Skip to main content

Treatment of Precancers with Topical Agents

  • Chapter
  • First Online:
Evidence-Based Procedural Dermatology
  • 1366 Accesses

Abstract

Actinic keratosis (AK) is one of the most common skin conditions worldwide. AK represents an intraepidermal dysplastic proliferation of keratinocytes (Berman B, Cockerell CJ. J Am Acad Dermatol 68:S10–9, 2013). It is a potential precursor to squamous cell carcinoma (SCC), with estimates of AK progression to invasive SCC ranging from 0.025% to 20%. With the incidence of non-melanoma skin cancer on the rise, treatment for AKs has been recommended to reduce the development of invasive SCC, lower healthcare expenditure, and improve patient well-being (Vale SM, Hill D, Feldman SR. Pharmacoeconomics 107:674–680, 2016). Several treatment modalities have been employed to treat AKs in an attempt to prevent progression to invasive SCC. The modalities which will be discussed and evaluated in this chapter include topical sunscreen, cryotherapy with liquid nitrogen, topical 5% (Efudex) and 0.5% (Carac) 5-fluorouracil (5-FU), topical 5% imiquimod cream (Aldara), topical diclofenac with sodium hyaluronate gel (Solaraze), ingenol mebutate (Picato), topical retinoids, and chemical peels including trichloroacetic acid and Jessner’s solution applied to affected skin.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
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. Berman B, Cockerell CJ. Pathobiology of actinic keratosis: ultraviolet-dependent keratinocyte proliferation. J Am Acad Dermatol. 2013;68(1 Suppl 1):S10–9.

    PubMed  Google Scholar 

  2. Vale SM, Hill D, Feldman SR. Pharmacoeconomic considerations in treating actinic keratosis: an update. Pharmacoeconomics. 2017;35(2):177–90.

    Google Scholar 

  3. Weinstock MA, Bingham SF, Lew RA, Hall R, Eilers D, Kirsner R, et al. Topical tretinoin therapy and all-cause mortality. Arch Dermatol. 2009;145(1):18–24.

    PubMed  Google Scholar 

  4. Criscione VD, Weinstock MA, Naylor MF, Luque C, Eide MJ, Bingham SF, et al. Actinic keratoses: natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523–30.

    PubMed  Google Scholar 

  5. Siegel JA, Korgavkar K, Weinstock MA. Current perspective on actinic keratosis: a review. Br J Dermatol. 2016;177:350–8.

    PubMed  Google Scholar 

  6. Quaedvlieg PJ, Tirsi E, Thissen MR, Krekels GA. Actinic keratosis: how to differentiate the good from the bad ones? Eur J Dermatol. 2006;16(4):335–9.

    CAS  PubMed  Google Scholar 

  7. Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, Nast A. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169(3):502–18.

    CAS  PubMed  Google Scholar 

  8. Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic keratoses and the controversy over treatment. A patient-oriented perspective. Arch Dermatol. 1991;127(7):1029–31.

    CAS  PubMed  Google Scholar 

  9. Gurney B, Newlands C. Management of regional metastatic disease in head and neck cutaneous malignancy. 1. Cutaneous squamous cell carcinoma. Br J Oral Maxillofac Surg. 2014;52(4):294–300.

    PubMed  Google Scholar 

  10. Stockfleth E, Kerl H, Guideline Subcommittee of the European Dermatology F. Guidelines for the management of actinic keratoses. Eur J Dermatol. 2006;16(6):599–606.

    CAS  PubMed  Google Scholar 

  11. Drake LA, Ceilley RI, Cornelison RL, Dobes WL, Dorner W, Goltz RW, et al. Guidelines of care for actinic keratoses. Committee on Guidelines of Care. J Am Acad Dermatol. 1995;32(1):95–8.

    CAS  PubMed  Google Scholar 

  12. de Berker D, McGregor JM, Hughes BR, British Association of Dermatologists Therapy G, Audit S. Guidelines for the management of actinic keratoses. Br J Dermatol. 2007;156(2):222–30.

