Skip to main content
SpringerLink
Log in

Radioisotope Therapies: Iodine-131, I-131-MIBG, and Beyond

  • Chapter
  • First Online:
Imaging in Pediatric Oncology

Part of the book series: Pediatric Oncology ((PEDIATRICO))

  • 1125 Accesses

Abstract

Radioisotopes play an integral role in the imaging and treatment of certain types of pediatric malignancies, notably differentiated thyroid cancer (DTC) and high-risk neuroblastoma. This chapter focuses on radioactive iodine (I-131) therapy of pediatric DTC and I-131-metaiodobenzylguanidine (131I-mIBG) therapy of high-risk neuroblastoma. The epidemiology of pediatric DTC and the current status of I-131 therapy including the recommendations from the recent pediatric guidelines of the American Thyroid Association (ATA) are outlined. The role of diagnostic whole-body I-123 scintigraphy and dosimetry in guiding I-131 therapy is also discussed. Treatment-related considerations including outpatient versus inpatient setting, patient preparation, education, and radiation safety considerations are reviewed. This chapter also includes information on the epidemiology of neuroblastoma, as well as the background and current status of 131I-mIBG therapy in this disease. Logistics of establishing a 131I-mIBG therapy program and the process of safe delivery of 131I-mIBG to high-risk neuroblastoma patients are discussed in detail. Side effects of therapeutic 131I-mIBG are also outlined. Finally, a concise overview of novel radionuclide therapies such as peptide receptor radionuclide therapy, radionuclide antibody therapy, and palliative bone-seeking radionuclide therapies is presented.

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 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 139.99
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. Fahey FH, Grant FD, Thrall JH. Saul Hertz, MD, and the birth of radionuclide therapy. EJNMMI Phys. 2017;4:15.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Means JH. The use of radioactive iodine in the diagnosis and treatment of thyroid diseases. Bull N Y Acad Med. 1948;24:273–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Seidlin SM, Marinelli LD, Oshry E. Radioactive iodine therapy; effect on functioning metastases of adenocarcinoma of the thyroid. JAMA. 1946;132:838–47.

    Article  CAS  Google Scholar 

  4. Jadvar H. Targeted radionuclide therapy: an evolution toward precision cancer treatment. AJR Am J Roentgenol. 2017;209:277–88.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Zukotynski K, Jadvar H, Capala J, Fahey F. Targeted radionuclide therapy: practical applications and future prospects. Biomark Cancer. 2016;8:35–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Yeong C-H, Cheng M, Ng K-H. Therapeutic radionuclides in nuclear medicine: current and future prospects. J Zhejiang Univ Sci B. 2014;15:845–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, editors. SEER Cancer Statistics Review, 1975-2014. Bethesda, MD: National Cancer Institute; 2017. Available at https://seer.cancer.gov/csr/1975_2014/, based on November 2016 SEER data submission, posted to the SEER web site, April 2017. Accessed 10 Oct 2017.

    Google Scholar 

  8. Francis GL, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid. 2015;25:716–59.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI, Sola JE. Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J Surg Res. 2009;156:167–72.

    Article  PubMed  Google Scholar 

  10. LAG R, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR, editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995, SEER Program. NIH Pub. No. 99-4649. Bethesda, MD: National Cancer Institute; 1999. Available at https://seer.cancer.gov/archive/publications/childhood. Accessed 10 Oct 2017.

    Google Scholar 

  11. Kiratli PO, Volkan-Salanci B, Günay EC, Varan A, Akyüz C, Büyükpamukçu M. Thyroid cancer in pediatric age group: an institutional experience and review of the literature. J Pediatr Hematol Oncol. 2013;35:93–7.

    Article  PubMed  Google Scholar 

  12. Rivkees SA, Mazzaferri EL, Verburg FA, Reiners C, Luster M, Breuer CK, et al. The treatment of differentiated thyroid cancer in children: emphasis on surgical approach and radioactive iodine therapy. Endocr Rev. 2011;32:798–826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vergamini LB, Frazier AL, Abrantes FL, Ribeiro KB, Rodriguez-Galindo C. Increase in the incidence of differentiated thyroid carcinoma in children, adolescents, and young adults: a population-based study. J Pediatr. 2014;164:1481–5.

    Article  PubMed  Google Scholar 

  14. Pacini F. Thyroid cancer in children and adolescents. J Endocrinol Invest. 2002;25:572–3.

    Article  PubMed  Google Scholar 

  15. Hay ID, Gonzalez-Losada T, Reinalda MS, Honetschlager JA, Richards ML, Thompson GB. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008. World J Surg. 2010;34:1192–202.

    Article  PubMed  Google Scholar 

  16. Parisi MT, Eslamy H, Mankoff D. Management of differentiated thyroid cancer in children: focus on the american thyroid association pediatric guidelines. Semin Nucl Med. 2016;46:147–64.

    Article  PubMed  Google Scholar 

  17. Brink JS, van Heerden JA, McIver B, Salomao DR, Farley DR, Grant CS, et al. Papillary thyroid cancer with pulmonary metastases in children: long-term prognosis. Surgery. 2000;128:881–6. discussion 886–887.

    Article  CAS  PubMed  Google Scholar 

  18. Chow S-M, Law SCK, Mendenhall WM, Au S-K, Yau S, Mang O, et al. Differentiated thyroid carcinoma in childhood and adolescence-clinical course and role of radioiodine. Pediatr Blood Cancer. 2004;42:176–83.

