Triple-drug Neoadjuvant Therapy for Triple-negative Breast Cancer
Triple-drug Neoadjuvant Therapy for Triple-negative Breast Cancer
Abstract & Commentary
By William B. Ershler, MD
Synopsis: For patients with ER-, PR-, HER 2- breast cancer, neoadjuvant treatment, with eight weekly cycles of cisplatin, epirubicin, and paclitaxel (and G-CSF), resulted in impressive response rates and promising long-term, disease-free survival.
Source: Frasci G, et al. Preoperative weekly cisplatin-epirubicin-paclitaxel with G-CSF support in triple-negative large operable breast cancer. Ann Oncol. 2009;20:1185-1192.
For women who present with large primary breast cancers, there is increasing enthusiasm for the use of primary chemotherapy to allow breast-conserving surgery. Furthermore, it has been observed that the majority of patients who achieve the complete eradication of invasive tumor in both breast and axilla (pathologic complete remission [pCR]) with primary chemotherapy, have been shown to have a greater likelihood for long-term, disease-free survival (DFS).1 For the subset of patients who have breast cancers that are estrogen-receptor (ER) negative, progesterone-receptor (PR) negative and HER-2 negative (i.e., "triple negative"), long-term control often requires aggressive systemic therapy with cytotoxic drugs. Attaining a pCR is of critical importance for patients with triple-negative disease. If achieved, long-term survival is comparable to patients with non triple-negative disease. However, for those patients with triple-negative disease with residual invasive local disease after neoadjuvant chemotherapy, the rate of early relapse is dramatically higher and survival is shorter than for non triple-negative patients.2 Thus, there is a sound rationale for providing aggressive primary chemotherapy for this subset of patients. In this regard, Frasci et al previously reported the results of a three-drug regimen, including cisplatin, epirubicin, and paclitaxel (PET) for neoadjuvant treatment of ER-, PR-, HER-2+ breast cancer patients demonstrating a very impressive pCR rate of > 60%.3 In the current report, data for the same regimen applied to those with triple-negative disease is presented.
Overall, 74 consecutive patients (T2/T3 = 35/39; N0/N+ = 26/48) were treated from May 1999 to May 2008. All patients received epirubicin 50 mg/m2 as an i.v. bolus, followed by paclitaxel 120 mg/m2 as a 1-h infusion, and cisplatin 30 mg/m2 as a 30-min infusion weekly for eight weeks. Recombinant human G-CSF 300 ug/day was also given s.c. on days 3-5 of each week.
A short-term forced hydration (1:l of saline over 2 h) and antiemetic prophylaxis (HT3 receptor antagonists) also were carried out. Prophylaxis for hypersensitivity reactions consisted of dexamethasone 8 mg i.v. and promethazine 50 mg i.m., plus ranitidine 50 mg i.v. 30 min before paclitaxel administration.
Within three weeks from the end of chemotherapy, patients underwent surgery. Breast-sparing surgery was carried out when feasible. It consisted of quadrantectomy together with standard level I and II axillary lymph node dissection.
Four cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil were delivered after surgery in patients showing less than four axillary nodes involved at pathologic assessment. An additional four cycles of fluorouracil-epirubicin-cyclophosphamide (FEC) (epirubicin instead of methotrexate) were administered in those women showing four or more axillary nodes involved. On completion of postoperative chemotherapy, radiotherapy was carried out in those patients who underwent conservative surgery, as well as in those submitted to mastectomy who had shown more than three axillary nodes involved, skin and/or nipple involvement, or had T3 or G3 tumor at diagnosis.
All but one patient received the planned eight-weekly treatment cycles. Treatment delays due to hematological toxicity occurred in 16 of the 74 patients, and dose reductions were required in 29 patients. Sixty-three of the 74 (85.1%) patients received > 80% of the planned dose intensity. Severe non-hematological toxicity was recorded in < 20% of patients. Peripheral neuropathy was quite frequent but never severe. All 74 patients underwent surgery. Clinical CR was observed in 70% and PR in 28%, with only one patient demonstrating a "minor response" and no patients experiencing progressive disease.
At pathological assessment, 46 women (62%; 95% confidence interval 50-73) showed pCR in both breast and axilla. At a 41-month median follow-up (range 3-119), 13 events (nine distant metastases) had occurred, and the five-year projected disease-free survival (DFS) and distant disease-free survival were 76% and 84%, respectively. Five-year DFS was 90% and 56% in pCRs and non-pCRs, respectively.
Commentary
Triple-negative breast cancers are particularly aggressive, especially when they present as a large primary tumor. Accordingly, primary therapy needs to be aggressive, with the goal of achieving a pCR in every case. Short of that, relapse is typically quick and survival limited. Thus, the current report marks a definite step forward. The PET chemotherapy regimen is unique compared to others used in this setting because it includes cisplatin, it is administered on a weekly schedule, and the dosing, particularly of epirubicin, was quite intense. Accrual onto the study was relatively slow, and 32 of the 74 patients had less than three years of follow-up. Thus, continued follow-up of this cohort is warranted. Nonetheless, there seems enough here to provide sufficient rationale to warrant a larger-scale, phase III trial with this regimen. As suggested by Frasci et al, modifications could be introduced, such as early functional imaging studies (e.g., fluorodeoxyglucose positron emission tomography or dynamic magnetic resonance imaging), which could offer earlier prediction of response, allowing for diversion of likely non-responders to alternative interventions. Such an approach could, and should, also be included in the context of a clinical trial.
References
1. Wolff AC, et al. Research issues affecting preoperative systemic therapy for operable breast cancer. J Clin Oncol. 2008;26:806-813.
2. Liedtke C, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275-1281.
3. Frasci G, et al. A 2-month cisplatin-epirubicin-paclitaxel (PET) weekly combination as primary systemic therapy for large operable breast cancer: a phase II study. Ann Oncol. 2005;16:1268-1275.
For patients with ER-, PR-, HER 2- breast cancer, neoadjuvant treatment, with eight weekly cycles of cisplatin, epirubicin, and paclitaxel (and G-CSF), resulted in impressive response rates and promising long-term, disease-free survival.Subscribe Now for Access
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