    PubMed  Google Scholar 

  13. How to apply sunscreen n.d. [updated n.d. Available from: https://www.aad.org/public/spot-skin-cancer/learn-about-skin-cancer/prevent/how-to-apply-sunscreen

  14. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med. 1993;329(16):1147–51.

    CAS  PubMed  Google Scholar 

  15. Darlington S, Williams G, Neale R, Frost C, Green A. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol. 2003;139(4):451–5.

    PubMed  Google Scholar 

  16. Green A, Williams G, Neale R, Hart V, Leslie D, Parsons P, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet. 1999;354(9180):723–9.

    CAS  PubMed  Google Scholar 

  17. Thai KE, Sinclair RD. Cryosurgery of benign skin lesions. Australas J Dermatol. 1999;40(4):175–84. quiz 85–6.

    CAS  PubMed  Google Scholar 

  18. Thai KE, Fergin P, Freeman M, Vinciullo C, Francis D, Spelman L, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol. 2004;43(9):687–92.

    PubMed  Google Scholar 

  19. Foley P, Merlin K, Cumming S, Campbell J, Crouch R, Harrison S, et al. A comparison of cryotherapy and imiquimod for treatment of actinic keratoses: lesion clearance, safety, and skin quality outcomes. J Drugs Dermatol. 2011;10(12):1432–8.

    CAS  PubMed  Google Scholar 

  20. Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, Stockfleth E. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007;157(Suppl 2):34–40.

    CAS  PubMed  Google Scholar 

  21. Monheit GD. Medium-depth chemical peels. Dermatol Clin. 2001;19(3):413–25. vii.

    CAS  PubMed  Google Scholar 

  22. Lawrence N, Cox SE, Cockerell CJ, Freeman RG, Cruz PD Jr. A comparison of the efficacy and safety of Jessner’s solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Arch Dermatol. 1995;131(2):176–81.

    CAS  PubMed  Google Scholar 

  23. Tse Y, Ostad A, Lee HS, Levine VJ, Koenig K, Kamino H, et al. A clinical and histologic evaluation of two medium-depth peels. Glycolic acid versus Jessner’s trichloroacetic acid. Dermatol Surg. 1996;22(9):781–6.

    CAS  PubMed  Google Scholar 

  24. Witheiler DD, Lawrence N, Cox SE, Cruz C, Cockerell CJ, Freemen RG. Long-term efficacy and safety of Jessner’s solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Dermatol Surg. 1997;23(3):191–6.

    CAS  PubMed  Google Scholar 

  25. Humphreys TR, Werth V, Dzubow L, Kligman A. Treatment of photodamaged skin with trichloroacetic acid and topical tretinoin. J Am Acad Dermatol. 1996;34(4):638–44.

    CAS  PubMed  Google Scholar 

  26. Dillaha CJ, Jansen GT, Honeycutt WM, Holt GA. Further studies with topical 5-fluorouracil. Arch Dermatol. 1965;92(4):410–7.

    CAS  PubMed  Google Scholar 

  27. Eaglstein WH, Weinstein GD, Frost P. Fluorouracil: mechanism of action in human skin and actinic keratoses. I. Effect on DNA synthesis in vivo. Arch Dermatol. 1970;101(2):132–9.

    CAS  PubMed  Google Scholar 

  28. Pomerantz H, Hogan D, Eilers D, Swetter SM, Chen SC, Jacob SE, et al. Long-term efficacy of topical fluorouracil cream, 5%, for treating actinic keratosis: a randomized clinical trial. JAMA dermatol. 2015;151(9):952–60.

    PubMed  Google Scholar 

  29. Jorizzo J, Stewart D, Bucko A, Davis SA, Espy P, Hino P, et al. Randomized trial evaluating a new 0.5% fluorouracil formulation demonstrates efficacy after 1-, 2-, or 4-week treatment in patients with actinic keratosis. Cutis. 2002;70(6):335–9.

    PubMed  Google Scholar 

  30. Weiss J, Menter A, Hevia O, Jones T, Ling M, Rist T, et al. Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks. Cutis. 2002;70(2 Suppl):22–9.