    Article  PubMed  Google Scholar 

  19. Giuffrida D, Scollo C, Pellegriti G, Lavenia G, Iurato MP, Pezzin V, et al. Differentiated thyroid cancer in children and adolescents. J Endocrinol Invest. 2002;25:18–24.

    Article  CAS  PubMed  Google Scholar 

  20. Pawelczak M, David R, Franklin B, Kessler M, Lam L, Shah B. Outcomes of children and adolescents with well-differentiated thyroid carcinoma and pulmonary metastases following 131I treatment: a systematic review. Thyroid. 2010;20:1095–101.

    Article  CAS  PubMed  Google Scholar 

  21. Reiners C, Farahati J. 131I therapy of thyroid cancer patients. Q J Nucl Med. 1999;43:324–35.

    CAS  PubMed  Google Scholar 

  22. Robbins RJ, Schlumberger MJ. The evolving role of (131)I for the treatment of differentiated thyroid carcinoma. J Nucl Med. 2005;46(Suppl 1):28S–37S.

    CAS  PubMed  Google Scholar 

  23. Van Nostrand D. The benefits and risks of I-131 therapy in patients with well-differentiated thyroid cancer. Thyroid. 2009;19:1381–91.

    Article  PubMed  CAS  Google Scholar 

  24. Hay ID, Thompson GB, Grant CS, Bergstralh EJ, Dvorak CE, Gorman CA, et al. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg. 2002;26:879–85.

    Article  PubMed  Google Scholar 

  25. Iyer NG, Morris LGT, Tuttle RM, Shaha AR, Ganly I. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer. 2011;117:4439–46.

    Article  PubMed  Google Scholar 

  26. Jonklaas J, Cooper DS, Ain KB, Bigos T, Brierley JD, Haugen BR, et al. Radioiodine therapy in patients with stage I differentiated thyroid cancer. Thyroid. 2010;20:1423–4.

    Article  PubMed  Google Scholar 

  27. Schlumberger M, Catargi B, Borget I, Deandreis D, Zerdoud S, Bridji B, et al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med. 2012;366:1663–73.

    Article  CAS  PubMed  Google Scholar 

  28. Tuttle RM, Leboeuf R, Shaha AR. Medical management of thyroid cancer: a risk adapted approach. J Surg Oncol. 2008;97:712–6.

    Article  PubMed  Google Scholar 

  29. Jarzab B, Handkiewicz-Junak D, Wloch J. Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review. Endocr Relat Cancer. 2005;12:773–803.

    Article  CAS  PubMed  Google Scholar 

  30. Newman KD, Black T, Heller G, Azizkhan RG, Holcomb GW, Sklar C, et al. Differentiated thyroid cancer: determinants of disease progression in patients <21 years of age at diagnosis: a report from the Surgical Discipline Committee of the Children’s Cancer Group. Ann Surg. 1998;227:533–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Brown AP, Chen J, Hitchcock YJ, Szabo A, Shrieve DC, Tward JD. The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab. 2008;93:504–15.

    Article  CAS  PubMed  Google Scholar 

  32. Rubino C, de Vathaire F, Dottorini ME, Hall P, Schvartz C, Couette JE, et al. Second primary malignancies in thyroid cancer patients. Br J Cancer. 2003;89:1638–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hung W, Sarlis NJ. Current controversies in the management of pediatric patients with well-differentiated nonmedullary thyroid cancer: a review. Thyroid. 2002;12:683–702.

    Article  PubMed  Google Scholar 

  34. McClellan DR, Francis GL. Thyroid cancer in children, pregnant women, and patients with Graves’ disease. Endocrinol Metab Clin North Am. 1996;25:27–48.

    Article  CAS  PubMed  Google Scholar 

  35. Parisi MT, Mankoff D. Differentiated pediatric thyroid cancer: correlates with adult disease, controversies in treatment. Semin Nucl Med. 2007;37:340–56.

    Article  PubMed  Google Scholar 

  36. Welch Dinauer CA, Tuttle RM, Robie DK, McClellan DR, Svec RL, Adair C, et al. Clinical features associated with metastasis and recurrence of differentiated thyroid cancer in children, adolescents and young adults. Clin Endocrinol (Oxf). 1998;49:619–28.

    Article  CAS  Google Scholar 

  37. Treves ST. Pediatric nuclear medicine and molecular imaging. New York, NY: Springer; 2014.

    Book  Google Scholar 

  38. WFE L, Zacharin MR, Waters K, Wheeler G, Johnston V, Hicks RJ. Management of paediatric thyroid carcinoma: recent experience with recombinant human thyroid stimulating hormone in preparation for radioiodine therapy. Intern Med J. 2006;36:564–70.

    Article  CAS  Google Scholar 

  39. Luster M, Handkiewicz-Junak D, Grossi A, Zacharin M, Taïeb D, Cruz O, et al. Recombinant thyrotropin use in children and adolescents with differentiated thyroid cancer: a multicenter retrospective study. J Clin Endocrinol Metab. 2009;94:3948–53.

    Article  CAS  PubMed  Google Scholar 

  40. Luster M, Lippi F, Jarzab B, Perros P, Lassmann M, Reiners C, et al. rhTSH-aided radioiodine ablation and treatment of differentiated thyroid carcinoma: a comprehensive review. Endocr Relat Cancer. 2005;12:49–64.

    Article  CAS  PubMed  Google Scholar 

  41. Bural G, Drubach L, Treves ST, Grant F. Thymic uptake of radioiodine in children and young adults with thyroid cancer. J Nucl Med. 2010;51:489.

