Metastatic Breast Ca Rx Is 'a Book With Many Chapters'

NEW YORK-Treatment of metastatic breast cancer is "a book with many chapters, ie, with many opportunities for meaningful intervention, as opposed to pancreatic cancer, for example," Andrew Seidman, MD, said in his discussion of metastatic breast cancer at the Second Annual Advances in Oncology meeting, sponsored by the journal ONCOLOGY.

The most frequently used treatment strategies include combination chemotherapy, dose-intense or dose-dense regimens, and the incorporation of rationally designed, targeted, biologic therapies into treatment protocols.

These strategies are supported by data from phase III clinical trials and meta-analyses, and represent an attempt to approach the care of the patient from the perspective of "evidence-based" medicine, said Dr. Seidman, associate attending physician, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center. However, "this is not the whole story," he said, emphasizing that clinicians must consider treatment toxicities and effects on overall survival.

Combination Regimens

Dr. Seidman ascribes the enthusiasm for combination regimens to "the reports of objective responses and a certain comfort level with combinations in the treatment of other solid tumors," and questions whether A plus B is better than A followed by B.

He cited at least seven randomized comparisons of combination chemotherapy regimens (anthracyclines and nonanthracyclines) vs monotherapy for metastatic breast cancer that showed no survival advantage for the combination as well as significantly higher hematologic and nonhematologic adverse events.

These protocols (Sledge: J Clin Oncol, 2003; Joensuu: J Clin Oncol, 1998; Nabholtz: J Clin Oncol, 1999; Bishop: J Clin Oncol, 1999; Heidemann: Ann Oncol, 2002; Norris: J Clin Oncol, 2000; and Ejlertsen: J Clin Oncol, 2004), with a combined population of 2,490 patients "challenge the role of combination chemotherapy as the gold standard in the treatment of metastatic breast cancer," he said.

Dr. Seidman said he leans toward using single agents sequentially until disease progression or intolerable toxicity, then switching to another single agent or to a combination. "The heterogeneity of the biology of breast cancer argues strongly for flexibility in treatment," he commented.

A trial by O'Shaughnessy et al (J Clin Oncol 20:2812, 2002) that compared the combination of docetaxel (Taxotere) and capecitabine (Xeloda) to docetaxel alone reported a higher response rate for the combination, but the trial did not evaluate whether sequential use of docetaxel and capecitabine at progression would yield the same response as the combination. In an unplanned "post hoc (or ad hoc)" analysis of this trial, he said, patients who received capecitabine after docetaxel had an even better survival than patients who received the combination.

E1193 Study

The Sledge study, Eastern Cooperative Oncology Group (ECOG) trial 1193 (J Clin Oncol 21:588, 2003), also showed no clear advantage for combination chemotherapy over the use of sequential single agents, Dr. Seidman said. In this study, patients with metastatic breast cancer were randomized to doxorubicin alone, paclitaxel alone, or doxorubicin plus paclitaxel. Results showed that the combination did not improve either survival or quality of life, compared with sequential single-agent therapy.

As to the question of who would benefit from combination chemotherapy, Dr. Seidman said, "There is no one right answer. In the future, we may have tools-proteomics, genomics-that will tell us who may benefit from specific drugs or combinations, and we are beginning to develop those tools now." An analysis of ECOG 1193 found a number of prognostic factors as being associated with a shorter overall survival in metastatic breast cancer, with these patients possibly benefiting from combination chemotherapy (see Table on page 23).

Dose Intensity vs Dose Density

The efficacy of dose-intense therapy has been widely explored in metastatic breast cancer, with many trials demonstrating the lack of a survival advantage for dose-intense therapy, Dr. Seidman said. In Cancer and Leukemia Group B (CALGB) Trial 9342 (J Clin Oncol 22:2061, 2004), paclitaxel dose escalation caused more neuropathy but not a higher response rate or longer time to disease progression (TTP).

A phase III trial that compared three dose levels of docetaxel (100, 75, and 60 mg/m2) reported a higher response rate in the 100-mg group and an increased TTP but no real difference in survival among the groups (P = .30) (Breast Cancer Res Treat 76[suppl 1]:S88, 2002).

The Philadelphia experience in PBT-1 (N Engl J Med 342:1069-1076, 2000), which compared conventional-dose chemotherapy with high-dose chemotherapy plus hematopoietic stem cell transplant in metastatic breast cancer patients, showed no significant difference between groups in overall survival or TTP (32% vs 38%; 9.6 mo vs 9.0 mo, respectively).

"A single industrial strength dose of chemotherapy doesn't seem to get us to where we need to be, but perhaps multiple, more appropriate doses of chemotherapy given at shorter inter-treatment intervals would be more likely to get us there," Dr. Seidman said.

CALGB trial 9840 demonstrated that weekly paclitaxel can be more active than paclitaxel administered every 3 weeks (ASCO 2004 abstract 512), he said. Both response rate and TTP were higher in patients treated with the weekly paclitaxel regimen.

"The biggest story in metastatic breast cancer in 2005," Dr. Seidman said, was the results being reported from trials of targeted agents such as ECOG E2100.

In E2100, participants were randomized to receive weekly paclitaxel alone or with bevacizumab (Avastin). The addition of bevacizumab produced a significant improvement in outcome. The overall response rate in the bevacizumab group was 29.9% vs 13.8% in the paclitaxel-alone group. Time to progression was 11.4 month vs 6.1 months, respectively; among women who had received prior taxane therapy, TTP was 12.4 months vs 4 months, respectively. No differences were noted between groups in quality of life.

Ongoing studies, Dr. Seidman said, are looking at the combination of nab-paclitaxel (Abraxane) and bevacizumab and paclitaxel/bevacizumab with or without gemcitabine (Gemzar).

'Are Our Treatments Benefiting the Patient?

"We can never be certain that we are improving an individual patient's survival . . . one thing we can be sure of is whether the treatment is improving cancer-related symptoms," Dr. Seidman concluded. "We also know that as we continue to give chemotherapy, we see the accumulation of treatment-related toxicity. It is at this juncture, where the treatment starts to become worse than the disease, that we need to ask ourselves if our treatment is benefiting the patient. It is at this juncture where the examination of novel targeted agents could have a big impact."