    PubMed  Google Scholar 

  31. Jorizzo J, Weiss J, Furst K, VandePol C, Levy SF. Effect of a 1-week treatment with 0.5% topical fluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized, vehicle-controlled clinical trial. Arch Dermatol. 2004;140(7):813–6.

    CAS  PubMed  Google Scholar 

  32. Loven K, Stein L, Furst K, Levy S. Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther. 2002;24(6):990–1000.

    CAS  PubMed  Google Scholar 

  33. Jury CS, Ramraka-Jones VS, Gudi V, Herd RM. A randomized trial of topical 5% 5-fluorouracil (Efudix cream) in the treatment of actinic keratoses comparing daily with weekly treatment. Br J Dermatol. 2005;153(4):808–10.

    CAS  PubMed  Google Scholar 

  34. Hoover WD 3rd, Jorizzo JL, Clark AR, Feldman SR, Holbrook J, Huang KE. Efficacy of cryosurgery and 5-fluorouracil cream 0.5% combination therapy for the treatment of actinic keratosis. Cutis. 2014;94(5):255–9.

    PubMed  Google Scholar 

  35. Stockfleth E, Kerl H, Zwingers T, Willers C. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011;165(5):1101–8.

    CAS  PubMed  Google Scholar 

  36. Simon JC, Dominicus R, Karl L, Rodriguez R, Willers C, Dirschka T. A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis. J Eur Acad Dermatol Venereol. 2015;29(5):881–9.

    CAS  PubMed  Google Scholar 

  37. Werner RN, Jacobs A, Rosumeck S, Erdmann R, Sporbeck B, Nast A. Methods and Results Report – Evidence and consensus-based (S3) guidelines for the treatment of actinic keratosis -International League of Dermatological Societies in cooperation with the European Dermatology Forum. J Eur Acad Dermatol Venereol. 2015;29(11):e1–66.

    CAS  PubMed  Google Scholar 

  38. Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol. 2006;126(6):1251–5.

    CAS  PubMed  Google Scholar 

  39. Gebauer K, Shumack S, Cowen PS. Effect of dosing frequency on the safety and efficacy of imiquimod 5% cream for treatment of actinic keratosis on the forearms and hands: a phase II, randomized placebo-controlled trial. Br J Dermatol. 2009;161(4):897–903.

    CAS  PubMed  Google Scholar 

  40. Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, Levy S. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol. 2010;62(4):582–90.

    CAS  PubMed  Google Scholar 

  41. Tanghetti E, Werschler P. Comparison of 5% 5-fluorouracil cream and 5% imiquimod cream in the management of actinic keratoses on the face and scalp. J Drugs Dermatol. 2007;6(2):144–7.

    PubMed  Google Scholar 

  42. Pirard D, Vereecken P, Melot C, Heenen M. Three percent diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses: a meta-analysis of the recent studies. Arch Dermatol Res. 2005;297(5):185–9.

    CAS  PubMed  Google Scholar 

  43. Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000;60(5):1306–11.

    CAS  PubMed  Google Scholar 

  44. Spencer JM, Kahn SM, Jiang W, DeLeo VA, Weinstein IB. Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas. Arch Dermatol. 1995;131(7):796–800.

    CAS  PubMed  Google Scholar 

  45. Wolf JE Jr, Taylor JR, Tschen E, Kang S. Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol. 2001;40(11):709–13.

    CAS  PubMed  Google Scholar 

  46. Rivers JK, Arlette J, Shear N, Guenther L, Carey W, Poulin Y. Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol. 2002;146(1):94–100.

    CAS  PubMed  Google Scholar 

  47. Gebauer K, Brown P, Varigos G. Topical diclofenac in hyaluronan gel for the treatment of solar keratoses. Australas J Dermatol. 2003;44(1):40–3.

    PubMed  Google Scholar 

  48. Akarsu S, Aktan S, Atahan A, Koc P, Ozkan S. Comparison of topical 3% diclofenac sodium gel and 5% imiquimod cream for the treatment of actinic keratoses. Clin Exp Dermatol. 2011;36(5):479–84.