    Google Scholar 

  42. Benua RS, Cicale NR, Sonenberg M, Rawson RW. The relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer. Am J Roentgenol Radium Ther Nucl Med. 1962;87:171–82.

    CAS  PubMed  Google Scholar 

  43. Lassmann M, Hänscheid H, Verburg FA, Luster M. The use of dosimetry in the treatment of differentiated thyroid cancer. Q J Nucl Med Mol Imaging. 2011;55:107–15.

    CAS  PubMed  Google Scholar 

  44. Tuttle RM, Leboeuf R, Robbins RJ, Qualey R, Pentlow K, Larson SM, et al. Empiric radioactive iodine dosing regimens frequently exceed maximum tolerated activity levels in elderly patients with thyroid cancer. J Nucl Med. 2006;47:1587–91.

    PubMed  Google Scholar 

  45. Lassmann M, Hänscheid H, Chiesa C, Hindorf C, Flux G, Luster M, et al. EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry I: blood and bone marrow dosimetry in differentiated thyroid cancer therapy. Eur J Nucl Med Mol Imaging. 2008;35:1405–12.

    Article  PubMed  Google Scholar 

  46. Luster M, Lassmann M, Freudenberg LS, Reiners C. Thyroid cancer in childhood: management strategy, including dosimetry and long-term results. Hormones (Athens). 2007;6:269–78.

    Article  Google Scholar 

  47. Maxon HR, Englaro EE, Thomas SR, Hertzberg VS, Hinnefeld JD, Chen LS, et al. Radioiodine-131 therapy for well-differentiated thyroid cancer--a quantitative radiation dosimetric approach: outcome and validation in 85 patients. J Nucl Med. 1992;33:1132–6.

    PubMed  Google Scholar 

  48. Tuttle RM, Grewal RK, Larson SM. Radioactive iodine therapy in poorly differentiated thyroid cancer. Nat Clin Pract Oncol. 2007;4:665–8.

    Article  CAS  PubMed  Google Scholar 

  49. United States Nuclear Regulatory Commission Office of Federal and State. Material and environmental management programs 2009, 20555-0001. NRC Information Notice 2003-22, Supplement 1. Washington, DC: NRC; 2009. Available at www.nrc.gov/reading-rm/doc-collections/gen-comm/info-notices/2003/ml090500018.pdf. Accessed 10 Oct 2017.

    Google Scholar 

  50. American Thyroid Association Taskforce On Radioiodine Safety, Sisson JC, Freitas J, McDougall IR, Dauer LT, Hurley JR, et al. Radiation safety in the treatment of patients with thyroid diseases by radioiodine 131I : practice recommendations of the American Thyroid Association. Thyroid. 2011;21:335–46.

    Article  Google Scholar 

  51. U.S. Nuclear Regulatory Commission Regulatory Guide 8.39. Release of patients administered radioactive materials. 1997. Available at www.nucmed.com/nucmed/ref/8_39.pdf. Accessed 10 Oct 2017.

  52. United States Nuclear Regulatory Commission 2008 Standards for protection against radiation. Title 10, Code of Federal Regulations: Part 20, Subpart C—20.1201 Occupational dose limits for adults; 20.1207 Occupational dose limits for minors; Part 35, Subpart C—35.75 Release of individuals containing unsealed byproduct material or implants containing byproduct material. Available at www.nrc.gov/reading-rm/doc-collections/cfr. Accessed 10 Oct 2017.

  53. Nĕmec J, Röhling S, Zamrazil V, Pohunková D. Comparison of the distribution of diagnostic and thyroablative I-131 in the evaluation of differentiated thyroid cancers. J Nucl Med. 1979;20:92–7.

    PubMed  Google Scholar 

  54. Waxman A, Ramanna L, Chapman N, Chapman D, Brachman M, Tanasescu D, et al. The significance of 1-131 scan dose in patients with thyroid cancer: determination of ablation: concise communication. J Nucl Med. 1981;22:861–5.

    CAS  PubMed  Google Scholar 

  55. Ciappuccini R, Heutte N, Trzepla G, Rame J-P, Vaur D, Aide N, et al. Postablation (131)I scintigraphy with neck and thorax SPECT-CT and stimulated serum thyroglobulin level predict the outcome of patients with differentiated thyroid cancer. Eur J Endocrinol. 2011;164:961–9.

    Article  CAS  PubMed  Google Scholar 

  56. Goolden AW, Kam KC, Fitzpatrick ML, Munro AJ. Oedema of the neck after ablation of the thyroid with radioactive iodine. Br J Radiol. 1986;59:583–6.

    Article  CAS  PubMed  Google Scholar 

  57. Kloos RT, Duvuuri V, Jhiang SM, Cahill KV, Foster JA, Burns JA. Nasolacrimal drainage system obstruction from radioactive iodine therapy for thyroid carcinoma. J Clin Endocrinol Metab. 2002;87:5817–20.

    Article  CAS  PubMed  Google Scholar 

  58. Dottorini ME. Genetic risk assessment after iodine-131 exposure: an opportunity and obligation for nuclear medicine. J Nucl Med. 1996;37:612–5.

    CAS  PubMed  Google Scholar 

  59. Klubo-Gwiezdzinska J, Van Nostrand D, Burman KD, Vasko V, Chia S, Deng T, et al. Salivary gland malignancy and radioiodine therapy for thyroid cancer. Thyroid. 2010;20:647–51.

