Optimizing Adjuvant Chemotherapy in Early-Stage Breast Cancer

Drs. Perez and Muss provide a comprehensive review of the role of adjuvant chemotherapy in the management of breast cancer patients. The benefits of anthracycline vs nonanthracycline regimens are discussed, the taxanes are reviewed in detail, and data regarding dose intensity, dose density, and optimal number of chemotherapy cycles are explored. Data on newer agents and biologic agents also are presented. Debate continues regarding the subsets of patients who will derive the greatest benefit from chemotherapy and which regimen is most appropriate. While the review indicates the efficacy of several regimens as defined by randomized clinical trials, it does not emphasize patient-specific factors in determining the optimal therapy for a given patient. Assessing Benefits of Adjuvant Chemotherapy
The authors indicate that adjuvant chemotherapy improves disease-free and overall survival in breast cancer patients. However chemotherapy is associated with risks, which in some patients might offset the small benefit produced by chemotherapy. In order to assess the benefits of adjuvant chemotherapy, the risk of recurrence and the risk reduction from the chemotherapy must be determined for the individual patient. It is well known that estrogen receptor (ER)-positive tumors derive less benefit from chemotherapy than ER-negative tumors, particularly in the postmenopausal setting.[1,2] The magnitude of polychemotherapy benefit in ER-positive patients might depend on the overexpression of ER, with greater benefit seen in patients with lower levels of ER expression.[3] Adjuvant chemotherapy also produces greater benefits in younger women, reducing the annual breast cancer death rate by 38% in women < 50 years, and by 20% in women aged 50 to 69 years.[1] Few data are available for women more than 70 years old, although a recent retrospective analysis by Muss et al showed a significant survival benefit for more intensive chemotherapy in healthy older patients.[4] In 2005, experts have come to a consensus that endocrine responsiveness should be considered the primary factor determining treatment choice. Recommended treatment regimens are based on the matrix of the three groups of risk recurrence (low, intermediate, and high) and hormone responsiveness with subgrouping by menopausal status. Risk categories are defined using the number of axillary lymph nodes involved, HER2 overexpression, tumor size, histologic grade, peritumoral vascular invasion, and age.[5] Algorithms such as AdjuvantOnline, validated in a Canadian study of over 4,000 patients,[6] provide average estimates for various clinical scenarios and graphic presentation of risks and benefits, aiding in treatment discussions with patients. Molecular profiling research very likely will have a profound effect on the assessment of risk reduction and in defining optimum adjuvant chemotherapy. A 21-gene reverse transcriptase- polymerase chain reaction (RT-PCR) assay (Oncotype DX) was found to be useful for predicting recurrence in ERpositive, node-negative breast cancer patients.[7] Another study identified a 70-gene expression profile associated with the risk of early distant metastasis in young patients with node negative disease.[8] Further prospective validation of these methods is required. Moreover, the novel molecular classification of breast cancer into luminal, basal, and HER2 subtypes has identified subgroups of patients with different prognoses and responses to therapy and could be incorporated in clinical trials to better define which patient subgroup will benefit more from the given treatment.[9] Regimen With Greatest Impact on Risk Reduction
Choosing the optimal chemotherapy regimen is challenging. Anthracycline- containing regimens are associated with a greater reduction of recurrence and mortality rates than nonanthracycline regimens.[1] Taxanes have been shown to improve outcomes in node-positive breast cancer patients. Generally, the addition of an anthracycline, a taxane, and a dosedense delivery schedule improves outcomes by approximately 5%. At present, the most effective taxane regimens appear to be dose-dense AC followed by dose-dense paclitaxel(Drug information on paclitaxel) (ddAC → P),[10] six cycles of TAC (docetaxel [Taxotere], doxorubicin(Drug information on doxorubicin) [Adriamycin], cyclophosphamide(Drug information on cyclophosphamide)),[11] or three cycles of FEC (fluorouracil, epirubicin(Drug information on epirubicin) [Ellence], cyclophosphamide) followed by three cycles of docetaxel.[ 12] Ongoing adjuvant studies should clarify the optimal taxane schedule. Exciting and revolutionary data in early breast cancer treatment comes from recently published trials of adjuvant trastuzumab(Drug information on trastuzumab).[13-15] The combination of chemotherapy with trastuzumab was associated with a significant reduction in odds of recurrence (50%) and death (30%). Concurrent use of trastuzumab with chemotherapy produced a higher disease-free survival rate than sequential use. The cardiac toxicity rate in women receiving trastuzumab was 3% to 4%, but was much higher (20%) in women aged > 50 years and with impaired cardiac function at baseline. Newer studies are testing the cardiac toxicity of adjuvant trastuzumab in combination with other chemotherapy regimens. The Breast Cancer International Research Group (BCIRG) 006 trial compared a control arm of AC followed by docetaxel(Drug information on docetaxel) with two experimental arms: (1) AC followed by trastuzumab plus docetaxel and (2) docetaxel and carboplatin(Drug information on carboplatin) plus trastuzumab (TCH). Preliminary safety data from this trial showed that the cardiac toxicity rate in the TCH experimental arm was the same as that of the control arm (1.2%) and less than half that of the AC/trastuzumab/docetaxel arm (2.3%). Interim efficacy data also showed a 51% relative reduction in the risk of breast cancer recurrence in the AC/trastuzumab/docetaxel arm and a 39% risk reduction in the TCH arm. Continued follow-up is required to determine whether there is a significant difference between the two experimental arms.[16] Assessing Risks and Costs of Chemotherapy
While Perez and Muss emphasize the efficacy of adjuvant therapy, the benefits of adjuvant chemotherapy must be balanced with immediate and late toxicities including ovarian failure, cardiac effects, myelodysplastic syndrome/leukemia, cognitive dysfunctions, and neuropathy. Regimens such as TAC and ddAC → P cause significant myelosupression and require growth-factor support.[10,11] Recent data indicate that the doxorubicin/ docetaxel regimen is associated with a significant incidence of febrile neutropenia and a high risk of lifethreatening complications.[17,18] Another important issue in considering which chemotherapy combination to choose is that of costs and benefits. For example ddAC ? P with growth factor support costs over $20,000, whereas four cycles of every-3-week AC costs around $1,000. A number of factors influence the "costs" of adjuvant chemotherapy and should be considered in decision-making. These factors include the actual costs of drug acquisition (both for the chemotherapeutic agent as well as the ancillary drugs used to treat chemotherapy-related symptoms), out-of-pocket costs (eg, professional fees, diagnostic tests, pharmaceuticals not covered by insurance, etc), and other associated costs (eg, transportation, loss of wages for the patient or his/her caregiver, etc). A multiplying factor, depending upon the duration of the adjuvant treatment, must also be considered. Making an Informed Medical Decision
Another key issue that must be addressed is how best to present these complex data on adjuvant therapy to our patients and actively involve them in the decision-making process. Patient preferences for information and participation in decision-making should be solicited, since approximately two-thirds of patients desire to play an active role in determining which treatment they receive.[19] In discussing risks and benefits of adjuvant chemotherapy, patients seem to prefer the absolute survival benefit method to relative or absolute risk reduction. Discussion in terms of relative risk reduction usually leads to a higher rate of chemotherapy acceptance.[20] Quality of life during treatment does not appear to be the dominant factor for patients with early breast cancer since the disease is curable and the adverse effects of treatment are transient. Decision aids-for example, decision boards and multimedia computer-based programs-have generally been shown to improve decision- making outcomes.[21] Conclusions
In conclusion, this article concisely summarizes current therapies and knowledge about the adjuvant treatment of breast cancer patients. Ongoing studies will clarify the benefits of dose density, the optimal number of chemotherapy cycles, and the role of biologic agents in adjuvant therapy. More importantly, Perez and Muss demonstrate that a generation of clinical trials in the adjuvant therapy of breast cancer has already contributed to saving thousands of lives. Many factors must be incorporated in the selection of the best individualized treatment. Physicians should engage patients and their significant others in shared medical decisions that weigh the potential benefits and risks of the recommended adjuvant chemotherapy against alternative approaches.