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Evidence-based Breast Cancer Treatment Guidance - The State of the Art

Compiled by:
Constantine Kaniklidis, medical researcher

[ Breast Cancer Watch is a member of the Evidencewatch portal of evidence-based medicine sites ]

Breast Cancer Watch is a unique service providing the latest best evidence-based guidance on state-of-the-art breast cancer therapies, annotated with critical commentaries, and clinical practice recommendations. Critical appraisal and systematic review is undertaken aggressively with major updates monthly, and at least weekly revisions for high-impact findings. The series addresses two problems: (1) the lack of any timely single-source evidence-based systematic review of breast cancer treatment research findings for both healthcare professionals and informed patients, and (2) the rapid aging of breast cancer guidelines issued on less timely schedules (e.g., NCCN, ASCO and other guidelines).      [updated: 11/10/06]

Topics and Principles of Chemotherapy

§ Part 1: CMF - Optimal Deployment and Place in Current Chemotherapeutics

  • CMF Responsiveness and HER2 Overexpression
    However, these findings did not examine the potential influence of HER2/ expression level, an issue within the broader context of intense interest in biologic markers able to predict the response of cancer patients to therapy. It is already well established that HER2 overexpression is a potential indicator of positive responsiveness to doxorubicin and to paclitaxel, and of unresponsiveness to tamoxifen in patients with breast carcinoma, but the influence, if any, of HER2 overexpression in responsiveness to the CMF (cyclophosphamide, methotrexate, and fluorouracil) regimen has remained unclear. Several trials have examined this issue: Menard et a. (J Clin Oncol (2001: Response to Cyclophosphamide, Methotrexate, and Fluorouracil in Lymph Node–Positive Breast Cancer According to HER2 Overexpression and Other Tumor Biologic Variables) investigated this issue in the first CMF controlled clinical trial with a 20-year follow-up, finding that patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, concluding hopefully that the poor prognosis typically associated with HER2 overexpression could be completely overcome by CMF chemotherapy.

    Building on this, Moliterni et al. (J Clin Oncol (2003): HER2 Overexpression and Doxorubicin in Adjuvant Chemotherapy for Resectable Breast Cancer) examined whether therapy regimens including CMF + doxorubicin (ADM) versus CMF alone have the same therapeutic effect in patients with HER2+ and HER2- tumors in terms of relapse-free survival (RFS) and overall survival (OS), finding a clear therapeutic benefit of doxorubicin treatment in patients with HER2+ breast carcinoma, further confirming the conclusions from other studies suggesting that doxorubicin activity is restricted to the subset of breast carcinomas overexpressing the HER2 oncogene (the latest NCCN guidelines have added a footnote stating that doxorubicin-based chemotherapy may be superior to non-doxorubicin-containing regimens in the adjuvant treatment in patients whose tumors exhibit HER2 overexpression: see NCCN (2005): Practice Guidelines in Oncology - v.2.2005: Breast Cancer [pdf]). Their conclusions therefore demonstrate that the subset of HER2+ tumors seems to be more responsive to doxorubicin + CMF than to CMF alone, an advantage not observed in the subset of patients with HER2- tumors, where doxorubicin treatment did not significantly increase the therapeutic benefit achieved with CMF alone. This contrasts starkly with the fact that in metastatic disease, no direct association between HER2 overexpression and response to chemotherapy has been observed to date.

The Place of CMF in Current Chemotherapeutics

  • Anthracycline-based v. CMF Chemotherapy (AB-CT v. CMF-CT)
    An important question emerges once the anthracyclines - and later, taxenes - are introduced into modern chemotherapeutic regimens: where does CMF fit in, especially in terms of relative efficacy compared to anthracycline-based chemotherapy (AB-CT).

    Some earlier trials appear to have concluded that AC and CMF were equi-efficacious. A head-on comparison of different chemotherapy regimens was undertaken by Bang et al. (Cancer (2000): Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma). This study found no difference between AC and CMF with respect to both disease free and overall survival rates in premenopausal women with axillary lymph node positive breast carcinoma, and a complimentary study by Fisher et al. (J Clin Oncol (2001): Tamoxifen and Chemotherapy for Axillary Node-Negative, Estrogen Receptor–Negative Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-23) suggests no significant difference in the outcome of patients who received AC or CMF, adding the new finding that tamoxifen with either regimen resulted in no significant advantage over that achieved from chemotherapy alone. However, these isolated findings are in contradiction with the vast body of evidence to the contrary. So, Kuru et al. (J Exp Clin Cancer Res (2005): A comparison of the outcomes of non-randomised chemotherapy regimens in node positive breast cancer) compared the results of adjuvant FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy on DFS (disease-free survival), OS (overall survival) and LFS (loco-regional recurrence-free survival) for node positive breast carcinoma treated with mastectomy in a non-randomised setting, finding that adjuvant FAC was improved DFS, OS and LFS, all of which were longer at 5-years for patients treated with FAC as compared to CMF.

  • The Weight of the Evidence: Anthracycline-based v. the CMF Regimen
    The meta-analysis of Susan Burdette-Radoux & Hyman Muss of the University of Vermont College of Medicine (Clin Breast Cancer (2003): Optimizing the use of anthracyclines in the adjuvant treatment of early-stage breast cancer) established several principles of CMF therapy relative to anthracycline-based regimens:

    1. anthracycline-based regimens result in both better DFS (disease-free survival) and better OS (overall survival) than standard CMF;
    2. dose escalation of the anthracycline doxorubicin (Adriamycin) up to a threshold dose results in further outcome improvement;
    3. the alternative anthracycline, epirubicin (Ellence), can be escalated to higher doses than doxorubicin given its more favorable toxicity profile, yielding better outcomes associated with higher dose levels;
    4. in some patient populations, newer regimens of anthracycline + taxane appear to offer a modest additional DFS and OS advantage;
    5. dose-dense scheduling exhibits a greater survival benefit compared to conventional scheduling

    In addition, the Oxford Meta-Analysis (EBCTCG, Lancet (1992): Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group) clarified whether different CMF regimens demonstrated any clinically significant advantages over others. Most of the chemotherapy trials considered in this review meta-analysis used CMF-based regimens, and it was found that all versions of CMF were roughly comparable in efficacy, with no clear advantage noted for specific differences in routes of administration or in scheduling, and that six months of CMF was as effective as longer courses. A later IBCSG study conducted by researchers at the European Institute of Oncology (Goldhirsch et al., J Clin Oncol (1998): Adjuvant chemoendocrine therapy in postmenopausal breast cancer: cyclophosphamide, methotrexate, and fluorouracil dose and schedule may make a difference. International Breast Cancer Study Group) extended these conclusions, finding that classical CMF (oral cyclophosphamide on days 1 to 14 with i.v. methotrexate and fluorouracil on days 1 and 8, repeated every 28 days) yields better outcomes than the modified-CMF (all three agents administered i.v. every 21 days) both in the metastatic and adjuvant settings. (See also the same conclusions in the review of Francisco Esteva, Gabriel Hortobagyi at MD Anderson Cancer Center (Oncologist (1998): Integration of Systemic Chemotherapy in the Management of Primary Breast Cancer).

    The same EBCTCG group more recently reported on 10 and 15-year effects of various chemotherapies and endocrine (hormonal) therapies on recurrence and survival in EBC (early breast cancer), in their review of 194 unconfounded randomised trials beginning in 1995 (EBCTCG, Lancer (2005): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group). They found that allocation to approximately 6 months of anthracycline-based polychemotherapy (FAC or FEC) reduces the annual breast cancer death rate by about 38% for women younger than 50 years of age when diagnosed and by about 20% for those of age 50–69 years when diagnosed, largely irrespective of the use of tamoxifen and of estrogen receptor (ER) status, nodal status, or other tumour characteristics, and that such anthracycline-based regimens are significantly more effective than CMF chemotherapy, both in terms of decreases recurrence and increasing OS (overall survival). Their overall findings show a moderate but highly significant advantage of anthracyclines over CMF, with in each case the absolute difference between anthracycline-based and CMF chemotherapy being about 3% at 5 years and 4% at 10 years. And the superiority of the anthracycline-based regimens over CMF does appear to be about as great for older as for younger women.

  • The Weight of the Evidence: Anthracycline + CMF Regimens v. CMF Alone
    More recently, the NEAT (National Epirubicin Adjuvant Trial) and the BR9601 trial examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer: NEAT compared four cycles of epirubicin followed by four cycles of CMF with six cycles of CMF alone, while the BR9601 trial compared four cycles of epirubicin followed by four cycles of CMF, with eight cycles of CMF alone every 3 weeks. NEAT + BR9601 included 2391 women with early breast cancer, and a median follow-up was 48 months. The British researchers (Poole et al., New Engl J Med (2006): Epirubicin and Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy for Early Breast Cancer) found that RFS (relapse-free survival) and OS (overall survival) rates were significantly higher in the epirubicin–CMF groups than in the CMF-alone groups.

  • When CMF Alone may be Optimal
    The question remains however whether CMF may be optimal for any special population or subgroup. Chinese researchers (Lim et al., Jpn J Clin Oncol (2005): Identifying good prognosis group of breast cancer patients with 1-3 positive axillary nodes for adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy) identified a just such a subset of good prognosis patients: > 40 years of age, primary tumor size of < 3 cm, and with ER+ receptor status. The 5 year estimated DFS and OS for this group were 88.2 and 98.8%, respectively while in contrast, for patients with any unfavorable prognostic factor the estimated 5 year DFS and OS were 67.7 and 82.4%, respectively, and with the survival rates of the low-risk patients with 1–3 positive nodes being equal to high-risk node-negative patients; thus patients with 1–3 lymph node metastases and favorable prognostic factors could be treated as patients of high-risk node-negative breast cancer. But for patients with 1–3 nodes in the high-risk group, their outcomes were poorer, and the authors recommend anthracycline-based regimens with or without taxanes.

§ Part 2: Chemobiological Therapy - Chemotherapy + Bevacizumab

  • Off-Protocol BEV-CAP: Bevacizumab (Avastin) + Capacitabine (Xeloda)

    • Kathy Miller's seminal BEV-CAP trial of antiangiogenic therapy (Miller et al., J Clin Oncol (2005): Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer) compared the efficacy and safety of capecitabine (Xeloda) with or without the monoclonal antibody to VEGF (vascular endothelial growth factor) bevacizumab (Avastin) in patients with MBC (metastatic breast cancer) previously treated with an anthracycline and a taxane, most of whom had visceral involvement, finding that was generally well tolerated, with no significant increase in capecitabine-related toxicities, and although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.

    • Nonetheless, Breast Cancer Watch notes:

      (1) the addition of BEV doubled the response rate (an absolute increase of ~11% in overall response rate compared with CAP alone);
      (2) BEV has a non-overlapping toxicity profile with CAP;
      (3) the lack of a PFS or OS advantage for the combination regimen over CAPmonotherapy may be consequent to a potentially decreasing influence of VEGF in later phases of MBC.


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