    Article  CAS  PubMed  Google Scholar 

  60. Lee SL. Complications of radioactive iodine treatment of thyroid carcinoma. J Natl Compr Cancer Netw. 2010;8:1277–86. quiz 1287.

    Article  Google Scholar 

  61. Verburg FA, Hänscheid H, Biko J, Hategan MC, Lassmann M, Kreissl MC, et al. Dosimetry-guided high-activity (131)I therapy in patients with advanced differentiated thyroid carcinoma: initial experience. Eur J Nucl Med Mol Imaging. 2010;37:896–903.

    Article  PubMed  Google Scholar 

  62. Van Nostrand D, Freitas J. Side effects of I-131 for ablation and treatment of Well- differentiated thyroid carcinoma. In: Wartofsky L, Van Nostrand D, editors. Thyroid Cancer: A Comprehensive Guide to Clinical Management. Totowa, NJ: Humana Press; 2006. p. 459–84.

    Chapter  Google Scholar 

  63. Van Nostrand D, Neutze J, Atkins F. Side effects of “rational dose” iodine-131 therapy for metastatic well-differentiated thyroid carcinoma. J Nucl Med. 1986;27:1519–27.

    PubMed  Google Scholar 

  64. Sawka AM, Lakra DC, Lea J, Alshehri B, Tsang RW, Brierley JD, et al. A systematic review examining the effects of therapeutic radioactive iodine on ovarian function and future pregnancy in female thyroid cancer survivors. Clin Endocrinol (Oxf). 2008;69:479–90.

    Article  Google Scholar 

  65. Sawka AM, Lea J, Alshehri B, Straus S, Tsang RW, Brierley JD, et al. A systematic review of the gonadal effects of therapeutic radioactive iodine in male thyroid cancer survivors. Clin Endocrinol (Oxf). 2008;68:610–7.

    Article  Google Scholar 

  66. Garsi J-P, Schlumberger M, Rubino C, Ricard M, Labbé M, Ceccarelli C, et al. Therapeutic administration of 131I for differentiated thyroid cancer: radiation dose to ovaries and outcome of pregnancies. J Nucl Med. 2008;49:845–52.

    Article  PubMed  Google Scholar 

  67. Dottorini ME, Lomuscio G, Mazzucchelli L, Vignati A, Colombo L. Assessment of female fertility and carcinogenesis after iodine-131 therapy for differentiated thyroid carcinoma. J Nucl Med. 1995;36:21–7.

    CAS  PubMed  Google Scholar 

  68. Vini L, Hyer S, Al-Saadi A, Pratt B, Harmer C. Prognosis for fertility and ovarian function after treatment with radioiodine for thyroid cancer. Postgrad Med J. 2002;78:92–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rosário PWS, Barroso AL, Rezende LL, Padrão EL, Borges MAR, Guimarães VC, et al. Testicular function after radioiodine therapy in patients with thyroid cancer. Thyroid. 2006;16:667–70.

    Article  PubMed  Google Scholar 

  70. Wallace WHB. Oncofertility and preservation of reproductive capacity in children and young adults. Cancer. 2011;117:2301–10.

    Article  PubMed  Google Scholar 

  71. Baugnet-Mahieu L, Lemaire M, Léonard ED, Léonard A, Gerber GB. Chromosome aberrations after treatment with radioactive iodine for thyroid cancer. Radiat Res. 1994;140:429–31.

    Article  CAS  PubMed  Google Scholar 

  72. Puerto S, Marcos R, Ramírez MJ, Galofré P, Creus A, Surrallés J. Equal induction and persistence of chromosome aberrations involving chromosomes 1, 4 and 10 in thyroid cancer patients treated with radioactive iodine. Mutat Res. 2000;469:147–58.

    Article  CAS  PubMed  Google Scholar 

  73. Richter HE, Lohrer HD, Hieber L, Kellerer AM, Lengfelder E, Bauchinger M. Microsatellite instability and loss of heterozygosity in radiation-associated thyroid carcinomas of Belarussian children and adults. Carcinogenesis. 1999;20:2247–52.

    Article  CAS  PubMed  Google Scholar 

  74. Sawka AM, Thabane L, Parlea L, Ibrahim-Zada I, Tsang RW, Brierley JD, et al. Second primary malignancy risk after radioactive iodine treatment for thyroid cancer: a systematic review and meta-analysis. Thyroid. 2009;19:451–7.

    Article  CAS  PubMed  Google Scholar 

  75. Rall JE, Alpers JB, Lewallen CG, Sonenberg M, Berman M, Rawson RW. Radiation pneumonitis and fibrosis: a complication of radioiodine treatment of pulmonary metastases from cancer of the thyroid. J Clin Endocrinol Metab. 1957;17:1263–76.

    Article  CAS  PubMed  Google Scholar 

  76. Van Nostrand D, Atkins F, Yeganeh F, Acio E, Bursaw R, Wartofsky L. Dosimetrically determined doses of radioiodine for the treatment of metastatic thyroid carcinoma. Thyroid. 2002;12:121–34.

    Article  PubMed  Google Scholar 

  77. Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev. 2010;36:277–85.

    Article  PubMed  Google Scholar 

  78. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007;369:2106–20.

    Article  CAS  PubMed  Google Scholar 

  79. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am. 2008;55:97–120. x.

    Article  PubMed  Google Scholar 

  80. Sharp SE, Gelfand MJ, Shulkin BL. Pediatrics: diagnosis of neuroblastoma. Semin Nucl Med. 2011;41:345–53.

    Article  PubMed  Google Scholar 

  81. Brisse HJ, McCarville MB, Granata C, Krug KB, Wootton-Gorges SL, Kanegawa K, et al. Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project. Radiology. 2011;261:243–57.

    Article  PubMed  Google Scholar 

  82. Cohn SL, Pearson ADJ, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27:289–97.

    Article  PubMed  PubMed Central  Google Scholar 

  83. DuBois SG, Kalika Y, Lukens JN, Brodeur GM, Seeger RC, Atkinson JB, et al. Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol. 1999;21:181–9.

    Article  CAS  PubMed  Google Scholar 

  84. Brodeur GM, Seeger RC, Barrett A, Berthold F, Castleberry RP, D’Angio G, et al. International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol. 1988;6:1874–81.

    Article  CAS  PubMed  Google Scholar 

  85. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11:1466–77.

    Article  CAS  PubMed  Google Scholar 

  86. Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. 2009;27:298–303.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363:1324–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med. 1999;341:1165–73.

    Article  CAS  PubMed  Google Scholar 

  89. Vik TA, Pfluger T, Kadota R, Castel V, Tulchinsky M, Farto JCA, et al. (123)I-mIBG scintigraphy in patients with known or suspected neuroblastoma: results from a prospective multicenter trial. Pediatr. Blood Cancer. 2009;52:784–90.

    Article  Google Scholar 

  90. Wieland DM, Wu J, Brown LE, Mangner TJ, Swanson DP, Beierwaltes WH. Radiolabeled adrenergi neuron-blocking agents: adrenomedullary imaging with [131I]iodobenzylguanidine. J Nucl Med. 1980;21:349–53.

    CAS  PubMed  Google Scholar 

  91. Wieland DM, Brown LE, Tobes MC, Rogers WL, Marsh DD, Mangner TJ, et al. Imaging the primate adrenal medulla with [123I] and [131I] meta-iodobenzylguanidine: concise communication. J Nucl Med. 1981;22:358–64.

    CAS  PubMed  Google Scholar 

  92. Sisson J, Shapiro B, Beierwaltes WH, Nakajo M, Glowniak J, Mangner T, et al. Treatment of malignant pheochromocytoma with a new radiopharmaceutical. Trans Assoc Am Physicians. 1983;96:209–17.

    CAS  PubMed  Google Scholar 

  93. Treuner J, Klingebiel T, Feine U, Buck J, Bruchelt G, Dopfer R, et al. Clinical experiences in the treatment of neuroblastoma with 131I-metaiodobenzylguanidine. Pediatr Hematol Oncol. 1986;3:205–16.

    Article  CAS  PubMed  Google Scholar 

  94. Buck J, Bruchelt G, Girgert R, Treuner J, Niethammer D. Specific uptake of m-[125I]iodobenzylguanidine in the human neuroblastoma cell line SK-N-SH. Cancer Res. 1985;45:6366–70.

    CAS  PubMed  Google Scholar 

  95. Jaques S, Tobes MC, Sisson JC, Baker JA, Wieland DM. Comparison of the sodium dependency of uptake of meta-lodobenzylguanidine and norepinephrine into cultured bovine adrenomedullary cells. Mol Pharmacol. 1984;26:539–46.

    CAS  PubMed  Google Scholar 

  96. Jaques S, Tobes MC, Sisson JC. Sodium dependency of uptake of norepinephrine and m-iodobenzylguanidine into cultured human pheochromocytoma cells: evidence for uptake-one. Cancer Res. 1987;47:3920–8.

    PubMed  Google Scholar 

  97. Tobes MC, Jaques S, Wieland DM, Sisson JC. Effect of uptake-one inhibitors on the uptake of norepinephrine and metaiodobenzylguanidine. J Nucl Med. 1985;26:897–907.

    CAS  PubMed  Google Scholar 

  98. Smets LA, Loesberg C, Janssen M, Metwally EA, Huiskamp R. Active uptake and extravesicular storage of m-iodobenzylguanidine in human neuroblastoma SK-N-SH cells. Cancer Res. 1989;49:2941–4.

    CAS  PubMed  Google Scholar 

  99. Gaze MN, Huxham IM, Mairs RJ, Barrett A. Intracellular localization of metaiodobenzyl guanidine in human neuroblastoma cells by electron spectroscopic imaging. Int J Cancer. 1991;47:875–80.

    Article  CAS  PubMed  Google Scholar 

  100. Lashford LS, Hancock JP, Kemshead JT. Meta-iodobenzylguanidine (mIBG) uptake and storage in the human neuroblastoma cell line SK-N-BE(2C). Int J Cancer. 1991;47:105–9.

    Article  CAS  PubMed  Google Scholar 

  101. Wilson JS, Gains JE, Moroz V, Wheatley K, Gaze MN. A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma. Eur J Cancer. 2014;50:801–15.

    Article  CAS  PubMed  Google Scholar 

  102. Claudiani F, Garaventa A, Bertolazzi L, Villavecchia GP, Cabria M, Scopinaro G, et al. [131I]metaiodobenzylguanidine therapy in advanced neuroblastoma. J Nucl Biol Med. 1991;35:224–7.

    CAS  PubMed  Google Scholar 

  103. DuBois SG, Messina J, Maris JM, Huberty J, Glidden DV, Veatch J, et al. Hematologic toxicity of high-dose iodine-131-metaiodobenzylguanidine therapy for advanced neuroblastoma. J Clin Oncol. 2004;22:2452–60.

    Article  CAS  PubMed  Google Scholar 

  104. Garaventa A, Bellagamba O, Lo Piccolo MS, Milanaccio C, Lanino E, Bertolazzi L, et al. 131I-metaiodobenzylguanidine (131I-MIBG) therapy for residual neuroblastoma: a mono-institutional experience with 43 patients. Br J Cancer. 1999;81:1378–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hutchinson RJ, Sisson JC, Miser JS, Zasadny KR, Normolle DP, Shulkin BL, et al. Long-term results of [131I]metaiodobenzylguanidine treatment of refractory advanced neuroblastoma. J Nucl Biol Med. 1991;35:237–40.

    CAS  PubMed  Google Scholar 

  106. Hutchinson RJ, Sisson JC, Shapiro B, Miser JS, Normole D, Shulkin BL, et al. 131-I-metaiodobenzylguanidine treatment in patients with refractory advanced neuroblastoma. Am J Clin Oncol. 1992;15:226–32.

    Article  CAS  PubMed  Google Scholar 

  107. Hoefnagel CA, Voûte PA, De Kraker J, Valdés Olmos RA. [131I]metaiodobenzylguanidine therapy after conventional therapy for neuroblastoma. J Nucl Biol Med. 1991;35:202–6.

    CAS  PubMed  Google Scholar 

  108. Kang TI, Brophy P, Hickeson M, Heyman S, Evans AE, Charron M, et al. Targeted radiotherapy with submyeloablative doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma. J Pediatr Hematol Oncol. 2003;25:769–73.

    Article  PubMed  Google Scholar 

  109. Klingebiel T, Feine U, Treuner J, Reuland P, Handgretinger R, Niethammer D. Treatment of neuroblastoma with [131I]metaiodobenzylguanidine: long-term results in 25 patients. J Nucl Biol Med. 1991;35:216–9.

    CAS  PubMed  Google Scholar 

  110. Lashford LS, Lewis IJ, Fielding SL, Flower MA, Meller S, Kemshead JT, et al. Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom Children’s Cancer Study Group investigation. J Clin Oncol. 1992;10:1889–96.

    Article  CAS  PubMed  Google Scholar 

  111. Lumbroso J, Hartmann O, Schlumberger M. Therapeutic use of [131I]metaiodobenzylguanidine in neuroblastoma: a phase II study in 26 patients. “Société Française d’Oncologie Pédiatrique” and Nuclear Medicine Co-investigators. J Nucl Biol Med. 1991;35:220–3.

    CAS  PubMed  Google Scholar 

  112. Matthay KK, Huberty JP, Hattner RS, Ablin AR, Engelstad BL, Zoger S, et al. Efficacy and safety of [131I]metaiodobenzylguanidine therapy for patients with refractory neuroblastoma. J Nucl Biol Med. 1991;35:244–7.

    CAS  PubMed  Google Scholar 

  113. Troncone L, Rufini V, Riccardi R, Lasorella A, Mastrangelo R. The use of [131I]metaiodobenzylguanidine in the treatment of neuroblastoma after conventional therapy. J Nucl Biol Med. 1991;35:232–6.

    CAS  PubMed  Google Scholar 

  114. Matthay KK, Yanik G, Messina J, Quach A, Huberty J, Cheng S-C, et al. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol. 2007;25:1054–60.

    Article  CAS  PubMed  Google Scholar 

  115. Howard JP, Maris JM, Kersun LS, Huberty JP, Cheng S-C, Hawkins RA, et al. Tumor response and toxicity with multiple infusions of high dose 131I-MIBG for refractory neuroblastoma. Pediatr Blood Cancer. 2005;44:232–9.

    Article  PubMed  Google Scholar 

  116. Johnson K, McGlynn B, Saggio J, Baniewicz D, Zhuang H, Maris JM, et al. Safety and efficacy of tandem 131I-metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma. Pediatr Blood Cancer. 2011;57:1124–9.

    Article  PubMed  Google Scholar 

  117. Matthay KK, Quach A, Huberty J, Franc BL, Hawkins RA, Jackson H, et al. Iodine-131--metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol. 2009;27:1020–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Yanik GA, Villablanca JG, Maris JM, Weiss B, Groshen S, Marachelian A, et al. 131I-metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. A new approaches to neuroblastoma therapy (NANT) phase II study. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transpl. 2015;21:673–81.

    Article  CAS  Google Scholar 

  119. Klingebiel T, Bader P, Bares R, Beck J, Hero B, Jürgens H, et al. Treatment of neuroblastoma stage 4 with 131I-meta-iodo-benzylguanidine, high-dose chemotherapy and immunotherapy. A pilot study. Eur J Cancer. 1998;34:1398–402.

    Article  CAS  PubMed  Google Scholar 

  120. Parisi MT, Eslamy H, Park JR, Shulkin BL, Yanik GA. 131I-Metaiodobenzylguanidine theranostics in neuroblastoma: historical perspectives; practical applications. Semin Nucl Med. 2016;46:184–202.

    Article  PubMed  Google Scholar 

  121. Streby KA, Shah N, Ranalli MA, Kunkler A, Cripe TP. Nothing but NET: a review of norepinephrine transporter expression and efficacy of 131I-mIBG therapy. Pediatr Blood Cancer. 2015;62:5–11.

    Article  CAS  PubMed  Google Scholar 

  122. De Kraker J, Hoefnagel CA, Caron H, Valdés Olmos RA, Zsiros J, Heij HA, et al. First line targeted radiotherapy, a new concept in the treatment of advanced stage neuroblastoma. Eur J Cancer. 1995;31A:600–2.

    Article  PubMed  Google Scholar 

  123. Mastrangelo S, Rufini V, Ruggiero A, Di Giannatale A, Riccardi R. Treatment of advanced neuroblastoma in children over 1 year of age: the critical role of 131I-metaiodobenzylguanidine combined with chemotherapy in a rapid induction regimen. Pediatr Blood Cancer. 2011;56:1032–40.

    Article  PubMed  Google Scholar 

  124. de Kraker J, Hoefnagel KA, Verschuur AC, van Eck B, van Santen HM, Caron HN. Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age. Eur J Cancer. 2008;44:551–6.

    Article  PubMed  CAS  Google Scholar 

  125. Hoefnagel CA, De Kraker J, Valdés Olmos RA, Voûte PA. 131I-MIBG as a first-line treatment in high-risk neuroblastoma patients. Nucl Med Commun. 1994;15:712–7.

    Article  CAS  PubMed  Google Scholar 

  126. Kraal KCJM, Bleeker GM, van Eck-Smit BLF, van Eijkelenburg NKA, Berthold F, van Noesel MM, et al. Feasibility, toxicity and response of upfront metaiodobenzylguanidine therapy therapy followed by German Pediatric Oncology Group Neuroblastoma 2004 protocol in newly diagnosed stage 4 neuroblastoma patients. Eur J Cancer. 2017;76:188–96.

    Article  CAS  PubMed  Google Scholar 

  127. DuBois SG, Matthay KK. Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma. Nucl Med Biol. 2008;35(Suppl 1):S35–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Grünwald F, Ezziddin S. 131I-metaiodobenzylguanidine therapy of neuroblastoma and other neuroendocrine tumors. Semin Nucl Med. 2010;40:153–63.

    Article  PubMed  Google Scholar 

  129. Sharp SE, Trout AT, Weiss BD, Gelfand MJ. MIBG in neuroblastoma diagnostic imaging and therapy. Radiogr Rev. 2016;36:258–78.

    Google Scholar 

  130. Shusterman S, Grant FD, Lorenzen W, Davis RT, Laffin S, Drubach LA, et al. Iodine-131-labeled meta-iodobenzylguanidine therapy of children with neuroblastoma: program planning and initial experience. Semin Nucl Med. 2011;41:354–63.

    Article  PubMed  Google Scholar 

  131. Taggart D, Dubois S, Matthay KK. Radiolabeled metaiodobenzylguanidine for imaging and therapy of neuroblastoma. Q J Nucl Med Mol Imaging. 2008;52:403–18.

    CAS  PubMed  Google Scholar 

  132. Giammarile F, Lumbroso J, Ricard M, Aubert B, Hartmann O, Schlumberger M, et al. Radioiodinated metaiodobenzylguanidine in neuroblastoma: influence of high dose on tumour site detection. Eur J Nucl Med. 1995;22:1180–3.

    Article  CAS  PubMed  Google Scholar 

  133. Hickeson MP, Charron M, Maris JM, Brophy P, Kang TI, Zhuang H, et al. Biodistribution of post-therapeutic versus diagnostic (131)I-MIBG scans in children with neuroblastoma. Pediatr Blood Cancer. 2004;42:268–74.

    Article  PubMed  Google Scholar 

  134. Parisi MT, Matthay KK, Huberty JP, Hattner RS. Neuroblastoma: dose-related sensitivity of MIBG scanning in detection. Radiology. 1992;184:463–7.

    Article  CAS  PubMed  Google Scholar 

  135. Markelewicz RJ, Lorenzen WA, Shusterman S, Grant FD, Fahey FH, Treves ST. Radiation exposure to family caregivers and nurses of pediatric neuroblastoma patients receiving 131I-metaiodobenzylguanidine (131I-MIBG) therapy. Clin Nucl Med. 2013;38:604–7.

    Article  PubMed  Google Scholar 

  136. Wong T, Matthay KK, Boscardin WJ, Hawkins RA, Brakeman PR, DuBois SG. Acute changes in blood pressure in patients with neuroblastoma treated with 131I-metaiodobenzylguanidine (MIBG). Pediatr Blood Cancer. 2013;60:1424–30.

    Article  CAS  PubMed  Google Scholar 

  137. Polishchuk AL, Dubois SG, Haas-Kogan D, Hawkins R, Matthay KK. Response, survival, and toxicity after iodine-131-metaiodobenzylguanidine therapy for neuroblastoma in preadolescents, adolescents, and adults. Cancer. 2011;117:4286–93.

    Article  CAS  PubMed  Google Scholar 

  138. Clement SC, Van Eck-Smit BLF, Van Trotsenburg ASP, Kremer LCM, Tytgat GAM, Van Santen HM. Long-term follow-up of the thyroid gland after treatment with 131I-Metaiodobenzylguanidine in children with neuroblastoma: importance of continuous surveillance. Pediatr Blood Cancer. 2013;60:1833–8.

    Article  CAS  PubMed  Google Scholar 

  139. Weiss B, Vora A, Huberty J, Hawkins RA, Matthay KK. Secondary myelodysplastic syndrome and leukemia following 131I-metaiodobenzylguanidine therapy for relapsed neuroblastoma. J Pediatr Hematol Oncol. 2003;25:543–7.

    Article  PubMed  Google Scholar 

  140. Garaventa A, Gambini C, Villavecchia G, Di Cataldo A, Bertolazzi L, Pizzitola MR, et al. Second malignancies in children with neuroblastoma after combined treatment with 131I-metaiodobenzylguanidine. Cancer. 2003;97:1332–8.

