ixempra), and combination therapy for symptomatic patients or those with rapidly progressing disease.

Taking the pro side was Hope Rugo, MD, of the UCSF Comprehensive Cancer Center. She argued for the rational use of combinations in metastatic patients (see Table), citing improvements in disease-free survival and in some cases overall survival. "You can improve upon being asymptomatic," she said.

Part of the difference in opinion on the question "Is A+B superior to A followed by B?" boils down to the definitions of "superior" and quality of life. Dr. Rugo argued that improvement in progression-free survival is a quality-of-life endpoint and is generally superior with combination therapy.

She also argued for the goal of reducing disease to its smallest amount, probably best achieved with combination therapy, so long as the patient tolerates treatment. "If you treat patients until you have minimal residual disease, their survival is increased," she said, citing Swenerton et al: Cancer Res 39:1552-1562, 1979.

She noted that supportive care has improved dramatically over the last 10 years, allowing many patients to receive full-dose combination therapy.

E1193: Sequential vs combination

To support single-agent sequential therapy, Dr. Muss pointed to the E1193 study (J Clin Oncol 21:588-592, 2003) comparing doxorubicin alone, paclitaxel alone, or both in combination. Dr. Muss called the study "seminal" because it had a built-in crossover design.

Response rates, "as in all combination studies," he said, were better with the combination, as was time to treatment failure, "but if you look at survival, it's not different, because everybody had access to the second drug. In addition, quality of life was better in patients who received sequential therapy, compared with combination therapy."

Dr. Rugo responded: "This study is often used to show that combination therapy is not of greater benefit, but response rates were markedly higher with the combination, despite the fact that combination patients received slightly lower doses of each drug, and combination patients lived a median of 2 months longer without progression."

When this study was done, she said, "we weren't using myeloid growth factors as often as now, and there was more toxicity from combination therapy. Now, most metastatic disease patients have already been exposed to anthracyclines and taxanes, so this combination isn't the way to go, but it does show what combination therapy could potentially achieve."

Approved combinations

Both speakers discussed the FDA-approved combination regimens for metastatic breast cancer: gemcitabine (Gemzar)/paclitaxel, docetaxel (Taxotere)/capecitabine, trastuzumab/paclitaxel, and, more recently, lapatinib/capecitabine and ixabepilone/capecitabine. (As ONI went to press, FDA was considering approval of bevacizumab/paclitaxel.)

"One of the nice things about gemcitabine/paclitaxel," Dr. Rugo said, "is the relatively less toxicity up front. You don't need to do the same amount of dose reduction and careful observation in the beginning."

Dr. Muss noted that many patients in the pivotal gemcitabine/paclitaxel trial did not get sequential therapy due to lack of crossover, but Dr. Rugo pointed out that gemcitabine was not approved as a single agent for breast cancer, "so it's not clear that all patients had access."

Docetaxel/capecitabine

In the pivotal study of docetaxel/capecitabine (J Clin Oncol 20:2812-2823, 2002), survival was improved with the combination, but Dr. Muss pointed out that the crossover patients, who received the taxane and then capecitabine, had better survival than the combination patients. "Sequential was better," he said.

Dr. Rugo, however, referred to this finding as "data mining." An alternative explanation is that the patients who went on to receive capecitabine "were just doing better so they were able to get capecitabine, and they lived longer because they had less aggressive disease." She also noted there were more grade 3 adverse events with the combination, "but with dose reduction, quality of life was similar in the two arms."

Both speakers were enthusiastic about combination regimens involving biologics and, in the end, seemed to agree that both approaches represent a standard of care in different clinical situations.