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Medline ® Abstracts for References 1,3,6-12

of 'General principles of neoadjuvant therapy for breast cancer'

1
TI
Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease.
AU
Gralow JR, Burstein HJ, Wood W, Hortobagyi GN, Gianni L, von Minckwitz G, Buzdar AU, Smith IE, Symmans WF, Singh B, Winer EP
SO
J Clin Oncol. 2008;26(5):814.
 
PURPOSE: To review the state of the science with respect to preoperative systemic therapy and pathologic assessment in operable breast cancer.
METHODS: This article reviews data presented at the National Cancer Institute State of the Science Conference on Preoperative Therapy in Invasive Breast Cancer as well as supporting published data.
RESULTS: Preoperative chemotherapy in operable breast cancer has been shown to improve breast conservation rates as a result of tumor response to therapy. When patients are given preoperative systemic therapy, regimens should be the same as those established as safe and active in the adjuvant setting. At present, there are no data to suggest that systemic treatment should be tailored based on initial tumor response, or based on the extent of residual disease. In operable breast cancer, there seems to be no survival advantage from initiation of systemic therapy before surgery. A variety of clinical, imaging, and pathologic measurements are available to gauge tumor response to treatment. There is a clear correlation between tumor response in the breast and lymph nodes and both disease-free and overall survival. Pathologic complete response and other pathologic measures may be useful as surrogate end points in evaluating and understanding new therapies.
CONCLUSION: In operable breast cancer, preoperative systemic therapy is effective and can improve breast conservation rates. Unless the tumor is large or the patient is in a clinical trial, postoperative adjuvant systemic therapy is the standard of care. To achieve optimal outcomes, preoperative systemic therapy must be administered as part of a coordinated, multimodality treatment program. The preoperative setting provides a unique opportunity to study the impact of systemic therapies on breast cancer biology.
AD
Seattle Cancer Care Alliance, Department of Medicine, 825 Eastlake Ave, EMS G3-200, Seattle, WA 98109-1023, USA. pink@u.washington.edu
PMID
3
TI
Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26-28, 2003, Philadelphia, Pennsylvania.
AU
Schwartz GF, Hortobagyi GN
SO
Cancer. 2004;100(12):2512.
 
AD
Department of Surgery, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA. gordonschwartz@yahoo.com
PMID
6
TI
Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6.
AU
Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, Dorval T, PalangiéT, Jouve M, Beuzeboc P
SO
Eur J Cancer. 1994;30A(5):645.
 
The aim of this study was to assess a potential advantage in survival by neoadjuvant as compared to adjuvant chemotherapy. 414 premenopausal patients with T2-T3 N0-N1 M0 breast cancer were randomised to receive either four cycles of neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, 5-fluorouracil), followed by local-regional treatment (group I) or four cycles of adjuvant chemotherapy after primary irradiation +/- surgery (group II). Surgery was limited to those patients with a persisting mass after irradiation, and aimed to be as conservative as possible. 390 patients were evaluable. With a median follow-up of 54 months, we observed a statistically significant difference (P = 0.039) in survival in favour of the neoadjuvant chemotherapy group. A similar trend was seen when the time to metastatic recurrence was evaluated (P = 0.09). At this stage, no difference in disease-free interval or local recurrence between these two groups could be observed. The mean total dose of chemotherapy administered was similar in both groups. On average, group I had more intensive chemotherapy regimes (doxorubicin P = 0.02) but fewer treatment courses (P = 0.008) as compared to the treated patients in group II. Haematological tolerance was reduced when chemotherapy succeeded to exclusive irradiation. Breast conservation was identical for both groups at the end of primary treatment (82 and 77% for groups I and II, respectively). Of the 191 evaluable patients in the neoadjuvant treatment arm, 65% had an objective response (>50% regression) following four cycles of chemotherapy. The objective response rate to primary irradiation (55 Gy) was 85%. Improved survival figures in the neoadjuvant treatment arm could be the result of the early initiation of chemotherapy, but we cannot exclude that this difference might be attributable to a slightly more aggressive treatment. So far, the trend in favour of decreased metastases was not statistically significant. The local control appeared similar in both subgroups.
AD
Département de Médecine, Institut Curie, Paris, France.
PMID
7
TI
Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902.
AU
van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L
SO
J Clin Oncol. 2001;19(22):4224.
 
PURPOSE: To evaluate whether preoperative neoadjuvant chemotherapy in patients with primary operable breast cancer results in better overall survival (OS) and relapse-free survival rates and whether preoperative chemotherapy permits more breast-conserving surgery procedures than postoperative chemotherapy.
PATIENTS AND METHODS: Six hundred ninety-eight breast cancer patients (T1c, T2, T3, T4b, N0 to 1, and M0) were enrolled onto a randomized phase III trial that compared four cycles of fluorouracil, epirubicin, and cyclophosphamide administered preoperatively versus the same regimen administered postoperatively (the first cycle administered within 36 hours after surgery). Patients were followed up for OS, progression-free survival (PFS), and locoregional recurrence (LRR).
RESULTS: At a median follow-up of 56 months, there was no significant difference in terms of OS (hazards ratio, 1.16; P =.38), PFS (hazards ratio, 1.15; P =.27), and time to LRR (hazards ratio, 1.13; P =.61). Fifty-seven patients (23%) were downstaged by the preoperative chemotherapy, whereas 14 patients (18%) underwent mastectomy and not the planned breast-conserving therapy.
CONCLUSION: The use of preoperative chemotherapy yields similar results in terms of PFS, OS, and locoregional control compared with conventional postoperative chemotherapy. In addition, preoperative chemotherapy enables more patients to be treated with breast-conserving surgery. Because preoperative chemotherapy does not improve disease outcome compared with postoperative chemotherapy, future trials should involve quality-of-life studies to investigate whether patients will benefit from this treatment modality.
AD
European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium. velde@lumc.nl
PMID
8
TI
Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18.
AU
Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B
SO
J Natl Cancer Inst Monogr. 2001;
 
National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was initiated in 1988 to determine whether four cycles of doxorubicin/cyclophosphamide given preoperatively improve survival and disease-free survival (DFS) when compared with the same chemotherapy given postoperatively. Secondary aims included the evaluation of preoperative chemotherapy in downstaging the primary breast tumor and involved axillary lymph nodes, the comparison of lumpectomy rates and rates of ipsilateral breast tumor recurrence (IBTR) in the two treatment groups, and the assessment of the correlation between primary tumor response and outcome. Initially published findings were based on a follow-up of 5 years; this report updates results through 9 years of follow-up. There continue to be no statistically significant overall differences in survival or DFS between the two treatment groups. Survival at 9 years is 70% in the postoperative group and 69% in the preoperative group (P =.80). DFS is 53% in postoperative patients and 55% in preoperative patients (P =.50). A statistically significant correlation persists between primary tumor response and outcome, and this correlation has become statistically stronger with longer follow-up. Patients assigned to preoperative chemotherapy received notably more lumpectomies than postoperative patients, especially among patients with tumors greater than 5 cm at study entry. Although the rate of IBTR was slightly higher in the preoperative group (10.7% versus 7.6%), this difference was not statistically significant. Marginally statistically significant treatment-by-age interactions appear to be emerging for survival and DFS, suggesting that younger patients may benefit from preoperative therapy, whereas the reverse may be true for older patients.
AD
National Surgical Adjuvant Breast and Bowel Project (NSABP), 320 E. North Ave., Pittsburgh, PA 15212, USA. nwolmark@wpahs.org
PMID
9
TI
Sometimes a great notion--an assessment of neoadjuvant systemic therapy for breast cancer.
AU
Davidson NE, Morrow M
SO
J Natl Cancer Inst. 2005;97(3):159.
 
AD
PMID
10
TI
Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy.
AU
Gianni L, Baselga J, Eiermann W, Guillem Porta V, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Llombart Cussac A, Bozhok A, Martinez-AgullóA, Greco M, Byakhov M, Lopez Lopez JJ, Mansutti M, Valagussa P, Bonadonna G, European Cooperative Trial in Operable Breast Cancer Study Group
SO
Clin Cancer Res. 2005;11(24 Pt 1):8715.
 
PURPOSE: The European Cooperative Trial in Operable breast cancer (ECTO) randomly tested whether efficacy of adjuvant doxorubicin followed by i.v. cyclophosphamide, methotrexate, and fluorouracil (CMF; doxorubicin-->CMF, arm A) could be improved by adding paclitaxel (doxorubicin/paclitaxel-->CMF) as adjuvant (arm B) or primary systemic therapy (PST, arm C). We report here feasibility, tolerability, locoregional antitumor activity, and breast conservation rate.
METHODS: A total of 1,355 women entered the study. Feasibility and safety were compared in arm A versus arms B plus C. Surgical findings were compared in arms A plus B versus arm C.
RESULTS: Grade 3 or 4 National Cancer Institute toxicities were low (<5%) in all arms. Neuropathy was more frequent in the paclitaxel-containing arms (grade 2, 20.5% versus 5.0%; grade 3, 1.3% versus 0.2%). At 31 months of follow-up, asymptomatic drop of left ventricular ejection fraction was similar in all arms, whereas symptomatic cardiotoxicity was recorded in three patients (0.5%) in A and in three patients (0.3%) in B plus C. PST induced clinical complete plus partial remission in 78%, with an in-breast pathologic complete response rate of 23% and an in-breast plus axilla pathologic complete response rate of 20%. In the multivariate analysis, only estrogen receptor (ER) status was significantly associated with pathologic complete response (odds ratio for ER negative, 5.77; 95% confidence interval, 3.49-9.52; P<0.0001). PTS induced a significant axillary downstaging (P<0.001), and breast sparing surgery was feasible in 65% versus 34% (P<0.001).
CONCLUSIONS: Doxorubicin/paclitaxel-->CMF is feasible, safe, and well tolerated. Given as PST, it is markedly active, allowing for breast-sparing surgery in a large fraction of patients.
AD
Istituto Nazionale Tumori, Milan, Italy, and Hospital Vall d'Hebron, Barcelona, Spain. gianni@istitutotumori.mi.it
PMID
11
TI
Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis.
AU
Mauri D, Pavlidis N, Ioannidis JP
SO
J Natl Cancer Inst. 2005;97(3):188.
 