    Article  CAS  PubMed  Google Scholar 

  141. Albers AR, O’Dorisio MS, Balster DA, Caprara M, Gosh P, Chen F, et al. Somatostatin receptor gene expression in neuroblastoma. Regul Pept. 2000;88:61–73.

    Article  CAS  PubMed  Google Scholar 

  142. Frühwald MC, O’Dorisio MS, Pietsch T, Reubi JC. High expression of somatostatin receptor subtype 2 (sst2) in medulloblastoma: implications for diagnosis and therapy. Pediatr Res. 1999;45:697–708.

    Article  PubMed  Google Scholar 

  143. Menda Y, O’Dorisio MS, Kao S, Khanna G, Michael S, Connolly M, et al. Phase I trial of 90Y-DOTATOC therapy in children and young adults with refractory solid tumors that express somatostatin receptors. J Nucl Med. 2010;51:1524–31.

    Article  PubMed  Google Scholar 

  144. Gains JE, Bomanji JB, Fersht NL, Sullivan T, D’Souza D, Sullivan KP, et al. 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma. J Nucl Med. 2011;52:1041–7.

    Article  PubMed  Google Scholar 

  145. Kong G, Hofman MS, Murray WK, Wilson S, Wood P, Downie P, et al. Initial experience with gallium-68 DOTA-octreotate PET/CT and peptide receptor radionuclide therapy for pediatric patients with refractory metastatic neuroblastoma. J Pediatr Hematol Oncol. 2016;38:87–96.

    Article  CAS  PubMed  Google Scholar 

  146. Modak S, Cheung N-KV. Antibody-based targeted radiation to pediatric tumors. J Nucl Med. 2005;46(Suppl 1):157S–63S.

    PubMed  Google Scholar 

  147. Cheung NK. Monoclonal antibody-based therapy for neuroblastoma. Curr Oncol Rep. 2000;2:547–53.

    Article  CAS  PubMed  Google Scholar 

  148. Cheung NK, Kushner BH, LaQuaglia M, Kramer K, Gollamudi S, Heller G, et al. N7: a novel multi-modality therapy of high risk neuroblastoma (NB) in children diagnosed over 1 year of age. Med Pediatr Oncol. 2001;36:227–30.

    Article  CAS  PubMed  Google Scholar 

  149. Mikles B, Levine J, Gindin T, Bhagat G, Satwani P. Brentuximab vedotin (SGN-35) in a 3-year-old child with relapsed systemic anaplastic large cell lymphoma. J Pediatr Hematol Oncol. 2014;36:e85–7.

    Article  PubMed  Google Scholar 

  150. Neville KA, Rosolen A, Landman-Parker J, Aladjidi N, Beishuizen A, Daw S, et al. Phase 1/2 study of brentuximab vedotin in pediatric patients with relapsed or refractory (R/R) hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL): preliminary phase 2 data for brentuximab vedotin 1.8 Mg/Kg in the HL study arm. Blood. 2013;122:4378.

    Google Scholar 

  151. Neville K, Gore L, Mauz-Körholz C, Rosolen A, Landman-Parker J, Sanchez de Toledo J, et al. Phase I/II study of brentuximab vedotin in pediatric patients (pts) with relapsed or refractory (RR) Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL): interim phase (ph) I safety data. J Clin Oncol. 2013;31:10028.

    Google Scholar 

  152. Sorge CE, McDaniel JK, Xavier AC. Targeted therapies for the treatment of pediatric non-hodgkin lymphomas: present and future. Pharmaceuticals (Basel) 2016;9(2).

    Google Scholar 

  153. Pizer BL, Kemshead JT. The potential of targeted radiotherapy in the treatment of central nervous system leukaemia. Leuk Lymphoma. 1994;15:281–9.

    Article  CAS  PubMed  Google Scholar 

  154. Pizer B, Papanastassiou V, Hancock J, Cassano W, Coakham H, Kemshead J. A pilot study of monoclonal antibody targeted radiotherapy in the treatment of central nervous system leukaemia in children. Br J Haematol. 1991;77:466–72.

    Article  CAS  PubMed  Google Scholar 

  155. Baiu DC, Marsh IR, Boruch AE, Shahi A, Bhattacharya S, Jeffery JJ, et al. Targeted molecular radiotherapy of pediatric solid tumors using a radioiodinated alkyl-phospholipid ether analog. J Nucl Med. 2018;59:244. https://doi.org/10.2967/jnumed.117.193748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiology, Boston Children’s Hospital, Boston, MA, USA

    Neha S. Kwatra

  2. Department of Radiology, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, WA, USA

    Marguerite T. Parisi

  3. Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Barry L. Shulkin

Authors
  1. Neha S. Kwatra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marguerite T. Parisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barry L. Shulkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Neha S. Kwatra .

Editor information

Editors and Affiliations

  1. Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Stephan D. Voss

  2. Department of Radiology, Great Ormond Street Hospital for Children, London, UK

    Kieran McHugh

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

Kwatra, N.S., Parisi, M.T., Shulkin, B.L. (2019). Radioisotope Therapies: Iodine-131, I-131-MIBG, and Beyond. In: Voss, S., McHugh, K. (eds) Imaging in Pediatric Oncology. Pediatric Oncology. Springer, Cham. https://doi.org/10.1007/978-3-030-03777-2_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-03777-2_14

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-03776-5

  • Online ISBN: 978-3-030-03777-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation