Skip to main content
SpringerLink
Log in

Neoadjuvant and Adjuvant Chemotherapy for Advanced Ovarian Cancer, Including Biological Agents

  • Chapter
  • First Online:
Pelvic Cancer Surgery

  • 1938 Accesses

Abstract

The majority of women with ovarian cancer continue to present at advanced stages and the overall 5-year survival rate remains just over 40 %. The principles of the initial management of advanced ovarian cancer consist of maximal cytoreductive surgery and platinum-based chemotherapy. Improvements in surgery and chemotherapy strategies have led to better clinical outcomes. However, disease recurrence and drug resistance present management challenges. Clinical trials evaluating the optimal schedule, mode of administration of established chemotherapy drugs and the integration of targeted agents have led to improvements in survival and practice change. This chapter provides an overview of the initial management of advanced ovarian cancer and the integration of targeted therapies in this setting.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917. PubMed PMID: 21351269. Epub 2011/02/26. eng.

    Article  CAS  PubMed  Google Scholar 

  2. CRUK. Cancer Research UK ovarian incidence statistics. 2010 http://info.cancerresearchuk.org/cancerstats/incidence/risk/. Accessed 2013.

  3. du Bois A, Quinn M, Thigpen T, Vermorken J, Avall-Lundqvist E, Bookman M, et al. 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol. 2005;16 Suppl 8:viii 7–12. PubMed PMID: 16239238.

    Google Scholar 

  4. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334(1):1–6. PubMed PMID: 7494563.

    Article  CAS  PubMed  Google Scholar 

  5. Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst. 2000;92(9):699–708. PubMed PMID: 10793106.

    Article  CAS  PubMed  Google Scholar 

  6. Muggia FM, Braly PS, Brady MF, Sutton G, Niemann TH, Lentz SL, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2000;18(1):106–15. PubMed PMID: 10623700.

    CAS  PubMed  Google Scholar 

  7. Group. ICON. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet. 2002;360(9332):505–15. PubMed PMID: 12241653. Epub 2002/09/21. eng.

    Article  Google Scholar 

  8. du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003;95(17):1320–9. PubMed PMID: 12953086.

    Article  PubMed  Google Scholar 

  9. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21(17):3194–200. PubMed PMID: 12860964.

    Article  CAS  PubMed  Google Scholar 

  10. Neijt JP, Engelholm SA, Tuxen MK, Sorensen PG, Hansen M, Sessa C, et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol. 2000;18(17):3084–92. PubMed PMID: 10963636.

    CAS  PubMed  Google Scholar 

  11. Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst. 2004;96(22):1682–91. PubMed PMID: 15547181.

    Article  CAS  PubMed  Google Scholar 

  12. Kristensen GB, Vergote I, Stuart G, Del Campo JM, Kaern J, Lopez AB, et al. First-line treatment of ovarian cancer FIGO stages IIb-IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/carboplatin. Int J Gynecol Cancer. 2003;13 Suppl 2:172–7. PubMed PMID: 14656276.

    Article  PubMed  Google Scholar 

  13. du Bois A, Weber B, Rochon J, Meier W, Goupil A, Olbricht S, et al. Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens. J Clin Oncol. 2006;24(7):1127–35. PubMed PMID: 16505432.

    Article  PubMed  Google Scholar 

  14. Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009;27(9):1419–25. PubMed PMID: 19224846. Pubmed Central PMCID: 2668552.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009;374(9698):1331–8. PubMed PMID: 19767092.

    Article  CAS  PubMed  Google Scholar 

  16. Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol. 2013;14(10):1020–6. PubMed PMID: 23948349.

    Article  CAS  PubMed  Google Scholar 

  17. Pignata S, Scambia G, Katsaros D, Gallo C, Pujade-Lauraine E, De Placido S, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2014;15(4):396–405. PubMed PMID: 24582486.

    Article  CAS  PubMed  Google Scholar 

  18. Markman M, Liu PY, Wilczynski S, Monk B, Copeland LJ, Alvarez RD, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003;21(13):2460–5. PubMed PMID: 12829663.

    Article  CAS  PubMed  Google Scholar 

  19. Markman M, Liu PY, Moon J, Monk BJ, Copeland L, Wilczynski S, et al. Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial. Gynecol Oncol. 2009;114(2):195–8. PubMed PMID: 19447479. Epub 2009/05/19. eng.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Pecorelli S, Favalli G, Gadducci A, Katsaros D, Panici PB, Carpi A, et al. Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: final results of the after-6 protocol 1. J Clin Oncol. 2009;27(28):4642–8. PubMed PMID: 19704064. Epub 2009/08/26. eng.

    Article  CAS  PubMed  Google Scholar 

  21. Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol. 2006;103(3):1070–6. PubMed PMID: 16875720.