    CAS  PubMed  Google Scholar 

  49. Kose O, Koc E, Erbil AH, Caliskan E, Kurumlu Z. Comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% imiquimod cream in the treatment of actinic keratosis. J Dermatolog Treat. 2008;19(3):159–63.

    CAS  PubMed  Google Scholar 

  50. Anderson L, Schmieder GJ, Werschler WP, Tschen EH, Ling MR, Stough DB, et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 2009;60(6):934–43.

    PubMed  Google Scholar 

  51. Ogbourne SM, Suhrbier A, Jones B, Cozzi SJ, Boyle GM, Morris M, et al. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 2004;64(8):2833–9.

    CAS  PubMed  Google Scholar 

  52. Challacombe JM, Suhrbier A, Parsons PG, Jones B, Hampson P, Kavanagh D, et al. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J Immunol. 2006;177(11):8123–32.

    CAS  PubMed  Google Scholar 

  53. Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366(11):1010–9.

    CAS  PubMed  Google Scholar 

  54. Lebwohl M, Shumack S, Stein Gold L, Melgaard A, Larsson T, Tyring SK. Long-term follow-up study of ingenol mebutate gel for the treatment of actinic keratoses. JAMA Dermatol. 2013;149(6):666–70.

    CAS  PubMed  Google Scholar 

  55. Berman B, Goldenberg G, Hanke CW, Tyring SK, Werschler WP, Knudsen KM, et al. Efficacy and safety of ingenol mebutate 0.015% gel after cryosurgery of actinic keratosis: 12-month results. J Drugs Dermatol. 2014;13(6):741–7.

    CAS  PubMed  Google Scholar 

  56. Bagatin E, Parada MO, Miot HA, Hassun KM, Michalany N, Talarico S. A randomized and controlled trial about the use of oral isotretinoin for photoaging. Int J Dermatol. 2010;49(2):207–14.

    CAS  PubMed  Google Scholar 

  57. Lens M, Medenica L. Systemic retinoids in chemoprevention of non-melanoma skin cancer. Expert Opin Pharmacother. 2008;9(8):1363–74.

    CAS  PubMed  Google Scholar 

  58. Wright TI, Spencer JM, Flowers FP. Chemoprevention of nonmelanoma skin cancer. J Am Acad Dermatol. 2006;54(6):933–46. quiz 47–50

    PubMed  Google Scholar 

  59. Mrass P, Rendl M, Mildner M, Gruber F, Lengauer B, Ballaun C, et al. Retinoic acid increases the expression of p53 and proapoptotic caspases and sensitizes keratinocytes to apoptosis: a possible explanation for tumor preventive action of retinoids. Cancer Res. 2004;64(18):6542–8.

    CAS  PubMed  Google Scholar 

  60. Phillips TJ. An update on the safety and efficacy of topical retinoids. Cutis. 2005;75(2 Suppl):14–22. 4; discussion -3.

    PubMed  Google Scholar 

  61. Kockaert M, Neumann M. Systemic and topical drugs for aging skin. J Drugs Dermatol. 2003;2(4):435–41.

    PubMed  Google Scholar 

  62. Alirezai M, Dupuy P, Amblard P, Kalis B, Souteyrand P, Frappaz A, et al. Clinical evaluation of topical isotretinoin in the treatment of actinic keratoses. J Am Acad Dermatol. 1994;30(3):447–51.

    CAS  PubMed  Google Scholar 

  63. Kang S, Goldfarb MT, Weiss JS, Metz RD, Hamilton TA, Voorhees JJ, et al. Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: a randomized trial. J Am Acad Dermatol. 2003;49(1):83–90.

    PubMed  Google Scholar 

  64. Kligman AL, Thorne EG. Topical therapy of actinic keratosis with tretinoin. In: Marks R, editor. Retinoids in cutaneous malignancy. Oxford, UK: Blackwell Scientific Publications. 1991. p. 66–73.

    Google Scholar 

  65. Bollag W, Ott F. Retinoic acid: topical treatment of senile or actinic keratoses and basal cell carcinomas. Agents Actions. 1970;1(4):172–5.

    CAS  PubMed  Google Scholar 

  66. Weinstock MA, Bingham SF, Digiovanna JJ, Rizzo AE, Marcolivio K, Hall R, et al. Tretinoin and the prevention of keratinocyte carcinoma (Basal and squamous cell carcinoma of the skin): a veterans affairs randomized chemoprevention trial. J Invest Dermatol. 2012;132(6):1583–90.

    CAS  PubMed  Google Scholar 

  67. Campanelli A, Naldi L. A retrospective study of the effect of long-term topical application of retinaldehyde (0.05%) on the development of actinic keratosis. Dermatology. 2002;205(2):146–52.

    CAS  PubMed  Google Scholar 

  68. Ianhez M, Fleury LF Jr, Miot HA, Bagatin E. Retinoids for prevention and treatment of actinic keratosis. An Bras Dermatol. 2013;88(4):585–93.

    PubMed  PubMed Central  Google Scholar 

  69. Ulrich C, Busch JO, Meyer T, Nindl I, Schmook T, Sterry W, et al. Successful treatment of multiple actinic keratoses in organ transplant patients with topical 5% imiquimod: a report of six cases. Br J Dermatol. 2006;155(2):451–4.

    CAS  PubMed  Google Scholar 

  70. Barr BB, Benton EC, McLaren K, Bunney MH, Smith IW, Blessing K, et al. Papillomavirus infection and skin cancer in renal allograft recipients. Lancet. 1989;2(8656):224–5.

    CAS  PubMed  Google Scholar 

  71. Euvrard S, Kanitakis J, Pouteil-Noble C, Dureau G, Touraine JL, Faure M, et al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol. 1995;33(2 Pt 1):222–9.

    CAS  PubMed  Google Scholar 

  72. Ulrich C, Jurgensen JS, Degen A, Hackethal M, Ulrich M, Patel MJ, et al. Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study. Br J Dermatol. 2009;161(Suppl 3):78–84.

    PubMed  Google Scholar 

  73. Ulrich C, Bichel J, Euvrard S, Guidi B, Proby CM, van de Kerkhof PC, et al. Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol. 2007;157(Suppl 2):25–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Ulrich C, Johannsen A, Rowert-Huber J, Ulrich M, Sterry W, Stockfleth E. Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses. Eur J Dermatol. 2010;20(4):482–8.

    PubMed  Google Scholar 

  75. Smit JV, Cox S, Blokx WA, van de Kerhof PC, de Jongh GJ, de Jong EM. Actinic keratoses in renal transplant recipients do not improve with calcipotriol cream and all-trans retinoic acid cream as monotherapies or in combination during a 6-week treatment period. Br J Dermatol. 2002;147(4):816–8.

    CAS  PubMed  Google Scholar 

  76. Rook AH, Jaworsky C, Nguyen T, Grossman RA, Wolfe JT, Witmer WK, et al. Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation. 1995;59(5):714–9.

    CAS  PubMed  Google Scholar 

  77. Carneiro RV, Sotto MN, Azevedo LS, Ianhez LE, Rivitti EA. Acitretin and skin cancer in kidney transplanted patients. Clinical and histological evaluation and immunohistochemical analysis of lymphocytes, natural killer cells and Langerhans’ cells in sun exposed and sun protected skin. Clin Transpl. 2005;19(1):115–21.

    Google Scholar 

  78. Naylor MF, Boyd A, Smith DW, Cameron GS, Hubbard D, Neldner KH. High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol. 1995;131(2):170–5.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bahar Firoz .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Chamorro, P., Firoz, B. (2019). Treatment of Precancers with Topical Agents. In: Alam, M. (eds) Evidence-Based Procedural Dermatology. Springer, Cham. https://doi.org/10.1007/978-3-030-02023-1_41

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-02023-1_41

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-02022-4

  • Online ISBN: 978-3-030-02023-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics