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Showing content from https://pubmed.ncbi.nlm.nih.gov/29242041/ below:

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Review

doi: 10.1016/S1470-2045(17)30777-5. Epub 2017 Dec 11. Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Collaborators

Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Bernard Asselain, William Barlow, John Bartlett, Jonas Bergh, Elizabeth Bergsten-Nordström, Judith Bliss, Francesco Boccardo, Clare Boddington, Jan Bogaerts, Gianni Bonadonna, Rosie Bradley, Etienne Brain, Jeremy Braybrooke, Philippe Broet, John Bryant, Julie Burrett, David Cameron, Mike Clarke, Alan Coates, Robert Coleman, Raoul Charles Coombes, Candace Correa, Joe Costantino, Jack Cuzick, David Danforth, Nancy Davidson, Christina Davies, Lucy Davies, Angelo Di Leo, David Dodwell, Mitch Dowsett, Fran Duane, Vaughan Evans, Marianne Ewertz, Bernard Fisher, John Forbes, Leslie Ford, Jean-Claude Gazet, Richard Gelber, Lucy Gettins, Luca Gianni, Michael Gnant, Jon Godwin, Aron Goldhirsch, Pamela Goodwin, Richard Gray, Daniel Hayes, Catherine Hill, James Ingle, Reshma Jagsi, Raimund Jakesz, Sam James, Wolfgang Janni, Hui Liu, Zulian Liu, Caroline Lohrisch, Sibylle Loibl, Liz MacKinnon, Andreas Makris, Eleftherios Mamounas, Gurdeep Mannu, Miguel Martín, Simone Mathoulin, Louis Mauriac, Paul McGale, Theresa McHugh, Philip Morris, Hirofumi Mukai, Larry Norton, Yasuo Ohashi, Ivo Olivotto, Soon Paik, Hongchao Pan, Richard Peto, Martine Piccart, Lori Pierce, Philip Poortmans, Trevor Powles, Kathy Pritchard, Joseph Ragaz, Vinod Raina, Peter Ravdin, Simon Read, Meredith Regan, John Robertson, Emiel Rutgers, Suzy Scholl, Dennis Slamon, Lidija Sölkner, Joseph Sparano, Seth Steinberg, Rosemary Sutcliffe, Sandra Swain, Carolyn Taylor, Andrew Tutt, Pinuccia Valagussa, Cornelis van de Velde, Jos van der Hage, Giuseppe Viale, Gunter von Minckwitz, Yaochen Wang, Zhe Wang, Xiang Wang, Tim Whelan, Nicholas Wilcken, Eric Winer, Norman Wolmark, William Wood, Milvia Zambetti, Jo Anne Zujewski

PMID: 29242041
PMCID: PMC5757427
DOI: 10.1016/S1470-2045(17)30777-5

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Review

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet Oncol. 2018 Jan.

doi: 10.1016/S1470-2045(17)30777-5. Epub 2017 Dec 11. Collaborators

Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Bernard Asselain, William Barlow, John Bartlett, Jonas Bergh, Elizabeth Bergsten-Nordström, Judith Bliss, Francesco Boccardo, Clare Boddington, Jan Bogaerts, Gianni Bonadonna, Rosie Bradley, Etienne Brain, Jeremy Braybrooke, Philippe Broet, John Bryant, Julie Burrett, David Cameron, Mike Clarke, Alan Coates, Robert Coleman, Raoul Charles Coombes, Candace Correa, Joe Costantino, Jack Cuzick, David Danforth, Nancy Davidson, Christina Davies, Lucy Davies, Angelo Di Leo, David Dodwell, Mitch Dowsett, Fran Duane, Vaughan Evans, Marianne Ewertz, Bernard Fisher, John Forbes, Leslie Ford, Jean-Claude Gazet, Richard Gelber, Lucy Gettins, Luca Gianni, Michael Gnant, Jon Godwin, Aron Goldhirsch, Pamela Goodwin, Richard Gray, Daniel Hayes, Catherine Hill, James Ingle, Reshma Jagsi, Raimund Jakesz, Sam James, Wolfgang Janni, Hui Liu, Zulian Liu, Caroline Lohrisch, Sibylle Loibl, Liz MacKinnon, Andreas Makris, Eleftherios Mamounas, Gurdeep Mannu, Miguel Martín, Simone Mathoulin, Louis Mauriac, Paul McGale, Theresa McHugh, Philip Morris, Hirofumi Mukai, Larry Norton, Yasuo Ohashi, Ivo Olivotto, Soon Paik, Hongchao Pan, Richard Peto, Martine Piccart, Lori Pierce, Philip Poortmans, Trevor Powles, Kathy Pritchard, Joseph Ragaz, Vinod Raina, Peter Ravdin, Simon Read, Meredith Regan, John Robertson, Emiel Rutgers, Suzy Scholl, Dennis Slamon, Lidija Sölkner, Joseph Sparano, Seth Steinberg, Rosemary Sutcliffe, Sandra Swain, Carolyn Taylor, Andrew Tutt, Pinuccia Valagussa, Cornelis van de Velde, Jos van der Hage, Giuseppe Viale, Gunter von Minckwitz, Yaochen Wang, Zhe Wang, Xiang Wang, Tim Whelan, Nicholas Wilcken, Eric Winer, Norman Wolmark, William Wood, Milvia Zambetti, Jo Anne Zujewski

PMID: 29242041
PMCID: PMC5757427
DOI: 10.1016/S1470-2045(17)30777-5

Item in Clipboard

Abstract

Background: Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials.

Methods: We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality).

Findings: Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4-8·6]; rate ratio 1·37 [95% CI 1·17-1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92-1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95-1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94-1·15]; p=0·45).

Interpretation: Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy.

Funding: Cancer Research UK, British Heart Foundation, UK Medical Research Council, and UK Department of Health.

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Figures
Figure 1

BCT rate ratios Numbers with…

Figure 1

BCT rate ratios Numbers with BCT or mastectomy after chemotherapy. Excludes local therapy…

Figure 1

BCT rate ratios Numbers with BCT or mastectomy after chemotherapy. Excludes local therapy unknown (67 patients with NACT and 51 with adjuvant chemotherapies). BCT=breast-conserving therapy. ER=oestrogen receptor. PR=progesterone receptor. NACT=neoadjuvant chemotherapy.

Figure 2

Effect of neoadjuvant versus adjuvant…

Figure 2

Effect of neoadjuvant versus adjuvant chemotherapy on recurrence and mortality Local recurrence (A),…

Figure 2

Effect of neoadjuvant versus adjuvant chemotherapy on recurrence and mortality Local recurrence (A), distant recurrence (B), breast cancer mortality (C), and death from any cause (D). Three trials recorded causes of any deaths but only the first breast cancer event. Hence, for these trials, distant recurrence includes the first distant recurrence as the first event and death from breast cancer. Error bars are 95% CIs. NACT=neoadjuvant chemotherapy. O–E=observed minus expected. RR=rate ratio. V=variance of O–E.

Figure 3

Time to recurrence and breast…

Figure 3

Time to recurrence and breast cancer mortality Local recurrence for surgery commonly used…

Figure 3

Time to recurrence and breast cancer mortality Local recurrence for surgery commonly used (A) and less commonly used (B), distant recurrence for surgery commonly used (C) and less commonly used (D), and breast cancer mortality for surgery commonly used (E) and less commonly used (F). Heterogeneity by surgery use: local recurrence p=0·19, distant recurrence p=0·29, and breast cancer mortality p=0·24. Error bars are 95% CIs. NACT=neoadjuvant chemotherapy. O–E=observed minus expected. RR=rate ratio. V=variance of O–E. Three trials recorded causes of any deaths but only the first breast cancer event. Hence, for these trials, distant recurrence includes the first distant recurrence as the first event and death from breast cancer. *Includes Institut Bergonié Bordeaux (in NACT group, 33% had radiotherapy alone) and Institut Curie S6 (in NACT group, 51% had radiotherapy alone; in adjuvant chemotherapy group, 46% had radiotherapy alone) trials.

