Preoperative Chemotherapy for Operable Breast Cancer



Preoperative Chemotherapy for Operable Breast Cancer


Aditya Bardia

José Baselga



INTRODUCTION

Preoperative chemotherapy, also referred to as neoadjuvant chemotherapy or primary systemic therapy, today constitutes one of the standards of care in patients with newly diagnosed early stage breast cancer. This approach was initially introduced in the 1970s for the treatment of patients with locally advanced breast cancer (LABC) where it was found to result in high response rates, allow surgery for these initially unresectable tumors, and improve survival when compared to historical controls (1, 2).

The success of preoperative chemotherapy for locally advanced disease together with emerging data on the benefits of adjuvant chemotherapy has led to the conduct of a number of studies in patients with operable breast cancer. These studies, some of which will be discussed in this chapter, have provided a number of important clinical insights regarding preoperative chemotherapy that are applicable to the management of patients with breast cancer. First, the majority of patients achieve a clinical response to induction chemotherapy, and the progression of disease during therapy, a legitimate concern, is rare. Second, preoperative chemotherapy results in surgical downstaging of tumors and allows breast conservation in women who, otherwise, would have needed a mastectomy. Furthermore, preoperative chemotherapy does not limit or interfere with posterior surgery and radiation therapy. Third, disease-free control and overall survival are similar between preoperative and postoperative (adjuvant) therapy. Fourth, the same chemotherapy agents and sequence of administration used in the adjuvant setting is also used in the preoperative space. As such, there are not preoperative or adjuvant-restricted chemotherapy regimens. Fifth, emerging data suggests that a good response to therapy resulting in absence of tumor at the time of surgery (pathological complete remission [pCR]) may be a surrogate marker of improved disease-free survival and overall survival. Finally, investigational agents are being increasingly studied in the preoperative setting even before the launch of large adjuvant studies as the number of patients required is smaller than in the adjuvant settings and follow up is shorter as a result of using the pCR rate, an early readout as a surrogate marker of improved diseasefree survival and overall survival.

While preoperative chemotherapy is not for every patient and a large number of those patients with newly diagnosed breast cancer for whom chemotherapy is recommended will continue to be treated in the adjuvant setting, preoperative chemotherapy is a treatment approach to be considered and is likely to become a space for the rapid approval of active compounds in the early disease setting.


THE EVOLUTION OF PREOPERATIVE CHEMOTHERAPY

The first prospective preoperative study was launched in 1973 by investigators from the Milan Cancer Institute. The primary objective was to downstage the tumor and facilitate surgical resection. Women with stage III breast cancer received combination chemotherapy with adriamycin and vincristine for three cycles, followed by radiation therapy followed by additional chemotherapy. This preoperative approach was not only effective in downstaging the tumors
but also improved survival (3, 4). In the late 1970s and the 1980s, several preoperative trials assessed the benefit of chemotherapy in women with LABC, and, in addition to improving the rates of operability, most suggested a survival benefit as well (5, 6). Based on these results and the lack of effective alternative strategies, the administration of preoperative chemotherapy with or without radiation therapy prior to surgery thus became the standard for initially inoperable, nonmetastatic breast cancer.






FIGURE 54-1 Evolution of preoperative chemotherapy over the past 30 years. MDACC, MD Anderson Cancer Center, USA; MCI, Milan Cancer Institute, Italy; LABC, locally advanced breast cancer.

The success of preoperative chemotherapy in downstaging tumors and improving survival prompted further evaluation in operable tumors as well. Furthermore, there was a suggestion from preclinical models that chemotherapy before tumor removal may result in better outcomes than administration after surgery due to early eradication of micrometastasis (7, 8). Consequently, in the late 1980s and the 1990s, a new series of clinical trials were launched in the United States and Europe that compared preoperative and adjuvant therapies. The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a large phase III study (NSABP B-18), in which 1,523 women with operable breast cancer were randomly assigned to pre- or postoperative doxorubicin and cyclophosphamide (adriamycin cyclophosphamide [AC]; 60/600 mg/mg2 for four cycles) (9). Preoperative chemotherapy was associated with a higher rate of breast conservation surgery (68% vs. 60%; p = .001) as compared to adjuvant therapy. However, there was no difference in the Disease Free Survival (DFS, 55% vs. 58%) or Overall Survival (OS, 72% vs. 72%) observed between the preoperative and adjuvant groups. Among those patients who received preoperative therapy, achieving pCR was associated with significant improvement in DFS (HR = 0.47; p <.0001) and OS (HR = 0.32; p <.0001) compared with those who had residual tumor at the time of surgery. Similar results were observed in other randomized trials comparing preoperative and adjuvant regimens (10, 11 and 12).

Although any of these trials showed superiority in DFS or OS, the demonstration of equivalence between preoperative and adjuvant chemotherapy set the stage for the development in the preoperative setting of a number of treatment regimens that were developed in parallel with new adjuvant approaches. Today, similar guiding principles apply for the choice of agents, sequencing, and duration of therapy between the preoperative and adjuvant setting. In addition, new targeted agents are today being tested preoperatively. Figure 54-1 outlines the evolution of preoperative chemotherapy over the past 30 years.


CURRENT PREOPERATIVE REGIMENS AND PRACTICE

A number of conditions have to be met in order to consider the administration of preoperative therapy. First, appropriate tumor tissue in the diagnostic specimen should be available for histological diagnosis, including assessment of hormone receptor (HR) and Human epidermal receptor-2 (HER2) status. Ideally, enough tumor tissue for additional studies, such as gene-signature profile, should also be available. Second, it is helpful to place clips to mark the tumor location as it aids the radiologist, surgeon, and pathologist in providing posttreatment assessment. Third, biopsy of clinically palpable axillary lymph nodes, and sentinel lymph node biopsy in the absence of palpable lymph nodes, may be considered before initiating preoperative therapy. The management of sentinel lymph node (SLN) is detailed in Chapter 56. The determination of pathological involvement of axillary lymph nodes has prognostic significance and could influence the radiation therapy decision after surgery. Finally, preoperative chemotherapy requires a fully integrated, strong multidisciplinary team.

The commonly used preoperative regimens are summarized in Table 54-1. The salient features are reviewed below.









TABLE 54-1 Commonly Used Neoadjuvant Chemotherapy Therapy Regimens





























Regimen


Dose and Frequency


AC-Ta


Adriamycin/doxorubicin 60 mg/m2


Cyclophosphamide 600 mg/m2 every 3 weeks for four cycles, followed by


Paclitaxel 80 mg/m2b


ddAC-Ta


Adriamycin/doxorubicin 60 mg/m2


Cyclophosphamide 600 mg/m2 every 2 weeks for four cycles with pegfilgrastim, followed by


Paclitaxel 80 mg/m2b


TCa


Docetaxel 75 mg/m2


Cyclophosphamide 600 mg/m2 every 3 weeks for six cycles


TAC


Docetaxel 75 mg/m2


Doxorubicin 50 mg/m2


Cyclophosphamide 500 mg/m2 every 3 weeks for six cycles with pegfilgrastim


FAC


5-Fluorouracil 500 mg/m2 (days 1, 8 or days 1, 4)


Doxorubicin 50 mg/m2


Cyclophosphamide 500 mg/m2 every 3 weeks for six cycles


FEC-D


5-Fluorouracil 500 mg/m2


Epirubicin 100 mg/m2


Cyclophosphamide 500 mg/m2 every 3 weeks for three cycles, followed by


Docetaxel 100 mg/m2 day 1 every 3 weeks for three cycles


CMF


Cyclophosphamide 100 mg/m2 PO (days 1-14)


Methotrexate 40 mg/m2 IV (days 1, 8)


5-Fluorouracil 600 mg/m2 IV (days 1, 8) every 4 weeks for six cycles


a Preferred regimen.

a Can also be given as paclitaxel 175 mg/m2 every 2 weeks with pegfilgrastim or every 3 weeks.



Choice of Drugs

A standard preoperative chemotherapy regimen should ideally include an anthracycline such as doxorubicin or epirubicin. Doxorubicin is usually given as 50 to 60 mg/m2 every 2 to 3 weeks, and epirubicin as 90 to 100 mg/m2 every 3 weeks. A baseline evaluation of heart function (ejection fraction) should be obtained before initiating anthracyclines.

The addition of taxanes to anthracycline-containing regimens should also be strongly considered as it improves efficacy and clinical outcomes. This was well demonstrated in the NSABP-27 trial, wherein 2,400 patients were randomly assigned to receive either (a) preoperative AC alone (every 3 weeks for four cycles) followed by surgery or (b) preoperative AC followed by docetaxel (100 mg/m2 every 3 weeks for four cycles) followed by surgery or (c) preoperative AC followed by surgery followed by adjuvant docetaxel (13). Preoperative AC-docetaxel significantly improved pCR rate as compared to AC alone (26.1% vs. 13.7%; p <.001). Like the NSABP B-18, the pCR was a significant predictor of DFS (HR = 0.49; p <.0001) and OS (HR = 0.36; p <.0001) regardless of treatment. Multiple other preoperative trials have demonstrated the advantage of adding docetaxel (14, 15 and 16), and paclitaxel (17, 18) in the preoperative setting.

If there is a contraindication to use of anthracyclines, a non-anthracycline regimen preferably with a taxane, such as TC, should be considered based on extrapolation from the adjuvant studies (19). The TC regimen involves the administration of docetaxel 75 mg/m2 with cyclophosphamide 600 mg/m2 every 3 weeks for a total of four cycles. This should be given in conjunction with appropriate antiemetic prophylaxis and growth factor support.


Schedule

Weekly paclitaxel seems to be superior to every-3-week paclitaxel, similar to that observed in the adjuvant setting. For example, in a preoperative trial led by investigators at MDACC, 258 patients were randomly assigned to receive a) weekly paclitaxel (either 80 mg/m2 for 12 weeks to those with clinically node-positive disease or 150 mg/m2 3 weeks on and 1 week off for 12 weeks to those with clinically nodepositive disease) or b) every-3-week paclitaxel (225 mg/m2 every 3 weeks for four cycles). Both the pCR rates (28.2% vs. 15.7%; p = .02) and breast conservation rate (47% vs. 38%; p = .05) were higher in those who received weekly paclitaxel than those who received every-3-week paclitaxel (20).

Conceptually, the same regimen and schedule used for adjuvant therapy could be used for preoperative therapy. Thus, as in the adjuvant setting, the administration of chemotherapy cycles every 2 weeks instead of every 3 weeks, an approach that is being referred to as dose-dense chemotherapy, might be superior to a conventional dose regimen, though strong data from randomized clinical trials is lacking. Trials comparing dose-dense regimens to conventional regimens have had differences in the dose and regimen between the groups, making it difficult to draw clear conclusions. For example, in the AGO-1 trial (21), eligible patients (n = 668) were randomly assigned to receive either a) dose-dense epirubin (150 mg/m2 every 2 weeks for three cycles) followed by paclitaxel (225 mg/m2 every 2 weeks for three cycles) or b) a conventional dose of epirubicin (90 mg/m2 every 3 weeks for four cycles) and paclitaxel (175 mg/m2 every 3 weeks for four cycles); the dose-dense sequential schedule was associated with higher pCR (18% vs. 10%; p = .008) as well as improvement in DFS (HR = 0.71; p = .011), and OS (HR = 0.83; p = .041) as compared to the conventional combination schedule. However, it is unclear whether the superiority of the dose-dense regimen was due to the dose-dense schedule or the addition of taxanes.

Nevertheless, in the U.S., dose-dense AC (followed by paclitaxel) is commonly used in clinical practice. This involves the administration of Adriamycin 60 mg/m2 every 2 weeks along with cyclophosphamide 600 mg/m2 every 2 weeks for a total of four cycles. This should be given in conjunction with appropriate antiemetic prophylaxis and growth factor support.


Sequence

The sequential administration of taxane following anthracyclines appears to be better than combination therapy. In the German Preoperative Adriamycin Docetaxel Trial (Gepar-DUO) trial, women (n = 913) were randomized to either a) a combination of doxorubicin and docetaxel (AD; 50/75 mg/m2 every 2 weeks for four cycles) or b) AC (60/600 mg/m2 every 3 weeks for four cycles) followed by docetaxel (100 mg/m2 every 3 weeks for four cycles) (16). As compared to the AD
group, the AC-D group had better clinical responses (75.2% vs. 85%; p <.001), radiographic responses (68.6% vs. 78.6%; p <.001), breast conservation surgery rate (58.1% vs. 63.4%; p = .05), and pCR rate (7% vs. 14.3%; p <.001). The Hoosier Oncology Group trial also demonstrated the superiority of the sequential adriamycin-docetaxel regimen over the combination regimen (22).


Duration

There is a consensus of opinion based on currently available data that preoperative chemotherapy should be administered for at least six cycles, as in the adjuvant setting (2). The continuation of the same regimen beyond the standard number of cycles is not recommended, and sequential use of cross-resistant therapy is preferred over a longer duration of the same regimen (14, 15). A German meta-analysis has suggested that duration of chemotherapy might be more important for HR+ tumors, and dose intensity more important for triple-negative breast cancers (TNBCs) (23), but this approach has not been validated in prospective studies.

In general, it is recommended that the full preoperative regimen should be administered before surgery, particularly if breast conservation surgery is desired. Sometimes preoperative therapy is used as a “bridge” until the mastectomy and reconstruction can be scheduled, and, in such settings, a sandwich technique (i.e., delivering part of chemotherapy before surgery and the remainder after surgery) can be used. The survival outcomes are similar as demonstrated by the NSABP-27 trial (13).

After preoperative chemotherapy, definitive breast surgery should be performed. The American Joint Committee on Cancer Staging manual uses “y” to indicate pathologic staging after preoperative therapy. After surgery, radiation and/or biologic therapy as appropriate (i.e., trastuzumab in HER2-positive disease, hormonal therapy for HR+ disease) should be pursued. The presence of residual disease after completion of preoperative therapy can be a therapeutic challenge, particularly for TNBCs. While the presence of residual disease is associated with worse outcomes as compared to pCR, there is no data that demonstrates additional postoperative chemotherapy improves outcomes. This is an area of active research and several clinical trials are investigating the role of additional therapies in this setting (NCT01401959, NCT0087750, NCT00925652, NCT01772472).


ADDITIONAL CHEMOTHERAPY AGENTS

In addition to the standard anthracyclines and taxanes discussed above, other chemotherapeutic agents have been studied in the preoperative setting. While they have shown clinical activity, they are not considered to be standard of care at this time.


Platinum

Gene-expression profiling of breast cancer has demonstrated that triple-negative breast cancer shares molecular features with basal-like BRCA-1 tumors, which are very sensitive to DNA cross-linking agents such as cisplatin (24). This has led to a renewed interest in the role of platinum agents in breast cancer.

Various small preoperative trials have investigated the role of platinums in TNBC. In a small phase II trial, women with triple-negative breast cancer (n = 28) were treated with preoperative cisplatin (75 mg/m2 every 3 weeks for four cycles), and a pCR rate of 22% was observed (25). Other authors have reported a higher pCR rate (as high as 67%) with platinum and taxane combinations (26, 27), albeit still lower than the >80% pCR rate reported for BRCA tumors (28). Randomized trials comparing platinum-containing chemotherapy to nonplatinum-based chemotherapy, such as CALGB 40603, are ongoing and will help identify predictive biomarkers of platinum response.

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Jul 9, 2016 | Posted by in ONCOLOGY | Comments Off on Preoperative Chemotherapy for Operable Breast Cancer

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