BACKGROUND: Interest in the use of preoperative systemic treatment in the management of breast cancer has increased because such neoadjuvant therapy appears to reduce the extent of local surgery required. We compared the clinical end points of patients with breast cancer treated preoperatively with systemic therapy (neoadjuvant therapy) and of those treated postoperatively with the same regimen (adjuvant therapy) in a meta-analysis of randomized trials.
METHODS: We evaluated nine randomized studies, including a total of 3946 patients with breast cancer, that compared neoadjuvant therapy with adjuvant therapy regardless of what additional surgery and/or radiation treatment was used. Fixed and random effects methods were used to combine data. Primary outcomes were death, disease progression, distant disease recurrence, and loco-regional disease recurrence. Secondary outcomes were local response and conservative local treatment. All statistical tests were two-sided.
RESULTS: We found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms associated with death (summary risk ratio [RR]= 1.00, 95% confidenceinterval [CI]= 0.90 to 1.12), disease progression (summary RR = 0.99, 95% CI = 0.91 to 1.07), or distant disease recurrence (summary RR = 0.94, 95% CI = 0.83 to 1.06). However, neoadjuvant therapy was statistically significantly associated with an increased risk of loco-regional disease recurrences (RR = 1.22, 95% CI = 1.04 to 1.43), compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant, than the adjuvant, arm received radiation therapy without surgery (RR = 1.53, 95% CI = 1.11 to 2.10). Across trials, we observed heterogeneity in the rates of complete clinical response (range = 7%-65%; P for heterogeneity of<.001), pathologic response (range = 4%-29%; P for heterogeneity of<.001), and adoption of conservative local treatment (range = 28%-89% in neoadjuvant arms, P for heterogeneity of<.001).
CONCLUSIONS: Neoadjuvant therapy was apparently equivalent to adjuvant therapy in terms of survival and overall disease progression. Neoadjuvant therapy, compared with adjuvant therapy, was associated with a statistically significant increased risk of loco-regional recurrence when radiotherapy without surgery was adopted.
AD
Department of Medical Oncology, University of Ioannina School of Medicine, Ioannina, Greece.
PMID
12
TI
Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27.
AU
Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N
SO
J Clin Oncol. 2008;26(5):778.
 
PURPOSE: National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively. Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response rates, DFS, and OS.
PATIENTS AND METHODS: Analyses were limited to eligible patients. In B-18, 751 patients were assigned to receive preoperative AC, and 742 patients were assigned to receive postoperative AC. In B-27, 784 patients were assigned to receive preoperative AC followed by surgery, 783 patients were assigned to AC followed by T and surgery, and 777 patients were assigned to AC followed by surgery and then T.
RESULTS: Results from B-18 show no statistically significant differences in DFS and OSbetween the two groups. However, there were trends in favor of preoperative chemotherapy for DFS and OS in women less than 50 years old (hazard ratio [HR]= 0.85, P = .09 for DFS; HR = 0.81, P = .06 for OS). DFS conditional on being event free for 5 years also demonstrated a strong trend in favor of the preoperative group (HR = 0.81, P = .053). Protocol B-27 results demonstrated that the addition of T to AC did not significantly impact DFS or OS. Preoperative T added to AC significantly increased the proportion of patients having pathologic complete responses (pCRs) compared with preoperative AC alone (26% v 13%, respectively; P<.0001). In both studies, patients who achieved a pCR continue to have significantly superior DFS and OS outcomes compared with patients who did not.
CONCLUSION: B-18 and B-27 demonstrate that preoperative therapy is equivalent to adjuvant therapy. B-27 also showed that the addition of preoperative taxanes to AC improves response.
AD
University of Pittsburgh Cancer Institute/Magee Womens Hospital, 300 Halket St, Room 3524, Pittsburgh, PA 15213, USA. rastogip@upmc.edu
PMID