Figure 4

Rate ratios for the effect…

Figure 4

Rate ratios for the effect of neoadjuvant versus adjuvant chemotherapy on recurrence by…

Figure 4

Rate ratios for the effect of neoadjuvant versus adjuvant chemotherapy on recurrence by trial (A) Local recurrence. (B) Distant recurrence. Three trials recorded causes of any deaths but only the first breast cancer event. Hence, for these trials, distant recurrence includes the first distant recurrence as the first event and death from breast cancer. The appendix (pp 3–4) contains a full description of each trial's chemotherapy regimen. A=doxorubicin (adriamycin). BCCA=British Columbia Cancer Agency. BCSG=Breast Cancer Study Group. C=cyclophosphamide. E=epirubicin. ECTO=European Cooperative Trial in Operable Breast Cancer. EORTC=European Organisation for Research and Treatment of Cancer. F=fluorouracil. Fol=folinic acid. IB=Institut Bergonié. M=methotrexate. Mit=mitomycin-C. Mz=mitoxantrone. NCI=National Cancer Institute. NSABP=National Surgical Adjuvant Breast and Bowel Project. O–E=observed minus expected. P=paclitaxel. Tt=thiotepa. Vc=vincristine. Vd=vindesine. *Chemotherapy regimens given preoperatively in those allocated neoadjuvant and postoperatively in those allocated adjuvant chemotherapy. The number of cycles, agents, and drug doses (in mg/m²) per cycle are given. †The Austrian BCSG VII trial8 has two entries to take into account the two postoperative chemotherapies given to both randomised groups (appendix pp 3–4).

Figure 5

Local recurrence rate ratios For…

Figure 5

Local recurrence rate ratios For lumpectomy versus mastectomy, χ ² ₁ =3·3; p=0·07.…

Figure 5

Local recurrence rate ratios For lumpectomy versus mastectomy, χ²₁=3·3; p=0·07. ER=oestrogen receptor. PR=progesterone receptor. *408 women with missing data had planned local therapy imputed (appendix p 9). †Refers to Institut Curie S6 (appendix p 9).

Figure 6

Clinical complete response rate ratios…

Figure 6

Clinical complete response rate ratios Three trials are excluded, as individual responses are…

Figure 6

Clinical complete response rate ratios Three trials are excluded, as individual responses are not available; 440 women have missing clinical response data. CIs are group specific. Rate ratios are scaled such that, within each category, their inverse variance-weighted sum is 1—ie, ratios are with respect to the mean CR. The appendix (p 6) contains data available for each trial. CR=complete response. ER=oestrogen receptor. PR=progesterone receptor.

Comment in

Neoadjuvant chemotherapy in breast cancer: more than just downsizing.
Derks MGM, van de Velde CJH. Derks MGM, et al. Lancet Oncol. 2018 Jan;19(1):2-3. doi: 10.1016/S1470-2045(17)30914-2. Epub 2017 Dec 11. Lancet Oncol. 2018. PMID: 29242042 No abstract available.
Neoadjuvant chemotherapy for early breast cancer.
Charalampoudis P, Karakatsanis A. Charalampoudis P, et al. Lancet Oncol. 2018 Mar;19(3):e128. doi: 10.1016/S1470-2045(18)30115-3. Lancet Oncol. 2018. PMID: 29508753 No abstract available.
Neoadjuvant chemotherapy for early breast cancer.
Krug D, Loibl S. Krug D, et al. Lancet Oncol. 2018 Mar;19(3):e129. doi: 10.1016/S1470-2045(18)30118-9. Lancet Oncol. 2018. PMID: 29508754 No abstract available.
Neoadjuvant chemotherapy for early breast cancer - Author's reply.
McGale P, Dodwell D, Taylor C, Gray R; Early Breast Cancer Trialists' Collaborative Group. McGale P, et al. Lancet Oncol. 2018 Mar;19(3):e130. doi: 10.1016/S1470-2045(18)30120-7. Lancet Oncol. 2018. PMID: 29508755 No abstract available.