The goal of chemotherapy given in either adjuvant or neoadjuvant (preoperative) settings is to eradicate occult distant metastases and ultimately to increase the probability of disease-free survival.1 Neoadjuvant chemotherapy has been used for many years as a primary treatment for locally advanced or inflammatory breast cancer.2 The aim of neoadjuvant chemotherapy is to reduce the tumor size before surgery, and hopefully result in a lower rate of total mastectomy. More recently, neoadjuvant chemotherapy has been extended to operable breast cancer.3 However, only a few studies have published data concerning the outcomes of patients with stages II and III breast cancer after neoadjuvant chemotherapy. The present study was performed to assess the value of neoadjuvant chemotherapy for patients with stages II and III breast cancer. The rates for breast conservation operability, dermatoplasty, recurrence, overall and disease-free survivals in patients with stages II and III breast cancer were documented and analyzed.
The eligibility criteria for this study were as follows: age <70 years; histologically proven invasive carcinoma (diagnosed by core biopsy); no metastatic spread; and no prior specific treatment. Initial staging comprised a complete clinical examination, mammography and ultrasonography. A histological diagnosis was mandatory for the primary tumor.
From September 2002 to February 2004, 54 women with stages II and III breast cancer (according to the UICC TNM classification and stage) were enrolled in the study as a neoadjuvant chemotherapy group (Group 1), and 43 women with stages II and III breast cancer were assigned to a control group (Group 2).
The median age of the patients was 45 years (range, 24-69 years), and 52 women (53.6%) were premenopausal. In total, 12 tumors were ≤2 cm in diameter, 61 tumors were 2.1-5.0 cm and 24 tumors were >5 cm. The tumor characteristics are shown in Table 1. Overall, 22 patients (22.7%) were younger than 35 years, 53 patients (54.6%) had no clinically detectable lymph node involvement at diagnosis, 62 patients (63.9%) had stage II disease and 35 patients (36.1%) had stage III disease. In addition, all the patients had other prognostic factors as follows: pathology (invasive ductal tumors, 72 cases); hormone receptor status (positive for estrogen and/or progesterone receptors, 72 cases); Her-2/neu status (3+ by immunohistochemistry, 24 cases). As shown in Table 1, the clinicopathological characteristics of Group 1 and Group 2 were similar, and there were no significant differences between the two groups (P >0.05).
The patients in Group 1 received standard cyclophosphamide (Shanghai Hualian Pharmaceutical Factory, China), doxorubicin (Shenzhen Wanle Pharmaceuticals, China) or epidoxorubicin (Pfizer Pharmaceuticals, USA), and 5-fluorouracil (Shanghai Xudong Haipu Pharmaceuticals, China), designated the CA/E100F regimen. Cyclophosphamide 500 mg/m2 i.v.p., doxorubicin 50 mg/m2 i.v.p. or epidoxorubicin 100 mg/m2 i.v.p., and 5-fluorouracil 500 mg/m2 i.v.p. were given during each 21-day cycle.
Patients with an apparent complete clinical response proceeded to definitive surgery. Responding patients after four cycles of CA/E100F, underwent surgery and then received two other cycles of CA/E100F as adjuvant chemotherapy. Patients with progressive and stable disease during CA/E100F had early discontinuation and were subsequently given 2 cycles of paclitaxel (Bristol-Myers Squibb Company, USA) plus doxorubicin or epidoxorubicin (TA/E100 regimen). Paclitaxel 175 mg/m2 i.v.p. and doxorubicin 50 mg/m2 i.v.p. or epidoxorubicin 100 mg/m2 i.v.p. were given during each 21-day cycle, and two other cycles of TA/E100 were given as postoperative chemotherapy.
Surgery consisted of lumpectomy and axillary dissection if the residual tumor size was ≤3 cm, or modified radical mastectomy if the tumor size was >3 cm or extended intracanalar disease was present. Radiotherapy was given postoperatively to the patients with breast-conserving surgery, those with internal mammary lymph node metastasis and positive axillary lymph nodes.
