Efficacy and safety of neoadjuvant chemotherapy dose-dense regimen <i>versus</i> conventional regimen for locally advanced breast cancer: a meta-analysis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

DENG Jian , NIE Xianli , HU Yinghan , GAO Xudong , CHEN Jin ,  QUAN Yi

Department of Breast Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;

Corresponding author：

QUAN Yi, Email: 20783833@qq.com

Keywords：

breast cancer; neoadjuvant chemotherapy; dose-dense regimen; pathological complete response; meta-analysis

DOI：

10.7507/1007-9424.202106097

Video：

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Objective To systematically evaluate the efficacy and safety of dose-dense neoadjuvant chemotherapy (ddNACT) and conventional neoadjuvant chemotherapy (cNACT) for locally advanced breast cancer (LABC). Methods PubMed, Embase, Web of Science, CNKI, Wanfang Data, and VIP databases were searched for randomized controlled trials (RCT) comparing ddNACT regimen with cNACT regimen for breast cancer. The time limit for retrieval was from establishment to March 1st, 2021. Two reviewers independently screened literatures, extracted data and assessed risk bias of included studies; then, meta-analysis was performed by using Stata 15.0 software. Results A total of 13 RCTs were included, including 3 258 patients, of which 1 625 patients received ddNACT and 1 633 patients received cNACT. The results of meta-analysis showed that the ddNACT regimen could improve the pathological complete response rate (pCR, P<0.001), objective response rate (ORR, P<0.001), and disease free survival (DFS, P=0.037) as compared with the cNACT regimen, there was no significant difference in the overall survival (OS) between the two groups (P=0.098). The incidences of grade 3 or 4 oral stomatitis (P=0.005) and neurotoxicity (P<0.001) were higher and the incidence of grade 3 or 4 neutropenia was lower (P=0.025) in the patients with ddNACT regimen, there were no significant differences in grade 3 or 4 thrombocytopenia (P=0.152), grade 3 or 4 anemia (P=0.123), chemotherapy completion rate (P=0.161) and breast conservative surgery rate (P=0.186) between the two groups. Patients with hormone receptor (HR) negative (HR^–) were more likely to get pCR after neoadjuvant chemotherapy (P<0.001). Conclusions Current evidence shows that the use of anthracycline/taxane-based ddNACT regimen in LABC patients can improve the pCR, ORR, and DFS as compared with cNACT regimen. The pCR after neoadjuvant chemotherapy in the patients with HR^– is higher than that with HR⁺. Prophylactic use of granulocyte-colony stimulating factor could significantly reduce the incidence of neutropenia, and most patients are tolerant to ddNACT regimen, 2 regimens have similar chemotherapy completion rates.

Citation： DENG Jian, NIE Xianli, HU Yinghan, GAO Xudong, CHEN Jin, QUAN Yi. Efficacy and safety of neoadjuvant chemotherapy dose-dense regimen versus conventional regimen for locally advanced breast cancer: a meta-analysis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(4): 490-497. doi: 10.7507/1007-9424.202106097 Copy

1.	Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol, 2008, 26(5): 778-785.
2.	von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol, 2012, 30(15): 1796-1804.
3.	Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet, 2014, 384(9938): 164-172.
4.	Berruti A, Amoroso V, Gallo F, et al. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol, 2014, 32(34): 3883-3891.
5.	Norton L. A Gompertzian model of human breast cancer growth. Cancer Res, 1988, 48(24Pt1): 7067-7071.
6.	Norton L. Conceptual and practical implications of breast tissue geometry: toward a more effective, less toxic therapy. Oncologist, Jun-Jul 2005, 10(6): 370-381.
7.	Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol, 2003, 21(8): 1431-1439.
8.	Bonilla L, Ben-Aharon I, Vidal L, et al. Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst, 2010, 102(24): 1845-1854.
9.	Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet, 2019, 393(10179): 1440-1452.
10.	Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(7109): 629-634.
11.	Baldini E, Gardin G, Giannessi PG, et al. Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase Ⅲ trial in locally advanced breast cancer. Ann Oncol, 2003, 14(2): 227-232.
12.	Miller KD, McCaskill-Stevens W, Sisk J, et al. Combination versus sequential doxorubicin and docetaxel as primary chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group. J Clin Oncol, 1999, 17(10): 3033-3037.
13.	Therasse P, Mauriac L, Welnicka-Jaskiewicz M, et al. Final results of a randomized phase Ⅲ trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol, 2003, 21(5): 843-850.
14.	Untch M, Möbus V, Kuhn W, et al. Intensive dose-dense compared with conventionally scheduled preoperative chemotherapy for high-risk primary breast cancer. J Clin Oncol, 2009, 27(18): 2938-2945.
15.	Ellis GK, Barlow WE, Gralow JR, et al. Phase Ⅲ comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol, 2011, 29(8): 1014-1021.
16.	Arun BK, Dhinghra K, Valero V, et al. Phase Ⅲ randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results. Oncologist, 2011, 16(11): 1527-1534.
17.	Untch M, von Minckwitz G, Konecny GE, et al. 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. Ann Oncol, 2011, 22(9): 1999-2006.
18.	冯俊, 吴云飞, 徐惠绵, 等. Ⅲ期乳腺癌新辅助化疗中ET 2周与3周方案的疗效对比研究. 中国癌症杂志, 2009, 19(7): 562-564.
19.	刘慧, 张恒伟, 崔树德. 新辅助“FEC”密集与标准方案化疗在可手术乳腺癌中的对比研究. 肿瘤, 2009, 29(4): 383-385.
20.	阚士锋, 贾锋. ET2周与3周方案在局部进展期乳腺癌新辅助治疗中的应用对比观察. 现代肿瘤医学, 2007, 15(9): 1285-1287.
21.	孟祥悦. EC序贯P剂量密集、FEC、TEC方案在乳腺癌新辅助化疗中的应用效果. 中国药物经济学, 2017, 12(10): 78-80.
22.	仇爱峰, 苗志龙, 葛国侃, 等. 蒽环联合或序贯紫衫类不同给药间期对Luminal B型乳腺癌新辅助化疗疗效的影响. 中华医学杂志, 2017, 97(44): 3466-3470.
23.	王梅, 王雅杰, 施俊义, 等. 局部晚期乳腺癌新辅助化疗每周方案与三周方案疗效分析. 临床肿瘤学杂志, 2010, 15(4): 336-338.
24.	Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol, 2006, 24(13): 2019-2027.
25.	Bear HD, Anderson S, Brown A, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol, 2003, 21(22): 4165-4174.
26.	Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet, 2010, 375(9712): 377-384.
27.	International Breast Cancer Study Group. Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol, 1996, 14(6): 1885-1894.
28.	Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet, 2015, 386(10001): 1341-1352.
29.	Houssami N, Macaskill P, von Minckwitz G, et al. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer, 2012, 48(18): 3342-3354.
30.	Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol, 2008, 26(8): 1275-1281.
31.	Untch M, Fasching PA, Konecny GE, et al. 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 ± darbepoetin alfa in primary breast cancer—results at the time of surgery. Ann Oncol, 2011, 22(9): 1988-1998.
32.	Criscitiello C, Golshan M, Barry WT, et al. Impact of neoadjuvant chemotherapy and pathological complete response on eligibility for breast-conserving surgery in patients with early breast cancer: A meta-analysis. Eur J Cancer, 2018, 97: 1-6.
33.	Gradishar WJ, Anderson BO, Abraham J, et al. Breast Cancer, Version 3. 2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 2020, 18(4): 452-478.

1. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol, 2008, 26(5): 778-785.
2. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol, 2012, 30(15): 1796-1804.
3. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet, 2014, 384(9938): 164-172.
4. Berruti A, Amoroso V, Gallo F, et al. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol, 2014, 32(34): 3883-3891.
5. Norton L. A Gompertzian model of human breast cancer growth. Cancer Res, 1988, 48(24Pt1): 7067-7071.
6. Norton L. Conceptual and practical implications of breast tissue geometry: toward a more effective, less toxic therapy. Oncologist, Jun-Jul 2005, 10(6): 370-381.
7. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol, 2003, 21(8): 1431-1439.
8. Bonilla L, Ben-Aharon I, Vidal L, et al. Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst, 2010, 102(24): 1845-1854.
9. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet, 2019, 393(10179): 1440-1452.
10. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(7109): 629-634.
11. Baldini E, Gardin G, Giannessi PG, et al. Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase Ⅲ trial in locally advanced breast cancer. Ann Oncol, 2003, 14(2): 227-232.
12. Miller KD, McCaskill-Stevens W, Sisk J, et al. Combination versus sequential doxorubicin and docetaxel as primary chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group. J Clin Oncol, 1999, 17(10): 3033-3037.
13. Therasse P, Mauriac L, Welnicka-Jaskiewicz M, et al. Final results of a randomized phase Ⅲ trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol, 2003, 21(5): 843-850.
14. Untch M, Möbus V, Kuhn W, et al. Intensive dose-dense compared with conventionally scheduled preoperative chemotherapy for high-risk primary breast cancer. J Clin Oncol, 2009, 27(18): 2938-2945.
15. Ellis GK, Barlow WE, Gralow JR, et al. Phase Ⅲ comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol, 2011, 29(8): 1014-1021.
16. Arun BK, Dhinghra K, Valero V, et al. Phase Ⅲ randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results. Oncologist, 2011, 16(11): 1527-1534.
17. Untch M, von Minckwitz G, Konecny GE, et al. 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. Ann Oncol, 2011, 22(9): 1999-2006.
18. 冯俊, 吴云飞, 徐惠绵, 等. Ⅲ期乳腺癌新辅助化疗中ET 2周与3周方案的疗效对比研究. 中国癌症杂志, 2009, 19(7): 562-564.
19. 刘慧, 张恒伟, 崔树德. 新辅助“FEC”密集与标准方案化疗在可手术乳腺癌中的对比研究. 肿瘤, 2009, 29(4): 383-385.
20. 阚士锋, 贾锋. ET2周与3周方案在局部进展期乳腺癌新辅助治疗中的应用对比观察. 现代肿瘤医学, 2007, 15(9): 1285-1287.
21. 孟祥悦. EC序贯P剂量密集、FEC、TEC方案在乳腺癌新辅助化疗中的应用效果. 中国药物经济学, 2017, 12(10): 78-80.
22. 仇爱峰, 苗志龙, 葛国侃, 等. 蒽环联合或序贯紫衫类不同给药间期对Luminal B型乳腺癌新辅助化疗疗效的影响. 中华医学杂志, 2017, 97(44): 3466-3470.
23. 王梅, 王雅杰, 施俊义, 等. 局部晚期乳腺癌新辅助化疗每周方案与三周方案疗效分析. 临床肿瘤学杂志, 2010, 15(4): 336-338.
24. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol, 2006, 24(13): 2019-2027.
25. Bear HD, Anderson S, Brown A, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol, 2003, 21(22): 4165-4174.
26. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet, 2010, 375(9712): 377-384.
27. International Breast Cancer Study Group. Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol, 1996, 14(6): 1885-1894.
28. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet, 2015, 386(10001): 1341-1352.
29. Houssami N, Macaskill P, von Minckwitz G, et al. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer, 2012, 48(18): 3342-3354.
30. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol, 2008, 26(8): 1275-1281.
31. Untch M, Fasching PA, Konecny GE, et al. 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 ± darbepoetin alfa in primary breast cancer—results at the time of surgery. Ann Oncol, 2011, 22(9): 1988-1998.
32. Criscitiello C, Golshan M, Barry WT, et al. Impact of neoadjuvant chemotherapy and pathological complete response on eligibility for breast-conserving surgery in patients with early breast cancer: A meta-analysis. Eur J Cancer, 2018, 97: 1-6.
33. Gradishar WJ, Anderson BO, Abraham J, et al. Breast Cancer, Version 3. 2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 2020, 18(4): 452-478.

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Efficacy and safety of neoadjuvant chemotherapy dose-dense regimen versus conventional regimen for locally advanced breast cancer: a meta-analysis

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