Locally advanced breast-carcinoma - results of a multimodal therapy including alternating neoadjuvant chemotherapy, surgery and radiotherapy

Thirty women with locally advanced breast cancer (LABC), but no evidence of distant metastases, were prospectively treated with four fixed cycles of neoadjuvant chemotherapy (CT). This regimen consisted of epidoxorubicin (Epi) alternated every 21 days with cyclophosphamide, methotrexate and 5-fluorouracil (CMF). After this induction CT, subsequent therapy was planned according to the response obtained as follows: (a) modified mastectomy with axillary dissection was performed in patients who had major objective response (complete or partial), followed by four doses of adjuvant CT and radiotherapy (RT); (b) debulking rescue surgery followed by RT and 2nd line CT with mitomycin C were given in patients with stable disease or minor response. The response rate to induction CT was 63% (19 of 30 patients) (95% confidence limits 46-80%). Overall, 43% of patients had no persistance of tumor at the end of the planned therapy. After a median follow-up time of 36 months, disease-free survival (DFS) and overall survival (OS) were 35% and 47%, respectively. The median duration of DFS was 16 + months (4-52+ months). A significantly better OS was observed in complete responders compared to the others (77% versus 23.5%; p=0.01). Compliance to treatment was high, gastrointestinal and hematological toxicities were the most common side-effects. Thus, this multimodal approach is effective in reducing primary tumor size with acceptable morbidity. Five of the 11 (45%) patients non responsive to induction CT obtained a transient local control of disease after debulking surgery, RT and mitomycin C. To assess the role of alternating non cross resistant regimens as induction therapy in LABC vs conventional schedules, phase III comparative studies are warrented.     

A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer

Backgound: A prospective randomised trial was undertaken to evaluate the role of neoadjuvant chemoendocrine therapy prior to surgery in primary operable breast cancer.Patients and methods: Three hundred nine women (median age 56 years, range 27–70) with primary operable breast cancer confirmed on fine needle aspiration (FNA) cytology were recruited to this study. They were treated with a combination of mitozantrone and methotrexate (± mitomycin-C) combined with tamoxifen (2MT). Patients received eight cycles of 2MT (four prior to surgery in the neoadjuvant group) and tamoxifen for five years with appropriate surgery and radiotherapy. The two groups were comparable for age, menopausal status, stage and surgical requirements.Results: The clinical response rates to neoadjuvant therapy were as follows: 22% complete response (CR), 29% minimal residual disease (MRD), 33% partial response (PR), 15% no change (NC) and only two patients had clinical evidence of progressive disease. Surgical requirements were reduced from 31 patients (22%) of the adjuvant group having mastectomy to 14 (10%) in the neoadjuvant group (P < 0.003). At a median follow-up of 48 months (range 10–70 months) there is no statistically significant difference between the two groups in terms of local relapse, metastatic relapse or overall survival. Symptomatic and haematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy.Conclusion: This randomised trial has shown a significant reduction in the surgical requirements for mastectomy, after treatment with neoadjuvant chemoendocrine therapy, with no deterioration in local or distal relapse.     

Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival

We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m2 intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). In conclusion, pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS. Half of the patients with HR negative tumors achieved a pathologic response.     

Randomised trial: One cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive,hormone receptor-negative breast cancer patients

AIM: A randomised, controlled clinical trial was initiated in 1984 to test whether 1 cycle of anthracycline-containing adjuvant chemotherapy improves the outcome of breast cancer patients presenting with stage II disease and negative oestrogen and progesterone receptors (ER, PgR), as compared with 6 cycles of dose-reduced CMF. PATIENTS AND METHODS: Within 7 years 263 women with stage II breast cancer were randomised either to receive 1 cycle of doxorubicin, vinblastine, cyclophosphamide, methotrexate and 5- fluorouracil (AV-CMF) or to receive 6 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Patients were stratified for tumour stage, nodal stage, menopausal status, type of surgery and participating centre. RESULTS: After a median follow-up of 100 months, neither disease-free (DFS) nor overall survival (OS) differed significantly between the two groups. CONCLUSIONS: Compared to 6 cycles of a non-standard low-dose CMF regimen 1 cycle of anthracycline- containing adjuvant chemotherapy failed to improve the outcome in women with stage II receptor-negative breast cancer in terms of DFS and OS.     

Neoadjuvant chemotherapy with infusional 5-fluorouracil, adriamycin and cyclophosphamide (iFAC) in locally advanced breast cancer: an early response predicts good prognosis.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of neoadjuvant chemotherapy with infusional 5-fluorouracil (5-FU), adriamycin and cyclophosphamide (iFAC) in locally advanced breast cancer (LABC). PATIENTS AND METHODS: Eighty-two LABC patients were treated with neoadjuvant iFAC chemotherapy including infusional 5-FU (1000 mg/m2, continuous intravenous infusion, days 1-3), adriamycin (40 mg/m2, intravenous bolus, day 1) and cyclophosphamide (600 mg/m2, intravenous bolus, day 1) every 3 weeks until maximum tumor response. Patients subsequently received surgery, adjuvant chemotherapy, radiotherapy and hormonal therapy as appropriate. RESULTS: Downstaging occurred in 71 of the 82 patients (86.6%). Seventy-two patients (67 patients with downstaging and five patients without downstaging) were resectable (resectability rate, 87.8%). The clinical response rate was 84.2%, with a complete response (CR) rate of 17.1% and a pathological CR rate of 7.8%. During 891 cycles of chemotherapy, the most common grade 3/4 hematological toxicity was leukopenia (36.0%). There were no treatment-related deaths. The median follow-up period was 51 months, with a median overall survival (OS) of 66 months, and a 5 year OS rate of 50.9% for all patients. The 5 year OS and disease-free survival (DFS) rates of the 64 patients who underwent surgery were 55.8% and 44.7%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy with iFAC had a comparable response rate and DFS to the conventional bolus FAC regimen, with an acceptable toxicity in LABC using the AJCC 2002 staging system. An early response to neoadjuvant iFAC was a favorable prognostic factor.     

Dose-intense ifosfamide/doxorubicin/cisplatin based chemotherapy for osteosarcoma in adults

The efficacy of neoadjuvant and adjuvant chemotherapy has been clearly established in the treatment of osteosarcoma; however, the most active regimen remains to be identified. This prospective study evaluated the efficacy and toxicity of a dose-intense ifosfamide, doxorubicin, and cisplatin-based neoadjuvant regimen in adults with osteosarcoma. We prospectively treated 20 patients with osteogenic sarcoma with two cycles of ifosfamide/doxorubicin followed by two cycles of doxorubicin/cisplatin every 2 weeks. Surgical specimens were analyzed for percent tumor necrosis. Patients who demonstrated a "good response" (GR) to chemotherapy received the same combination postoperatively at a lower dose rate. Patients who demonstrated a "poor response" (PR) received four cycles of high-dose methotrexate alternating with two cycles of ifosfamide/etoposide and two cycles of cisplatin/etoposide after the surgery. Neoadjuvant chemotherapy was well tolerated with moderate hematologic toxicity. Twelve of 19 evaluable patients (63%) were treated according to the GR arm and 7 according to the PR arm. At median follow-up of 5.5 years, disease-free survival (DFS) and overall survival (OS) are 68% and 74%, respectively. Patients treated on the GR arm had DFS and OS of 75% and 83%, respectively, whereas patients on the PR arm had DFS and OS of 57%. Intensive neoadjuvant chemotherapy is effective and moderately well tolerated in patients with de novo osteosarcoma. The outcome data suggest that lack of a near complete response to preoperative chemotherapy reflects inherent biologic resistance to chemotherapy and hence a poor prognosis.     

Serum markers and prognosis in locally advanced breast cancer

BACKGROUND: Locally advanced breast cancer (LABC) represents a heterogeneous subgroup of breast cancer with an often dismal outcome. Identifying prognostic factors has acquired great significance for the selection of optimal treatment in individual patients. METHODS: Between January 1993 and December 1997, 103 patients were treated in our institution with multimodality treatment consisting of neoadjuvant chemotherapy followed by surgery, adjuvant chemotherapy and radiotherapy; tamoxifen was added in hormone receptor-positive cases. In the search for prognostic factors well-established parameters (clinical, pathological and treatment-related) as well as new features with potential value (c-erbB-2, baseline serum levels of CA 15.3 and CEA) were included in the univariate and multivariate analysis. RESULTS: At a median follow-up of 92 months (range, 8-130), the estimated five-year cancer-specific overall survival (OS) and disease-free survival (DFS) were 71.34% and 57.7%, respectively. Among the 22 different variables studied, only 10 were significantly correlated with OS and DFS. In multivariate analysis five retained independent prognostic value for both OS and DFS: tumor grade, serum markers, features of inflammatory breast cancer (IBC), response to neoadjuvant chemotherapy and lymph node status. With cutoff values of 35 U/mL for CA 15.3 and 5 ng/mL for CEA, the probability of five-year OS (Cox hazard ratio 3.91, P = 0.0009) and DFS (Cox hazard ratio 2.40, P = 0.02) decreased from 78% to 52% and from 68% to 47%, respectively, when at least one of these markers was abnormal. CONCLUSIONS: Baseline serum levels of CEA and CA 15.3 emerged from this study as strong independent predictors of outcome in LABC, whose value adds to other established prognostic factors such as postoperative nodal status, IBC, histological grade and response to neoadjuvant chemotherapy.     

Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial.

PURPOSE: Bisphosphonates have effectively reduced the development and progression of bone metastases in advanced breast cancer. The aim of this study was to determine whether bone metastases could be prevented by adjuvant clodronate treatment in patients with primary breast cancer. PATIENTS AND METHODS: Between 1990 and 1993, 299 women with primary node-positive breast cancer were randomized to clodronate (n = 149) or control groups (n = 150). Clodronate 1,600 mg daily was given orally for 3 years. All patients received adjuvant therapy: premenopausal six cycles of CMF chemotherapy and postmenopausal antiestrogens (randomized to tamoxifen 20 mg or toremifene 60 mg/d for 3 years). Seventeen patients were excluded from the analyses because of major protocol violations. The final population was 282 patients. Intent-to-treat analyses were also performed for all major end points. The follow-up time was 5 years for all patients. RESULTS: Bone metastases were detected equally often in the clodronate and control groups: 29 patients (21%) versus 24 patients (17%) (P: = .27). The development of nonskeletal recurrence was significantly higher in the clodronate group compared with controls: 60 patients (43%) versus 36 patients (25%) (P: = .0007). The overall survival (OS) and disease-free survival (DFS) rates were also significantly lower in the clodronate group than in the controls (OS, 70% v 83%, P: = .009; DFS, 56% v 71%, P: = .007, respectively). In multivariate analyses, clodronate remained significantly associated with DFS (P: = .009). CONCLUSION: Adjuvant clodronate treatment does not prevent the development of bone metastases in node-positive breast cancer patients. However, clodronate seems to have a negative effect on DFS by increasing the development of nonskeletal metastases.     

Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy

IntroductionSmall cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC).Patients and MethodsClinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed.ResultsOne hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (<pT2pN0) and pathologic complete response (pT0pN0) rates of 48% and 38%, respectively, with median follow-up of 7.2 years, and median DFS and OS of 5.6 and 14.5 years, respectively. NAC responders (<ypT2N0) had superior median DFS (14.5 vs. 0.6 years, hazard ratio [HR] 0.24, P< .001) and OS (14.5 vs. 2.5 years, HR 0.31, P = .002). DFS rates for responders and nonresponders were 76% and 27% at 5 years, and 71% and 23% at 10 years, respectively. Local and central nervous system recurrences were infrequent. Median progression-free survival (PFS) and OS for M1 disease were 6.9 and 10.3 months, respectively. Genomic profiling was performed on 47 NAC patients. Loss of ERCC2 function was significantly enriched among those with pathologic complete response to NAC (mutations present in 50% of pathologic complete responders vs. 15% nonresponders, P = .045).ConclusionM0 SCCB is chemo-sensitive and patients have excellent long-term survival following response to NAC. Patients with M1 disease have poor survival despite systemic therapy. Loss-of-function mutations of ERCC2 were associated with pathologic complete response to NAC.     

A high serum matrix metalloproteinase-2 level is associated with an adverse prognosis in node-positive breast carcinoma.

PURPOSE: The aim of this study was to determine whether serum matrix metalloproteinase (MMP) -2 and MMP-9 levels could predict overall and disease-free survival in primary node-positive breast cancer. EXPERIMENTAL DESIGN: MMP-2 and MMP-9 levels were quantitatively measured in serum after surgery from 133 patients with primary node-positive breast cancer using enzyme-linked immunoassays. All of the patients received adjuvant therapy, postmenopausal endocrine treatment (tamoxifen or toremifen for 3 years) and premenopausal six cycles of CMF chemotherapy. The follow-up time for all of the patients was 5 years. RESULTS: Overall survival (OS) and disease-free survival (DFS) rates were better among patients with low MMP-2 levels than in patients with high levels (OS, 91% versus 75%, P = 0.020; DFS, 82% versus 58%, P = 0.005). The appearance of bone and visceral metastases was also significantly lower in patients with low serum MMP-2 levels (bone metastases, 10% versus 23%, P = 0.050; visceral metastases, 12% versus 34%, P = 0.018). The prognostic value of MMP-2 levels was most pronounced among a subgroup of estrogen receptor-positive patients (OS, 96% versus 78%, P = 0.052; DFS, 85% versus 58%, P = 0.014), whereas no significant difference was found among estrogen receptor-negative patients (OS, 73% versus 69%, P = 0.25; DFS, 73% versus 63%, P = 0.32). In multivariate analysis, MMP-2 level together with nodal status (NS), progesterone receptor (PgR), and tumor size (T) remained independent predictors for DFS (NS, P = 0.002; PgR, P = 0.004; T, P = 0.023; MMP2, P = 0.039) and OS (NS, P = 0.0002; PgR, P = 0.004; T, P = 0.004; MMP2, P = 0.032). MMP-9 levels did not correlate with survival. CONCLUSIONS: The results suggest that serum postoperative MMP-2 level is a predictor of DFS and OS, and could help to stratify breast cancer patients with primary node-positive disease into low- and high-risk groups.     

A comparison of the outcomes of non-randomised chemotherapy regimens in node positive breast cancer

Adjuvant chemotherapy increases disease-free survival (DFS) and overall survival (OS) following surgery for breast cancer. However, debates concerning the type of adjuvant chemotherapy continue. The effect of adjuvant chemotherapy on loco-regional recurrence-free survival (LFS) was also reported. The present study was undertaken to compare the results of adjuvant FAC (5-fluorouracil, Doxorubicin, Cyclophosphamide) and CMF (Cyclophosphamide, Methotrexate, 5-fluorouracil) chemotherapy on DFS, OS and LFS for node positive breast carcinoma treated with mastectomy in a non-randomised setting. Data from 688 consecutive lymph node positive breast cancer patients who underwent radical or modified radical mastectomy and received adjuvant FAC (600/60/600 mgr/m2 for 6 cycles every three weeks) or CMF (600/40/600 mgr/m2 for 6 cycles on days land 8 every four weeks) chemotherapy were reviewed. The effect of FAC on DFS, OS and LFS as compared with CMF was analysed. Survival curves were generated by the Kaplan-Meier method, and a multivariate analysis was performed by the Cox proportional hazard model. Adjuvant FAC was found to improve DFS, OS and LFS. 5-year DFS, OS and LFS were longer for patients treated with FAC as compared to CMF (67% versus 53%, p < 0.001; 77% versus 66%, p < 0.001, and 97% versus 91%). Adjusted hazard ratio (HR) for potential risk factors and tamoxifen treatment showed that FAC treated patients much benefitted in terms of survival as compared to CMF treated patients (HR 0.53, CI 0.40-0.69 for DFS; HR 0.48, CI 0.35-0.65 for OS, and HR 0.33, CI 0.16-0.65 for LFS). In conclusion, adjuvant FAC improves DFS, OS and LFS as compared to CMF in node positive breast carcinoma patients treated with mastectomy.     

曲妥珠单抗治疗141例人表皮生长因子受体2阳性乳腺癌的回顾性分析

目的 总结曲妥珠单抗在人表皮生长因子受体2(Her-2)阳性乳腺癌患者新辅助、辅助和复发转移治疗中的临床应用经验,评价其与化疗联用的疗效.方法 对2004年1月至2008年12月门诊应用曲妥珠单抗治疗的141乳腺癌患者进行回顾性分析.随访时间为3～319个月.分析患者的无病生存时间(DFS),比较患者辅助、复发转移一线及二线使用曲妥珠单抗治疗的总生存时间(OS)、治疗失败时间(TTF)和临床有效率的差异.结果 与曲妥珠单抗治疗联用的新辅助化疗中,紫杉醇联合卡铂方案占66.7%;辅助治疗中,蒽环类和蒽环类序贯紫杉类方案占53.9%.复发转移的患者治疗后中位DFS为17个月.复发转移的患者经一线曲妥珠单抗联合化疗治疗后,临床总有效 率为84.5%,中位TTF为24个月;二线治疗有效率为44.4%,中位TTF为5个月.两者比较,差异有统计学意义(P=0.002).结论 紫杉醇和卡铂化疗联合曲妥珠单抗,值得在新辅助治疗中推广,紫杉类和蒽环类联合或序贯靶向治疗仍是辅助治疗的标准方案.转移性乳腺癌一线应用曲妥珠单抗联合化疗比二线治疗的临床有效率更高,在继续应用曲妥珠单抗的基础上改用化疗方案,可提高治疗有效率,减少治疗失败的概率.     

Long-term results of combined-modality therapy for inflammatory breast carcinoma

Sixty-eight patients with inflammatory breast carcinoma (IBC) received treatment in 2 prospective randomized trials of multimodality therapy for locally advanced breast cancer. The treatment plan consisted of 3 courses of neoadjuvant chemotherapy with CAF (cyclophosphamide/doxorubicin/5-fluorouracil [5-FU]) or CEF (cyclophosphamide/epirubicin/5-FU) followed by surgery and 6 adjuvant courses of CAF or CEF alternated with CMF (cyclophosphamide/methotrexate/5-FU). Radiation therapy was administered at the end of adjuvant treatment. All patients with estrogen receptor-positive tumors received tamoxifen 20 mg daily for 5 years. The response rate to induction chemotherapy was 73.6% (95% CI, 61.4%-83.5%): 4 of 68 patients (6%) exhibited a pathologic remission of primary breast tumor (persistent disease in the axilla), and 2 patients (3%) exhibited a pathologic complete response. Median follow-up was 10 years (range, 5 months to 14.7 years). Disease-free survival (DFS) rates at 5 and 10 years were 29% and 20%, respectively, and median DFS was 2.2 years (range, 3.8 months to 11.5 years). Overall survival (OS) rates at 5 and 10 years were 44% and 32%, respectively, and median OS was 4 years (range, 5 months to 14.7 years). Significant prognostic factors for DFS and OS were the number of axillary nodes and residual disease in the breast at surgery. This analysis confirmed that patients with IBC obtained significant long-term survival benefit from combined-modality therapy.     

Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials.

PURPOSE: A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. METHODS: Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. RESULTS: The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. CONCLUSION: In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.     

Biological considerations in locally advanced breast cancer treated with anthracycline-based neoadjuvant chemotherapy: thymidine labelling index is an independent indicator of clinical outcome

The present retrospective study aims to determine the clinical value of thymidine labelling index (TLI) together with other established clinical and biological factors in 116 locally advanced breast cancer (LABC) patients treated with anthracycline-based neoadjuvant chemotherapy, surgery, adjuvant chemotherapy and radiotherapy. TLI was determined in 71 LABC patients with a median of 2.62% (0–23.64%) and a mean of 4.71%±5.54. As a result of neoadjuvant chemotherapy, 85 patients (73%) responded to chemotherapy (CT), whereas 31 patients were unresponsive (27%). No relationship has been found between the pretreatment biological variables including TLI, estrogen receptor (ER), progesteron receptor (PgR) status and clinical parameters such as the chemotherapy response rates and axillary lymph node involvement following chemotherapy. Median follow-up was 35 months (18–97 months) and the 3-year overall survival (OS) and disease free survival (DFS) rates were 71.6% and 52.2%, respectively. In univariate analysis, patients with inflammatory breast cancer, high TLI-index (2.62%), lymph node (LN) positivity or >3 positive lymph nodes following neoadjuvant chemotherapy and without any response to neoadjuvant chemotherapy were found to have worse DFS and OS-rates and high local and systemic recurrence rates. In multivariate analysis, TLI was estimated as the most powerful independent factor affecting the OS in LABC patients among the other established clinical and biological parameters (p=0.02). These results suggest that TLI is an important independent indicator of clinical outcome in patients with LABC and these patients with high TLI levels require more effective treatment modalities.     

Prognostic Factors in Patients with Stage II/III Breast Cancer Treated with Adjuvant Extension of Neoadjuvant Chemotherapy: A Retrospective Cohort Study with Ten-Years of Follow-Up Data

Purpose

The aim of this retrospective study was to identify the reliable long term prognostic factors in patients with stage II/III breast cancer who were treated with an adjuvant extension of neoadjuvant chemotherapy (NC).

Methods

Women under the age of 70-years, with previously untreated clinical stage II and III breast cancer, were treated with NC, which was comprised of three cycles of FEC (5-FU, epirubicin, and cyclophosphamide every 3 weeks) or MMM (methotrexate, mitoxantrone, and mitomycin-C every 3 weeks) with an adjuvant extension of three cycles of the same regimen.

Results

Cumulative 10-years disease-free survival (DFS) was 87.3% for patients with a good response and 55.5% for patients with no response (p=0.032); 92.9% for node negative patients, 75.0% for 1-3 positive nodes, 50.0% for 4-9 positive nodes and no survival for 10 or more positive nodes (p<0.001). Cumulative 10-years overall survival (OS) was 89.1% for patients with good response and 55.5% for patients with no response (p=0.024); 95.2% for node negative patients, 80.0% for 1-3 positive nodes, 50.0% for 4-9 positive nodes and no survival for 10 or more positive nodes (p<0.001). No significant difference was observed in DFS and OS between the FEC and MMM treated groups.

Conclusion

Based on a review of data with a long follow-up, only the clinical response to NC and the absolute number of metastatic axillary lymph node identified at surgical staging were independent predictors of both DFS and OS in patients with stage II/III breast cancer patients treated with adjuvant extension of NC.     

Long-term outcome of the REMAGUS 02 trial,a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status

BackgroundThe REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS).Patients and methodsFrom 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106).ResultsMedian follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021).ConclusionCelecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.     

Neoadjuvant chemotherapy for local advanced breast cancer with stage IIIB

In this study, we have done a retrospective evaluation of the clinical benefits of neoadjuvant chemotherapy in 25 patients with stage IIIB, locally advanced breast cancer in terms of response rate and survival benefit. Most of these patients were treated with an anthracycline-based regimen such as CAF and EC, and some were also treated sequentially with docetaxel. An overall objective response was observed in 15 patients (60%), composed of 1 patient (4%) with a complete response (CR) and 14 (56%) with a partial response (PR). No progressive disease was observed. Following neoadjuvant chemotherapy, locoregional treatment (mastectomy without partial resection) was carried out in 24 patients, 1 of whom also received radiotherapy. The rate of local recurrence in neoadjuvant chemotherapy with anthracycline-based regimens was lower than those of adjuvant chemotherapy with anthracycline-based and non-anthracycline-based regimens (10.0% versus 33.3% and 28.5%, respectively). By contrast, the rate of distant metastasis with neoadjuvant chemotherapy was higher than that seen with anthracycline-based adjuvant chemotherapy regimens (35.0% versus 11.1%, respectively), while the rate of distant metastasis in non-anthracycline-based regimens was even higher at 66.6%. The 5-year survival in the responders treated with neoadjuvant chemotherapy was better than in the non-responders (90.9% versus 50.0%; NS, P=0.28, log-rank test). The survival at 5 years in the patients treated with neoadjuvant chemotherapy was inferior to that with adjuvant anthracycline-based chemotherapy regimens (69.7% versus 77.8%), although the survival in neoadjuvant chemotherapy was better than those of non-anthracycline-based adjuvant regimen (69.7% versus 66.7%). However, at 10 years the overall survival with anthracycline-based neoadjuvant chemotherapy regimens was superior to that seen with either anthracycline or non-anthracycline-based adjuvant chemotherapy regimens. These results suggest that primary (neoadjuvant) systemic therapy with anthracycline-based regimens for locally advanced, stage IIIB, breast cancer may have a potential survival benefit when given in combination with adjuvant chemotherapy, as it will provide the best means of decreasing both local recurrence and distant metastasis.     

TAC方案在乳腺癌新辅助化疗中的临床疗效观察

目的：探讨TAC（多西他赛＋阿霉索＋环磷酰胺）方案在乳腺癌新辅助化疗中的临床疗效。方法：35例Ⅱb-Ⅲa乳腺癌患者术前应用TAC方案进行2—4周期新辅助化疗,观察其有效率,并中位随访2年观察无病生存率及总生存率。结果：新辅助化疗后临床完全缓解（CR）8例,部分缓解（PR）20例,稳定（SD）3例,总有效率88．57％。其2年无病生存率与对照组有显著差异（P〈0．05）,总生存率两组无差别（P〉0．05）。结论：应用TAC方案行新辅助化疗可有效提高乳腺癌患者临床缓解率,延长患者无病生存期。     

PREPARE trial: a randomized phase III trial comparing preoperative,dose-dense,dose-intensified chemotherapy with epirubicin,paclitaxel, and CMF versus a standard-dosed epirubicin–cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer—outcome on prognosis

BackgroundThe objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer.Patients and methodsA total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² every 3 weeks followed by four cycles of paclitaxel 175 mg/m² every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m² every 2 weeks followed by three cycles of paclitaxel 225 mg/m² every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (E_dd→T_dd→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of E_dd→T_dd→CMF compared with EC→T.ResultsEstimated 3-year DFS was 75.8% with EC→T versus 78.8% with E_dd→T_dd→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001).ConclusionNeoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.