When significant residual disease remained, adjuvant chemotherapy was considered on an individual basis and left to the clinician's judgment. Tamoxifen was given to premenopausal patients and aromatase inhibitor was advised to postmenopausal patients presenting with hormone receptor-positive tumors, and adjuvant hormonotherapy was advised for 5 years.
Statistical analyses were performed using the software SPSS 11.5 (SPSS Inc., USA). The data were expressed as frequency. Comparisons between the two groups were assessed by chi-square test. P values <0.05 were considered to indicate statistical significance.
Several CA/E100F regimen cycles (range, 3-4) were administered to the 54 patients in Group 1. Overall, 36 patients received 4 cycles of the CA/E100F regimen, 5 patients with an apparent complete clinical response proceeded to definitive surgery after CA/E100F administration (1 patient after 3 cycles and 4 patients after 4 cycles), and 13 patients with progressive or stable disease after 2 cycles of CA/E100F were subsequently given 2 cycles of TA/E100. The 43 patients in Group 2 did not receive neoadjuvant chemotherapy.
In Group 1, 51 patients received postoperative chemotherapy. Overall, 41 patients presenting complete or partial clinical responses received another 2 cycles of the CA/E100F regimen, and 13 patients with progressive or stable tumors were subsequently given 2-4 cycles of TA/E100. In Group 2, a median of 5 postoperative chemotherapy cycles (range, 4-6) was given to 43 patients, comprising CA/E100F to 30 patients and TA/E100 to 13 patients. Subsequently, 41 patients (25 in Group 1 and 16 in Group 2) received radiotherapy and 67 patients (39 in Group 1 and 28 in Group 2) received hormonotherapy for 3-5 years.
Breast-conserving surgery and dermatoplasty
In Group 1, 6 patients (11.1%) were available for breast-conserving surgery and 14 patients (22.2%) needed to receive dermatoplasty before neoadjuvant chemotherapy. After neoadjuvant chemotherapy, 19 patients (35.2%) were eligible for breast-conserving surgery, however, 3 patients refused. At the same time, 38 patients underwent a modified radical mastectomy and 3 patients (5.6%) underwent dermatoplasty.
As shown in Table 2, neoadjuvant chemotherapy significantly increased the operability rates for breast conservation from 17.1% to 40.0% in stage II (P=0.034) and 0% to 12.6% in stage III (P=0.016). Meanwhile, neoadjuvant chemotherapy significantly decreased the dermatoplasty rates from 17.1% to 2.8% in stage II (P=0.046) and 28.1% to 8.1% in stage III (P=0.027).
In Group 2, 43 eligible patients received surgery, comprising breast-conserving surgery in 7 patients (16.3%), a modified radical mastectomy in 36 patients (83.7%) and dermatoplasty in 10 patients (23.2%).
On March 3, 2009, the median follow-up period was 46.8 months (range, 13.1-78.2 months). In Group 1, 11 patients had died (5 in stage II and 6 in stage III) with the first death at 21.7 months, and 13 recurrences were observed (6 in stage II and 7 in stage III) with the first recurrence at 14.9 months. In Group 2, 15 patients had died (4 in stage II and 11 in stage III) with the first death at 18.6 months, and 19 recurrences were observed (7 in stage II and 12 in stage III) with the first recurrence at 13.4 months.
Overall and disease-free survival rates
As shown in Table 3, the overall survival rates of the patients with stages II and III disease were 85.7% and 68.4% in Group 1, and 85.2% and 31.2% in Group 2, respectively. The overall survival rate of stage III disease was significantly higher in Group 1 than in Group 2 (68.4% vs 31.2%, P=0.028). No significant elevation of the overall survival rate of stage II disease was observed in Group 1 compared with Group 2 (85.7% vs 85.2%, P=0.953).
The disease-free survival rates of the patients with stages II and III disease were 80.6% and 63.2% in Group 1, and 74.1% and 25.0% in Group 2, respectively. The disease-free survival rate of stage III disease was significantly higher in Group 1 than in Group 2 (63.2% vs 25.0%, P=0.024). No significant increase in the disease-free survival rate of stage II disease was observed in Group 1 compared with Group 2 (80.6% vs 74.1%, P=0.400).
Administration of neoadjuvant chemotherapy may offer some advantages for patients with breast cancer. First, down-staging of the primary tumor increases the chance that the patient may undergo breast-conserving surgery and can convert inoperable tumors into operable tumors. Second, monitoring of the primary tumor response allows chemosensitivity testing of the primary tumor and may provide a surrogate marker for the effect of treatment on survival.4 Third, early onset of systemic treatment may be more effective for obtaining control of micrometastases, with less chance of developing drug-resistant clones over time.5
In the present study, neoadjuvant chemotherapy decreased the dermatoplasty rates from 17.1% to 2.8% in stage II disease and 28.1% to 8.1% in stage III disease, and increased the operability rates for breast conservation from 17.1% to 40.0% in stage II disease and 0 to 12.6% in stage III disease. Breast-conserving surgery could be performed in 19 patients (including 5 with stage III disease) after neoadjuvant chemotherapy, although only 16 patients finally accepted this surgery. The breast-conservation rate in the present study was much lower than the reported rates of 40%-98% in previous studies.6-8 Breast- conserving surgery after neoadjuvant chemotherapy is affected by the surgeon's experience, the perception of operability and the patient's aspirations.9 The patients' aspirations played a crucial role in the decision for breast-conserving surgery among these three important factors in the present study. The adverse effects of neoadjuvant chemotherapy (such as alopecia, anemia, febrile neutropenia and other hematological toxicities) and the fear of recurrence could affect the patients' aspirations for breast-conserving surgery. Consequently, these patients may decline breast-conserving surgery and switch to mastectomy.
More recently, neoadjuvant chemotherapy has been performed and extended to operable breast cancer including early-stage invasive carcinoma. Neoadjuvant therapy shows better results in terms of the rate of response to treatment and a reduction in the requirement for mastectomy.10 The question then arises as to whether preoperative chemotherapy is more effective for prolonging overall and disease-free survival than the same chemotherapy given postoperatively. Several studies have been performed to compare preoperative and postoperative chemotherapy administrations in patients with operable breast cancer.10,11 However, the results for the survival rates are conflicting. Scholl et al9 initially observed a statistically significant difference in survival in favor of the neoadjuvant chemotherapy group, but later reported that this advantage became insignificant.13 The National Surgical Adjuvant Breast Project (NSABP) Study B-18 analyzed 1523 patients with operable breast cancer being treated with 4 cycles of AC. The authors concluded that there were no significant differences in the disease-free and overall survival rates between the two groups.12,13 Patients who achieved a partial clinical response with preoperative treatment had a longer recurrence-free survival than nonresponders or partial responders.16-18
In the present study, neoadjuvant chemotherapy seemed to show better results in terms of the recurrence, and overall and disease-free survival rates in stage III disease. However, there were no significant differences in the recurrence, and overall and disease-free survival rates in stage II disease between the two groups. Patients with stage II disease are composed of stages IIa and IIb breast cancer, of which stage IIb disease is classified as locally advanced breast cancer and stage IIa disease is classified as early-stage disease. Therefore, even if neoadjuvant chemotherapy appeared to show better results in terms of the recurrence, and overall and disease-free survival rates in stage III disease,19-21 this strategy did not demonstrate a greater survival for all invasive carcinoma cases. Hence there is a conflicting concept that all patients with invasive carcinoma (including early-stage cancer) need to receive neoadjuvant chemotherapy regardless the type of tumor and should be advised to receive neoadjuvant chemotherapy despite their demands and feelings.
In conclusion, the present study showed that neoadjuvant chemotherapy resulted in down-staging of bulky tumors, decreased rates of dermatoplasty and increased rates of breast conservation. Neoadjuvant chemotherapy demonstrated greater recurrence control, and overall and disease-free survival rates in stage III disease. However, neoadjuvant chemotherapy did not seem to show better results in terms of survival for stage II disease. Further studies are required to confirm the benefits of neoadjuvant vs postoperative chemotherapy administration for early-stage breast cancer.
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