Management of Locally Advanced and Metastatic Breast Cancer: Notable Findings Presented at ECCO 12September 21-25, 2003CopenhagenCharles H. Weaver MD , Co-Author: Dayna Deuter
In this era of multiple options for the treatment of metastatic breast cancer, a variety of regimens, schedules, and sequences have utility. The best treatment programs seek to combine maximum efficacy with minimum toxicity. Presentations at the 12th European Conference on Clinical Oncology (ECCO 12) shed light on current best practice chemotherapy regimens while expanding the possibilities for effective treatment with new combinations and the use of newer active agents with improved safety profiles. Notably, the combination of Herceptin® and Taxotere® was reported to be more effective than Taxotere® alone and Taxotere® may be more effective than paclitaxel.
AT vs. FAC : Researchers from the Netherlands reported that the combination of doxorubicin and Taxotere® (AT) produced a significantly longer progression-free survival than 5-FU, doxorubicin, and cyclophosphamide (FAC) in the first-line treatment of metastatic breast cancer.
This phase III trial included 216 patients with a median age of 53 years. One-third (33%) had received adjuvant chemotherapy. Patients were randomized to receive AT (50/75 mg/m²) or FAC (500/50/500 mg/m²) administered on day 1, every 3 weeks as first-line chemotherapy for metastatic breast cancer. Patients in the AT group received prophylactic ciprofloxacin. The median follow-up was 22 months. Treatment after study consisted of a taxane in 23% of the AT group and 67% of the FAC group.
Intent-to-treat analysis indicated that progression-free survival, the primary endpoint, was significantly longer in the AT treated patients (8.1 months) compared to the FAC treated patients (6.6 months, p=0.002). The patients in the AT group also demonstrated a higher overall response rate (ORR) and overall survival, both of which were secondary endpoints in this study. The researchers stated that “When clinical benefit was considered, the difference (in ORR) remained significant.”
The only increase in severe (grade 3-4) toxicity in the current analysis was in the incidence of febrile neutropenia, which occurred at a significantly higher rate in the AT arm compared to the FAC arm (34% vs. 9.7%, p=0001). 1< /SUP>
Bendamustine: German researchers reported that substitution of cyclophosphamide with bendamustine in the CMF regimen significantly increased anti-tumor activity in patients with metastatic breast cancer. Bendamustine is a bifunctional agent with alkylator and purine-like properties. The replacement of cyclophosphamide by bendamustine in the CMF-regimen was prospectively tested in a randomized phase III trial involving 364 patients with metastatic breast cancer. Patients had not been previously treated for metastatic disease with chemotherapy. Patients were randomized to receive either BMF (bendamustine 120 mg/m², methotrexate 40 mg/m², 5-FU 600 mg/m²) or CMF (cyclophosphamide 500 mg/m² instead of bendamustine).
A significant difference in median time to progression (TTP) was observed in favor of the BMF group. Moreover, the effect of BMF on TTP became significant in the patients with non-visceral metastases who had received prior adjuvant therapy (p=0.034). Confirmed clinical responses were observed with equal frequency and there was a non-statistically significant difference in the duration of response (p=0.076). The incidence of grade 3 toxicities was equally distributed (see table 1).
Table 1 Bendamustine combination vs. CMF
Leucopenia, thrombocytopenia, and stomatitis were more frequent in the BMF arm, whereas alopecia, amenorrhea, and constipation were more frequent in the CMF group. The incidence of CTC grade 4 toxicities was higher in the BMF arm compared to the CMF group. There were no differences in quality of life detected between the two treatments. 2
Results presented at ECCO 12 indicate that Taxotere® is superior to paclitaxel for the second-line treatment of metastatic breast cancer. In addition, Iressa® monotherapy also appears to be an effective second-line therapy for metastatic breast cancer.
Taxotere® superior to paclitaxel : In the first trial directly comparing Taxotere® to paclitaxel, researchers from the U.S. reported that Taxotere® demonstrated a higher response rate, longer time to progression, and improved median overall survival in the treatment of metastatic breast cancer after failure of anthracyclines.
Taxotere® and paclitaxel are among the most active agents for the treatment of patients with metastatic breast cancer. Clinical studies report response rates of 30-48% for Taxotere® and 16-29% for paclitaxel. This comparative trial involved 449 women, 90% of whom had metastatic disease. Half of the patients were either estrogen-receptor or progesterone-receptor positive. Patients were randomized to receive either Taxotere® 100 mg/m² or paclitaxel 175 mg/m².
Intent-to-treat analysis of major efficacy endpoints showed a higher response rate (the primary endpoint) for Taxotere® compared to paclitaxel, but this difference was not statistically significant. Secondary endpoints showed longer time to disease progression and median overall survival for Taxotere® than for paclitaxel (see table 2).
Table 2: Taxotere® vs. paclitaxel in second-line treatment of metastatic breast cancer
Toxicity was higher in the Taxotere® arm, including grade ¾ toxicities. Grade ¾ neutropenia occurred at a rate of 93.3% in the Taxotere® arm, compared to 54.5% in the paclitaxel arm. There was also at least 1 episode of febrile neutropenia per cycle in the Taxotere® arm, a rate of 15% compared to 2% for paclitaxel. Quality of life results are expected to be reported at the San Antonio Breast Cancer Symposium (SABCS) in December, 2003.
The researchers reported that potential bias may be due to some differences in treatment after study. However, they emphasized that most patients received chemotherapy after the study and this generally consisted of the other taxane.
While this study appears to point to the end of treatment with paclitaxel, the researchers indicated that there is still a need to balance efficacy with toxicity and quality of life. This question may be further clarified when the quality of life results are presented at the SABCS. 3
Iressa®: Researchers from Germany presented preliminary data at ECCO 12 indicating that Iressa® may be effective as monotherapy in the second-line treatment of metastatic breast cancer. In a heavily pre-treated population, Iressa® demonstrated anti-tumor efficacy and symptom improvement. This small, non-randomized, phase II trial involving 46 patients who received oral Iressa® 500 mg/day until disease progression, unacceptable toxicity, or withdrawal of consent.
Progression-free survival of e12 weeks occurred in 27 patients. Median time to progression was 84 days and median overall survival was 357 days. An improvement in quality of life was reported in 33 patients in the Treatment Outcome Index (TOI) and 35 patients in the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. Improvements in FACT-B were maintained in 16 patients (30.8%). Adverse events consisted predominantly of mild grade 1-2 diarrhea and skin toxicity. Grade 3-4 toxicities occurred in 10 patients (17.2%). 4
HER-2/neu Positive Metastatic Breast Cancer
Patients overexpressing HER-2/neu as measured by immunohistochemistry or FISH represent a distinct subpopulation of breast cancer, characterized by an aggressive course, suboptimal response to standard chemotherapy, and an enhanced response to chemotherapy plus Herceptin®. A pivotal trial evaluating Herceptin® demonstrated improved survival for patients receiving chemotherapy plus Herceptin® compared with chemotherapy alone. 5 Use of concurrent anthracyclines plus Herceptin® is, however, limited by a fairly high rate of usually reversible cardiac toxicity.
Herceptin® and Taxotere®: A multicenter, phase II trial indicated that patients with HER-2/neu-positive metastatic breast cancer who received Herceptin® and Taxotere® had a significantly higher response rate, longer time to disease progression, and longer survival compared to patients who were treated with Taxotere® alone.
This trial involved 188 patients, who were randomized to receive Herceptin® (4 mg IV loading dose followed by 2 mg/m² IV every 3 weeks until disease progression) in combination with Taxotere® (100 mg/m² IV every 3 weeks for 6 cycles) or Taxotere® alone. Patients who received Taxotere® monotherapy were allowed to crossover to receive Herceptin® at the time of disease progression.
Preliminary results demonstrated a significantly higher response rate in the combination arm (61%) compared to the Taxotere® monotherapy arm (36%). The secondary endpoints also showed statistically significant improvements in time to disease progression and overall survival for patients treated with Taxotere® and Herceptin® (see Table 4). Results for both primary and secondary objectives are in keeping with other prior studies with these agents.
Table 4 Herceptin®/Taxotere® vs. Taxotere® alone in HER-2/neu positive metastatic breast cancer
Preliminary safety data further indicated that Herceptin® plus Taxotere® was “generally well tolerated.” Although there was a slight increase in febrile neutropenia in the combination arm compared to Taxotere® monotherapy (19% vs. 16%, respectively), there were no unexpected toxicities reported in this study. Minor and asymptomatic reductions in left ventricular ejection fraction (LVEF) were common, but the number of patients with no significant change in LVEF was the same for both groups. Only one patient developed congestive heart failure, which is equivalent to a rate of about 1%. This patient had received prior adjuvant doxorubicin. 6
Researchers from Brazil presented a trial at ECCO 12 that demonstrated substantial clinical activity and minimal toxicity of Herceptin® and Taxotere® in patients with locally advanced breast cancer and a poor prognosis (large tumors and HER-2 +++). This was a small trial involving 32 patients, including 22% with stage IIIA and 78% with stage IIIB. Treatment consisted of Herceptin® 4 mg/kg week 1 followed by 2 mg/kg weekly combined with 2 cycles of Taxotere®. The overall clinical response rate was 72%. Treatment was well tolerated with only 1 patient (3%) experiencing grade IV toxicity (anasarca). The most frequent grade III adverse events were alopecia (16%), neutropenia (9%), and headache (6%). 7
Advances in Staging
The false negative rate in sentinel node biopsy (SNB) has usually been 5% or even lower. The more accurate histological examination with serial sectioning and immunohistochemistry of the sentinel nodes is assumed to compensate the false negatives of SNB.