    Article  CAS  PubMed  Google Scholar 

  22. Kumar L, Hariprasas R, Kumar S. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery versus upfront surgery followed by chemotherapy (CT) in advanced epithelial ovarian carcinoma (EOC): a prospective randomized study – interim results. J Clin Oncol. 2007;25(18S):abstr 5531.

    Google Scholar 

  23. van der Burg ME, van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for research and treatment of cancer. N Engl J Med. 1995;332(10):629–34. PubMed PMID: 7845426. Epub 1995/03/09. eng.

    Article  PubMed  Google Scholar 

  24. Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–53. PubMed PMID: 20818904.

    Article  CAS  PubMed  Google Scholar 

  25. Kehoe S, Hook J, Nankivell M, Jayson G, Kitchener H, Lopes T, et al. Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: results from the MRC CHORUS trial. J Clin Oncol. 2013;31(Suppl):abstr 5500.

    Google Scholar 

  26. Mahner S, Eulenburg C, Staehle A, Wegscheider K, Reuss A, Pujade-Lauraine E, et al. Prognostic impact of the time interval between surgery and chemotherapy in advanced ovarian cancer: analysis of prospective randomised phase III trials. Eur J Cancer. 2013;49(1):142–9. PubMed PMID: 22921185.

    Article  CAS  PubMed  Google Scholar 

  27. Alberts DS, Liu PY, Hannigan EV, O’Toole R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335(26):1950–5. PubMed PMID: 8960474.

    Article  CAS  PubMed  Google Scholar 

  28. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34–43. PubMed PMID: 16394300.

    Article  CAS  PubMed  Google Scholar 

  29. Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19(4):1001–7. PubMed PMID: 11181662.

    CAS  PubMed  Google Scholar 

  30. Tewari D, Java J, Salani R, Armstrong D, Markman M, Herzog T, et al. Long-term survival advantage of intraperitoneal chemotherapy treatment in advanced ovarian cancer: an analysis of a Gynecologic Oncology Group ancillary data study. Gynecol Oncol. 2013;130:e4.

    Article  Google Scholar 

  31. Lesnock JL, Darcy KM, Tian C, Deloia JA, Thrall MM, Zahn C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231–7. PubMed PMID: 23462720. Pubmed Central PMCID: 3619264. Epub 2013/03/07. eng.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Banerjee S, Kaye SB. New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin Cancer Res. 2013;19(5):961–8. PubMed PMID: 23307860. Epub 2013/01/12. eng.

    Article  CAS  PubMed  Google Scholar 

  33. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83. PubMed PMID: 22204724. Epub 2011/12/30. eng.

    Article  CAS  PubMed  Google Scholar 

  34. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484–96. PubMed PMID: 22204725. Epub 2011/12/30. eng.

    Article  CAS  PubMed  Google Scholar 

  35. Oza A, Perren T, Swart A, Schroder W, Pujade-Lauraine E, Havsteen H, et al. ICON7: final overall survival results in the GCIG phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. Eur J Cancer. 2013;49 Suppl 3:abstr 6.

    Google Scholar 

  36. Stone RL, Sood AK, Coleman RL. Collateral damage: toxic effects of targeted antiangiogenic therapies in ovarian cancer. Lancet Oncol. 2010;11(5):465–75. PubMed PMID: 20226736. Pubmed Central PMCID: 3199129. Epub 2010/03/17. eng.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, 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(17):2039–45. PubMed PMID: 22529265.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–8. PubMed PMID: 24637997.

    Article  CAS  PubMed  Google Scholar 

  39. Chan J, Brady M, Penson R, Monk B, Boente M, Walker J, et al., editors. Phase III trial of every-3-weeks paclitaxel versus dose dense weekly paclitaxel with carboplatin+/−bevacizumab in epithelial ovarian, peritoneal, fallopian tube cancer: GOG 262 (NCT0116712). Oral presentation at the 18th International Meeting of the European Society of Gynecological Oncology, Liverpool, UK; 2013.

    Google Scholar 

  40. Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012;30(32):4026–34. PubMed PMID: 23008289. Pubmed Central PMCID: 3488272. Epub 2012/09/26. eng.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Andreas Du Bois AF, Kim JW, Rau J, Del Campo JM, Friedlander M, Pignata S, Fujiwara K, Vergote I, Colombo C, Mirza MR, Monk BJ, Wimberger P, Ray-Coquard I, Zang R, Diaz-Padilla I, Baumann KH, Kim JH, Harter P. Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): results of an international intergroup trial (AGO-OVAR16). J Clin Oncol. 2013;31(Suppl):abstr LBA5503.

    Google Scholar 

  42. Du Bois A, Kristensen G, Ray-Coquard I, Reuss A, Pignata S, Colombo N, et al., editors. Ago-ovar 12: a randomized placebo-controlled gcig/engot-intergroup phase iii trial of standard frontline chemotherapy plus/-nintedanib for advanced ovarian cancer. Int J Gynecol Cancer; 2013: Philadelphia: Lippincott Williams & Wilkins. 23(8 Suppl 1)7–8.

    Google Scholar 

  43. Ledermann J, Perren T, Raja F, et al. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: results of the ICON6 trial. European Society for Medical Oncology Congress 2013; September 27–October 1, 2013; Amsterdam, The Netherlands. Abstract 10

    Google Scholar 

  44. Monk BJ, Poveda A, Vergote I, Raspagliesi F, Fujiwara K, Bae DS, et al. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(8):799–808. PubMed PMID: 24950985.

    Article  CAS  PubMed  Google Scholar 

  45. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26(22):3785–90. PubMed PMID: 18591545. Epub 2008/07/02. eng.

    Article  CAS  PubMed  Google Scholar 

  46. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34. PubMed PMID: 19553641. Epub 2009/06/26. eng.

    Article  CAS  PubMed  Google Scholar 

  47. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512–9. PubMed PMID: 20406929. Epub 2010/04/22. eng.

    Article  CAS  PubMed  Google Scholar 

  48. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382–92. PubMed PMID: 22452356. Epub 2012/03/29. eng.

    Article  CAS  PubMed  Google Scholar 

  49. Jonathan A, Ledermann PH, Gourley C, Friedlander M, Vergote I, Rustin GJS, Scott GL, Meier W, Shapira-Frommer R, Safra T, Matei T, Fielding A, Macpherson E, Dougherty B, Jürgensmeier JM, Orr M, Matulonis U. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm). J Clin Oncol. 2013;31(Suppl):abstr 5505.

    Google Scholar 

  50. Vergote IB, Joly F, Katsaros D, Corneel Coens AR, Marcia H, Steer CB, Nicoletta C, Anne L, Antonio C, Edgar P, John G, Martin B, Isabelle Laure R-C, Annamaria F, Laure F, Nicholas R, Herve C, Jimeno A, Pujade-Lauraine E. Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: a GCIG and EORTC-GCG study. J Clin Oncol. 2012;30(Suppl):abstr LBA5000.

    Google Scholar 

  51. Berek J, Taylor P, McGuire W, Smith LM, Schultes B, Nicodemus CF. Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer. J Clin Oncol. 2009;27(3):418–25. PubMed PMID: 19075271. Epub 2008/12/17. eng.

    Article  CAS  PubMed  Google Scholar 

  52. Vergote J, Armstrong D, Scambia G, Fujiwara K, Gorbunova V, Schweizer C. Phase III double-blind, placebo-controlled study of weekly farletuzumab with carboplatin/taxane in subjects with platinum-sensitive ovarian cancer in first relapse. Int J Gynecol Cancer. 2013;23(8 Suppl 1):11.

    Google Scholar 

  53. Naumann RW, Coleman RL, Burger RA, Sausville EA, Kutarska E, Ghamande SA, et al. PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2013;31(35):4400–6. PubMed PMID: 24127448.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge support from the National Institute of Health Research (NIHR) Biomedical Research Centre.

Author information

Authors and Affiliations

  1. Department of Medicine, Royal Marsden NHS Foundation Trust, Sutton, London, UK

    Shelize S. Khakoo MBChB, BSc, MRCP & Susana Banerjee MA, MBBS, MRCP, PhD

Authors
  1. Shelize S. Khakoo MBChB, BSc, MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susana Banerjee MA, MBBS, MRCP, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susana Banerjee MA, MBBS, MRCP, PhD .

Editor information

Editors and Affiliations

  1. Urology, University Hospital of North Norway, Tromsø, Norway

    Hitendra R.H. Patel

  2. University College London Hospital, London, United Kingdom

    Tim Mould

  3. Laparoscopic and Robotic Surgery, University of Rochester Medical Center, Rochester, New York, USA

    Jean V. Joseph

  4. Colorectal Surgery, University Hospitals Case Medical Center, Cleveland, Ohio, USA

    Conor P. Delaney

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag London

About this chapter

Cite this chapter

Khakoo, S.S., Banerjee, S. (2015). Neoadjuvant and Adjuvant Chemotherapy for Advanced Ovarian Cancer, Including Biological Agents. In: Patel, H., Mould, T., Joseph, J., Delaney, C. (eds) Pelvic Cancer Surgery. Springer, London. https://doi.org/10.1007/978-1-4471-4258-4_41

Download citation

  • DOI: https://doi.org/10.1007/978-1-4471-4258-4_41

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-4471-4257-7

  • Online ISBN: 978-1-4471-4258-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation