Annals of Surgical Oncology

, Volume 21, Issue 8, pp 2517–2524 | Cite as

Surgical Outcome after Neoadjuvant Chemotherapy and Bevacizumab: Results from the GeparQuinto Study (GBG 44)

  • Bernd Gerber
  • Gunter von Minckwitz
  • Holger Eidtmann
  • Mahdi Rezai
  • Peter Fasching
  • Hans Tesch
  • Holm Eggemann
  • Iris Schrader
  • Kornelia Kittel
  • Claus Hanusch
  • Christine Solbach
  • Christian Jackisch
  • Georg Kunz
  • Jens-Uwe Blohmer
  • Jens Huober
  • Maik Hauschild
  • Valentina Nekljudova
  • Sibylle Loibl
  • Michael Untch
Breast Oncology



Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has shown increased pathological complete response rates when added to neoadjuvant chemotherapy. In various cancer types, bevacizumab treatment was accompanied by an increased risk of bleedings and other surgical complications. We assessed associated surgical complications.


In the GeparQuinto trial, 1,948 patients were randomized to receive four cycles epirubicin/cyclophosphamide (EC, 90/600 mg/m2 q3w) followed by four cycles docetaxel (D, 100 mg/m2 q3w) each with (ECB-DB) or without (EC-D) bevacizumab (B, 15 mg/kg q3w) concurrent with chemotherapy. Surgery had to be performed not earlier than 28 days after the last bevacizumab infusion, but within days 21 and 35 after the last chemotherapy.


In 743 (38.1 %) patients, a surgical complication (bleedings, hematomas, necrosis, wound infections, abscess) was documented prospectively. Baseline characteristics of the patients were well balanced between both arms. The breast-conserving surgery (BCS) rate (N = 502) was 69.1 % (EC-D) and 71.9 % (ECB-DB; p = 0.464). The first surgical procedure was performed at a median of 29 (EC-D) and 34 days (ECB-DB) after last chemotherapy with or without bevacizumab infusion (p < 0.001). Surgical complications were documented in 38 (10.9 %; EC-D) and 59 (15.0 %; ECB-DB) patients (p = 0.103). Surgical complications were significantly higher after ECD-DB only in patients treated with BCS (N = 53; p = 0.029) or in those requiring repeat surgery in order achieve clear margins (N = 23; p = 0.037) compared to the EC-D group.


Addition of bevacizumab to neoadjuvant chemotherapy might be associated with an increased risk for surgical complications in patients treated with BCS or after repeated surgeries.


Bevacizumab Chemotherapy Infusion Bevacizumab Treatment Bevacizumab Administration Wound Healing Disturbance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank all patients and investigators for participation and Sanofi-Aventis and Roche, Germany, for financial support of this trial (NCT 00567554).


Gunter von Minckwitz has received honoraria and research found from Roche. Holger Eidtmann has received personal fees from Roche. Claus Hanusch has received personal fees from Novartis, Amgen, and Boeringer Ingelheim. Jens Blohmer has received honoraria from Roche. Jens Huober has received personal fees from Roche and Sanofi Aventis. Sibylle Loibl has received honoraria and research found from Roche. The other authors declare no conflict of interest.


  1. 1.
    Chang HY, Nuyten DS, Sneddon JB, et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci USA. 2005;102:3738–43.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012;366:299–309.CrossRefGoogle Scholar
  3. 3.
    Gerber B, Loibl S, Eidtmann H, et al. Neoadjuvant bevacizumab and anthrcycline-taxane based chemotherapy in 678 triple negative primary breast cancers; results from the GEPARQUINTO study (GBG 44). Ann Oncol. 2013;24(12):2978–84. doi: 10.1093/annonc/mdt361.PubMedCrossRefGoogle Scholar
  4. 4.
    Makhoul I, Klimberg VS, Korourian S, et al. Combined neoadjuvant chemotherapy with bevacizumab improves pathologic complete response in patients with hormone receptor negative operable or locally advanced breast cancer. Am J Clin Oncol. 2013. doi: 10.1097/COC.0b013e31828940c3.
  5. 5.
    Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039–45.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473–83.PubMedCrossRefGoogle Scholar
  7. 7.
    Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–44.PubMedCrossRefGoogle Scholar
  9. 9.
    Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol. 2005;91:173–80.PubMedCrossRefGoogle Scholar
  10. 10.
    Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697–705.PubMedCrossRefGoogle Scholar
  11. 11.
    Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96.PubMedCrossRefGoogle Scholar
  12. 12.
    Reck M, Barlesi F, Crinò L, et al. Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts. Ann Oncol. 2012;23:1111–20.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009;27:1227–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Soria JC, Mauguen A, Reck M, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol. 2013;24:20–30.PubMedCrossRefGoogle Scholar
  15. 15.
    Smith IE, Pierga JY, Biganzoli L, et al. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol. 2011;22:595–602.PubMedCrossRefGoogle Scholar
  16. 16.
    Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol. 2006;24:769–77.PubMedCrossRefGoogle Scholar
  17. 17.
    Kriegel I, Cottu PH, Fourchotte V, et al. Wound healing and catheter thrombosis after implantable venous access device placement in 266 breast cancers treated with bevacizumab therapy. Anticancer Drugs. 2011;22:1020–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Cottu PH, Fourchotte V, Vincent-Salomon A, Kriegel I, Fromantin I. Necrosis in breast cancer patients with skin metastases receiving bevacizumab-based therapy. J Wound Care. 2011;20:403–4, 406, 408.Google Scholar
  19. 19.
    Lecarpentier E, Ouaffi L, Mir O, et al. Bevacizumab-induced small bowel perforation in a patient with breast cancer without intraabdominal metastases. Invest New Drugs. 2011;29:1500–3.PubMedCrossRefGoogle Scholar
  20. 20.
    Lazzati V, Zygon J, Lohsiriwat V, Veronesi P, Petit JY. Impaired wound healing and bilateral mastectomy flap necrosis in a patient with locally advanced breast cancer after neoadjuvant Paclitaxel with bevacizumab. Aesthetic Plast Surg. 2010;34:796–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Kube R, Meyer F, Bien N, et al. Surgical management of bevacizumab-associated peritonitis due to perforation. Zentralbl Chir. 2009;134:462–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Kim HR, Jung KH, Im SA, et al. Multicentre phase II trial of bevacizumab combined with docetaxel-carboplatin for the neoadjuvant treatment of triple-negative breast cancer (KCSG BR-0905). Ann Oncol. 2013;24:1485–90.PubMedCrossRefGoogle Scholar
  23. 23.
    Li CY, Shan S, Huang Q, et al. Initial stages of tumor cell–induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst. 2000;92:143–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Huober J, Fasching PA, Hanusch C, et al. Neoadjuvant chemotherapy with paclitaxel and everolimus in breast cancer patients with non-responsive tumours to epirubicin/cyclophosphamide (EC) +/− bevacizumab—results of the randomised GeparQuinto study (GBG 44). Eur J Cancer. 2013;49:2284–93.PubMedCrossRefGoogle Scholar
  25. 25.
    Bear HD, Tang G, Rastogi P, et al. The effect on surgical complications of bevacizumab added to neoadjuvant chemotherapy: NSABP protocol B-40. Cancer Res. 2011. doi: 10.1158/0008-5472.SABCS11-PD07-08.
  26. 26.
    Golshan M, Garber JE, Gelman R, et al. Does neoadjuvant bevacizumab increase surgical complications in breast surgery? Ann Surg Oncol. 2011;18:733–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Gordon CR, Rojavin Y, Patel M, et al. A review on bevacizumab and surgical wound healing: an important warning to all surgeons. Ann Plast Surg. 2009;62:707–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Erinjeri JP, Fong AJ, Kemeny NE, Brown KT, Getrajdman GI, Solomon SB. Timing of administration of bevacizumab chemotherapy affects wound healing after chest wall port placement. Cancer. 2011;117:1296–301.PubMedCrossRefGoogle Scholar
  29. 29.
    Cortes J, Caralt M, Delaloge S, et al. Safety of bevacizumab in metastatic breast cancer patients undergoing surgery. Eur J Cancer. 2012;48:475–81.PubMedCrossRefGoogle Scholar
  30. 30.
    NCI. Common Terminology Criteria for Adverse Events (CTCAE) and Common Toxicity Criteria (CTC). Accessed 5 Nov 2013.

Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Bernd Gerber
    • 1
  • Gunter von Minckwitz
    • 2
    • 11
  • Holger Eidtmann
    • 3
  • Mahdi Rezai
    • 4
  • Peter Fasching
    • 5
  • Hans Tesch
    • 6
  • Holm Eggemann
    • 7
  • Iris Schrader
    • 8
  • Kornelia Kittel
    • 9
  • Claus Hanusch
    • 10
  • Christine Solbach
    • 11
  • Christian Jackisch
    • 12
  • Georg Kunz
    • 13
  • Jens-Uwe Blohmer
    • 14
  • Jens Huober
    • 15
  • Maik Hauschild
    • 16
  • Valentina Nekljudova
    • 2
  • Sibylle Loibl
    • 2
  • Michael Untch
    • 17
  1. 1.Department of Obstetrics and GynaecologyUniversity of RostockRostockGermany
  2. 2.Department Medicine and ResearchGerman Breast GroupNeu-IsenburgGermany
  3. 3.Department of Obstetrics and GynaecologyUniversity of Schleswig-Holstein, Campus KielKielGermany
  4. 4.Department of SenologyLuisen-HospitalDüsseldorfGermany
  5. 5.Department of Obstetrics and GynaecologyUniversity of ErlangenErlangenGermany
  6. 6.Department of OncologyBethanien-HospitalFrankfurtGermany
  7. 7.Department of Obstetrics and GynaecologyUniversity of MagdeburgMagdeburgGermany
  8. 8.Gynaeco-oncological PracticeHannoverGermany
  9. 9.Breast CenterElisabeth HospitalKasselGermany
  10. 10.Department of SenologyRotkreuz-KlinikumMunichGermany
  11. 11.Department of Obstetrics and GynaecologyJ.-W. Goethe-UniversityFrankfurtGermany
  12. 12.Department of Obstetrics and GynaecologyHospital OffenbachOffenbachGermany
  13. 13.St. Johannes HospitalDortmundGermany
  14. 14.Department of Obstetrics and GynaecologySankt Gertrauden HospitalBerlinGermany
  15. 15.Department of Obstetrics and GynaecologyHeinrich-Heine University DüsseldorfDüsseldorfGermany
  16. 16.Department of SenologyHospitalRheinfeldenGermany
  17. 17.Department of Obstetrics and GynaecologyHelios Klinikum Berlin-BuchBerlinGermany

Personalised recommendations