It has been proposed that sentinel node biopsy (SNB) may provide even more accurate axillary staging than axillary lymph node dissection (ALND). Results from a Finish study that compared these two techniques indicates that SNB appears to be at least as accurate for axillary staging as ALND. Axillary metastases were evaluated in 166 breast cancer with SNB and compared with pair-matched control patients who underwent ALND. The matching factors included the age of the patient and grade, histological subtype, and histological size of the tumor. The proportion of patients with axillary metastases was 37% in the SNB group and 31% in the ALND group. The axillary nodes were involved in 41% of patients with invasive lobular carcinoma in the SNB group and in 29% in the ALND group. 8
Presentations at ECCO 12 indicate that research continues to focus on optimization of current therapeutics. The combination of Herceptin® and Taxotere® nearly doubles survival compared to Taxotere® alone in the management of Her-2/neu positive patients and Herceptin®/Taxotere® therapy appears promising for the management of metastatic breast cancer. The first trial directly comparing Taxotere® to paclitaxel suggests that Taxotere® may have greater efficacy. Quality of life data will be presented at SABCS further defining this therapeutic choice.
1.M. Bontenbal M, Braun JJ, Creemers GJ, de Boer AC, et al. Phase III study comparing AT (Doxorubicin, Docetaxel) to FAC (Fluorouracil, Doxorubicin, Cyclophosphamide) as first-line chemotherapy (CT) in patients with metastatic breast cancer (MBC). Proceedings from the 12th European Conference on Clinical Oncology, Sept 21-25, 2003, Copenhagen Denmark (Abstract #671).
2.von Minckwitz G, Chernozemsky I, Souchon R, Stuart N, et al. A phase III randomized trial of bendamustinehydrochloride, methotrexate, and 5-FU (BMF) versus CMF as first-line treatment of patients with metastatic breast cancer. European Journal of Cancer Supplements 2003;1(5):S201 (ECCO 12 Abstract #669).
3.Ravdin P, Erban J, Overmoyer B, Budd GT, et al. Phase III comparison of docetaxel and paclitaxel in patients with metastatic breast cancer. Proceedings from the 12th European Conference on Clinical Oncology, Sept 21-25, 2003, Copenhagen Denmark (Abstract #670).
4.von Minckwitz G, Jonat W, Beckmann M, de Bois A, et al. A multicenter Phase II trial to evaluate gefitinib (Iressa, ZD1839) (500 mg/day) in patients with metastatic breast cancer after previous chemotherapy treatment. Proceedings from the 12th European Conference on Clinical Oncology, September 21-25, 2003, Copenhagen Denmark (Abstract #437).
5.Slamon DJ, Leyland-Jones B, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11): 783-92.
6.Extra JM, Cognetti F, Chan S, Maraninichi D, et al. Randomised phase II trial of trastazumab (Herceptin®) plus docetaxel versus docetaxel alone, as first-line therapy in patients with HER2-positive metastatic breast cancer. Proceedings from the 12th European Conference on Clinical Oncology, September 21-25, 2003, Copenhagen Denmark (Abstract #672).
7.Bines J, Murad A, Lago S, Ferrari B, et al. Primary treatment with weekly docetaxel (Taxotere® ) and trastuzumab (Herceptin) for HER-2 overexpressing locally advanced breast cancer. European Journal of Cancer Supplements 2003;1(5):S114 (ECCO 12 Abstract #370).
8.Leidenius M, Krogerus L, Tukiainen E, von Smitten K. Accuracy of axillary staging using sentinel node biopsy or diagnostic axillary lymph node dissection. Proceedings from the 12th European Conference on Clinical Oncology, September 21-25, 2003, Copenhagen Denmark (Abstract #382).