Targeted Alpha Particle Therapy of Peritoneal Carcinomas

  • Christof Seidl
  • Reingard Senekowitsch-Schmidtke
Part of the Medical Radiology book series (MEDRAD)


Peritoneal carcinomatosis is the most common secondary cancerous disease to affect the peritoneal cavity. It is a frequent consequence of primary cancers especially of the gastrointestinal tract and of the ovary. Prognosis of peritoneal spread of a primary carcinoma is poor because effective treatment strategies do not exist. The primary therapeutic option is cytoreductive surgery in combination with adjuvant intraperitoneal chemotherapy. However, treatment related complications and still poor survival rates suggest that alternative treatment strategies should be investigated. To improve the therapeutic outcome targeted radionuclide therapy seems a promising option. However, the overall efficacy of targeted therapy with β-emitters did not turn out to be satisfactory. Because α-particles very efficiently eradicate single tumour cells or small tumour cell nodules they represent a promising option for treatment of disseminated tumour cells and micrometastatic disease characteristic for peritoneal carcinomatosis. Actually the α-emitters 225Ac, 213Bi, 212Bi and 211At coupled to carrier molecules that specifically target tumour cells have successfully been used in experimental studies for treatment of ovarian, colon, pancreatic, breast or gastric cancer. A first clinical phase I study has been initiated to evaluate the therapeutic potential of 211At-MX35 F(ab’)2, targeting the sodium-dependent phosphate transport protein 2b which is overexpressed in more than 90% of human ovarian epithelial cancers. The results of the study suggest that intraperitoneal 211At-radioimmunotherapy of ovarian cancer patients will be efficient without significant toxicity. Therefore, in spite of current problems concerning world-wide availability, α-emitters could become indispensable with regard to optimization of strategies for tumour therapy in the future. 


Ovarian Cancer Peritoneal Carcinomatosis Cytoreductive Surgery Disseminate Tumour Cell Nude Mouse Model 
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.


  1. Alvarez RD, Partridge EE, Khazaeli MB, Plott G, Austin M, Kilgore L, Russell CD, Liu T, Grizzle WE, Schlom J, LoBuglio AF, Meredith RF (1997) Intraperitoneal radioimmunotherapy of ovarian cancer with 177Lu-CC49: a phase I/II study. Gynecol Oncol 65:94–101PubMedCrossRefGoogle Scholar
  2. Andersson H, Palm S, Lindegren S, Bäck T, Jacobsson L, Leser G, Horvath G (2001) Comparison of the therapeutic efficacy of 211At- and 131I-labelled monoclonal antibody MOv18 in nude mice with intraperitoneal growth of human ovarian cancer. Anticancer Res 21:409–412PubMedGoogle Scholar
  3. Andersson H, Cederkrantz E, Bäck T, Divgi C, Elgqvist J, Himmelman J, Horvath G, Jacobsson L, Jensen H, Lindegren S, Palm S, Hultborn R (2009) Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab’)2—a phase I study. J Nucl Med 50:1153–1160PubMedCrossRefGoogle Scholar
  4. Apostolidis C, Molinet R, Rasmussen G, Morgenstern A (2005a) Production of Ac-225 from Th-229 for targeted alpha therapy. Anal Chem 77:6288–6291PubMedCrossRefGoogle Scholar
  5. Apostolidis C, Molinet R, McGinley J, Abbas K, Möllenbeck J, Morgenstern A (2005b) Cyclotron production of Ac-225 for targeted alpha therapy. Appl Radiat Isot 62:383–387PubMedCrossRefGoogle Scholar
  6. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA (2006) Gynecologic oncology group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354:34–43PubMedCrossRefGoogle Scholar
  7. Beck R, Seidl C, Pfost B, Morgenstern A, Bruchertseifer F, Baum H, Schwaiger M, Senekowitsch-Schmidtke R (2007) 213Bi-radioimmunotherapy defeats early-stage disseminated gastric cancer in nude mice. Cancer Sci 98:1215–1222PubMedCrossRefGoogle Scholar
  8. Blankenberg FG (2003) Molecular imaging: the latest generation of contrast agents and tissue characterization techniques. J Cell Biochem 90:443–453PubMedCrossRefGoogle Scholar
  9. Bloechl S, Beck R, Seidl C, Morgenstern A, Schwaiger M, Senekowitsch-Schmidtke R (2005) Fractionated locoregional low-dose radioimmunotherapy improves survival in a mouse model of diffuse-type gastric cancer using a 213Bi-conjugated monoclonal antibody. Clin Cancer Res 11(19 Pt 2):7070s–7074sPubMedCrossRefGoogle Scholar
  10. Borchardt PE, Quadri SM, Freedman RS, Vriesendorp HM (2000) Intraperitoneal radioimmunotherapy with human monoclonal IGM in nude mice with peritoneal carcinomatosis. Cancer Biother Radiopharm 15:53–64PubMedCrossRefGoogle Scholar
  11. Borchardt PE, Yuan RR, Miederer M, McDevitt MR, Scheinberg DA (2003) Targeted actinium-225 in vivo generators for therapy of ovarian cancer. Cancer Res 63:5084–5090PubMedGoogle Scholar
  12. Buchhorn HM, Seidl C, Beck R, Saur D, Apostolidis C, Morgenstern A, Schwaiger M, Senekowitsch-Schmidtke R (2007) Non-invasive visualisation of the development of peritoneal carcinomatosis and tumour regression after 213Bi-radioimmunotherapy using bioluminescence imaging. Eur J Nucl Med Mol Imaging 34:841–849PubMedCrossRefGoogle Scholar
  13. Buchsbaum DJ, Khazaeli MB, Axworthy DB, Schultz J, Chaudhuri TR, Zinn KR, Carpenter M, LoBuglio AF (2005) Intraperitoneal pretarget radioimmunotherapy with CC49 fusion protein. Clin Cancer Res 11:8180–8185PubMedCrossRefGoogle Scholar
  14. Chouin N, Bardiès M (2011) Alpha-particle microdosimetry. Curr Radiopharm 4:266–280PubMedCrossRefGoogle Scholar
  15. Chu DZ, Lang NP, Thompson C, Osteen PK, Westbrook KC (1989) Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors. Cancer 63:364–367PubMedCrossRefGoogle Scholar
  16. Drecoll E, Gaertner FC, Miederer M, Blechert B, Vallon M, Müller JM, Alke A, Seidl C, Bruchertseifer F, Morgenstern A, Senekowitsch-Schmidtke R, Essler M (2009) Treatment of peritoneal carcinomatosis by targeted delivery of the radio-labeled tumor homing peptide Bi-DTPA-[F3]2 into the nucleus of tumour cells. PLoS ONE 4(5):e5715PubMedCentralPubMedCrossRefGoogle Scholar
  17. Elias D, Blot F, El Otmany A, Antoun S, Lasser P, Boige V, Rougier P, Ducreux M (2001) Curative treatment of peritoneal carcinomatosis arising from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer 92:71–76PubMedCrossRefGoogle Scholar
  18. Elgqvist J, Andersson H, Bäck T, Claesson I, Hultborn R, Jensen H, Johansson BR, Lindegren S, Olsson M, Palm S, Warnhammar E, Jacobsson L (2006) Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: outcome related to measured tumor size and mean absorbed dose. J Nucl Med 47:1342–1350PubMedGoogle Scholar
  19. Elgqvist J, Andersson H, Haglund E, Jensen H, Kahu H, Lindegren S, Warnhammar E, Hultborn R (2009) Intraperitoneal alpha-radioimmunotherapy in mice using different specific activities. Cancer Biother Radiopharm 24:509–513PubMedCrossRefGoogle Scholar
  20. Elgqvist J, Andersson H, Jensen H, Kahu H, Lindegren S, Warnhammar E, Hultborn R (2010) Repeated intraperitoneal alpha-radioimmunotherapy of ovarian cancer in mice. J Oncol 2010:394913PubMedCentralPubMedCrossRefGoogle Scholar
  21. Epenetos AA, Hird V, Lambert H, Mason P, Coulter C (2000) Long term survival of patients with advanced ovarian cancer treated with intraperitoneal radioimmunotherapy. Int J Gynecol Cancer 10(S1):44–46Google Scholar
  22. Esquivel J, Vidal-Jove J, Steves MA, Sugarbaker PH (1993) Morbidity and mortality of cytoreductive surgery and intraperitoneal chemotherapy. Surgery 113:631–636PubMedGoogle Scholar
  23. Essler M, Gärtner FC, Neff F, Blechert B, Senekowitsch-Schmidtke R, Bruchertseifer F, Morgenstern A, Seidl C (2012) Therapeutic efficacy and toxicity of 225Ac-labelled vs. 213Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis. Eur J Nucl Med Mol Imaging 39:602–612PubMedCrossRefGoogle Scholar
  24. Finstad CL, Lloyd KO, Federici MG, Divgi C, Venkatraman E, Barakat RR, Finn RD, Larson SM, Hoskins WJ, Humm JL (1997) Distribution of radiolabeled monoclonal antibody MX35 F(ab’)2 in tissue samples by storage phosphor screen image analysis: evaluation of antibody localization to micrometastatic disease in epithelial ovarian cancer. Clin Cancer Res 3:1433–1442PubMedGoogle Scholar
  25. Gunn AJ, Brechbiel MW, Choyke PL (2007) The emerging role of molecular imaging and targeted therapeutics in peritoneal carcinomatosis. Expert Opin Drug Deliv 4:389–402PubMedCrossRefGoogle Scholar
  26. Gustafsson AM, Bäck T, Elgqvist J, Jacobsson L, Hultborn R, Albertsson P, Morgenstern A, Bruchertseifer F, Jensen H, Lindegren S (2012) Comparison of therapeutic efficacy and biodistribution of 213Bi- and 211At-labeled monoclonal antibody MX35 in an ovarian cancer model. Nucl Med Biol 39:15–22PubMedCrossRefGoogle Scholar
  27. Haddad F, Barbet J, Chatal JF (2011) The ARRONAX project. Curr Radiopharm 4:186–196PubMedCrossRefGoogle Scholar
  28. Horak E, Hartmann F, Garmestani K, Wu C, Brechbiel M, Gansow OA, Landolfi NF, Waldmann TA (1997) Radioimmunotherapy targeting of HER2/neu oncoprotein on ovarian tumor using lead-212-DOTA-AE1. J Nucl Med 38:1944–1950PubMedGoogle Scholar
  29. Huber R, Seidl C, Schmid E, Seidenschwang S, Becker KF, Schuhmacher C, Apostolidis C, Nikula T, Kremmer E, Schwaiger M, Senekowitsch-Schmidtke R (2003) Locoregional alpha-radioimmunotherapy of intraperitoneal tumor cell dissemination using a tumor-specific monoclonal antibody. Clin Cancer Res 9(10 Pt 2):3922S–3928SPubMedGoogle Scholar
  30. Kinuya S, Li XF, Yokoyama K, Mori H, Shiba K, Watanabe N, Shuke N, Bunko H, Michigishi T, Tonami N (2003) Intraperitoneal radioimmunotherapy in treating peritoneal carcinomatosis of colon cancer in mice compared with systemic radioimmunotherapy. Cancer Sci 94:650–654PubMedCrossRefGoogle Scholar
  31. Kinuya S, Yokoyama K, Fukuoka M, Hiramatsu T, Mori H, Shiba K, Watanabe N, Shuke N, Michigishi T, Tonami N (2007) Intraperitoneal radioimmunotherapy to treat the early phase of peritoneal dissemination of human colon cancer cells in a murine model. Nucl Med Commun 28:129–133PubMedCrossRefGoogle Scholar
  32. Knogler K, Grünberg J, Zimmermann K, Cohrs S, Honer M, Ametamey S, Altevogt P, Fogel M, Schubiger PA, Novak-Hofer I (2007) Copper-67 radioimmunotherapy and growth inhibition by anti-L1-cell adhesion molecule monoclonal antibodies in a therapy model of ovarian cancer metastasis. Clin Cancer Res 13(2 Pt 1):603–611PubMedCrossRefGoogle Scholar
  33. Koppe MJ, Oyen WJ, Bleichrodt RP, Verhofstad AA, Goldenberg DM, Boerman OC (2006a) Combination therapy using gemcitabine and radioimmunotherapy in nude mice with small peritoneal metastases of colonic origin. Cancer Biother Radiopharm 21:506–514PubMedCrossRefGoogle Scholar
  34. Koppe MJ, Hendriks T, Boerman OC, Oyen WJ, Bleichrodt RP (2006b) Radioimmunotherapy is an effective adjuvant treatment after cytoreductive surgery of experimental colonic peritoneal carcinomatosis. J Nucl Med 47:1867–1874PubMedGoogle Scholar
  35. Kouloulias VE, Nikita KS, Kouvaris JR, Uzunoglu NK, Golematis VC, Papavasiliou CG, Vlahos LJ (2001) Cytoreductive surgery combined with intraoperative chemo-hyperthermia and postoperative radiotherapy in the management of advanced pancreatic adenocarcinoma: feasibility aspects and efficacy. J Hepatobiliary Pancreat Surg 8:564–570PubMedCrossRefGoogle Scholar
  36. Liersch T, Meller J, Kulle B, Behr TM, Markus P, Langer C, Ghadimi BM, Wegener WA, Kovacs J, Horak ID, Becker H, Goldenberg DM (2005) Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: five-year safety and efficacy results. J Clin Oncol 23:6763–6770PubMedCrossRefGoogle Scholar
  37. Levy AD, Shaw JC, Sobin LH (2009) Secondary tumors and tumorlike lesions of the peritoneal cavity: imaging features with pathologic correlation. Radiographics 29:347–373PubMedCrossRefGoogle Scholar
  38. Los G, van Vugt MJ, Pinedo HM (1994) Response of peritoneal solid tumours after intraperitoneal chemohyperthermia treatment with cisplatin or carboplatin. Br J Cancer 69:235–241PubMedCentralPubMedCrossRefGoogle Scholar
  39. Mahé MA, Fumoleau P, Fabbro M, Guastalla JP, Faurous P, Chauvot P, Chetanoud L, Classe JM, Rouanet P, Chatal JF (1999) A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma. Clin Cancer Res 5(10 Suppl):3249s–3253sPubMedGoogle Scholar
  40. Milenic DE, Garmestani K, Brady ED, Albert PS, Ma D, Abdulla A, Brechbiel MW (2004) Targeting of HER2 antigen for the treatment of disseminated peritoneal disease. Clin Cancer Res 10:7834–7841PubMedCrossRefGoogle Scholar
  41. Milenic DE, Garmestani K, Brady ED, Albert PS, Ma D, Abdulla A, Brechbiel MW (2005) Alpha-particle radioimmunotherapy of disseminated peritoneal disease using a (212)Pb-labeled radioimmunoconjugate targeting HER2. Cancer Biother Radiopharm 20:557–568PubMedCrossRefGoogle Scholar
  42. Milenic DE, Garmestani K, Brady ED, Albert PS, Abdulla A, Flynn J, Brechbiel MW (2007) Potentiation of high-LET radiation by gemcitabine: targeting HER2 with trastuzumab to treat disseminated peritoneal disease. Clin Cancer Res 13:1926–1935PubMedCrossRefGoogle Scholar
  43. Milenic DE, Garmestani K, Brady ED, Baidoo KE, Albert PS, Wong KJ, Flynn J, Brechbiel MW (2008) Multimodality therapy: potentiation of high linear energy transfer radiation with paclitaxel for the treatment of disseminated peritoneal disease. Clin Cancer Res 14:5108–5115PubMedCentralPubMedCrossRefGoogle Scholar
  44. Milenic DE, Brady ED, Garmestani K, Albert PS, Abdulla A, Brechbiel MW (2010) Improved efficacy of alpha-particle-targeted radiation therapy: dual targeting of human epidermal growth factor receptor-2 and tumor-associated glycoprotein 72. Cancer 116(4 Suppl):1059–1066PubMedCrossRefGoogle Scholar
  45. Oei AL, Verheijen RH, Seiden MV, Benigno BB, Lopes A, Soper JT, Epenetos AA, Massuger LF (2007) Decreased intraperitoneal disease recurrence in epithelial ovarian cancer patients receiving intraperitoneal consolidation treatment with yttrium-90-labeled murine HMFG1 without improvement in overall survival. Int J Cancer 120:2710–2714PubMedCrossRefGoogle Scholar
  46. Palm S, Bäck T, Claesson I, Danielsson A, Elgqvist J, Frost S, Hultborn R, Jensen H, Lindegren S, Jacobsson L (2007) Therapeutic efficacy of astatine-211-labeled trastuzumab on radioresistant SKOV-3 tumors in nude mice. Int J Radiat Oncol Biol Phys 69:572–579PubMedCrossRefGoogle Scholar
  47. Rubin SC, Kostakoglu L, Divgi C, Federici MG, Finstad CL, Lloyd KO, Larson SM, Hoskins WJ (1993) Biodistribution and intraoperative evaluation of radiolabeled monoclonal antibody MX35 in patients with epithelial ovarian cancer. Gynecol Oncol 51:61–66PubMedCrossRefGoogle Scholar
  48. Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire M, Baulieux J, Fontaumard E, Brachet A, Caillot JL, Faure JL, Porcheron J, Peix JL, François Y, Vignal J, Gilly FN (2000) Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 88:358–363PubMedCrossRefGoogle Scholar
  49. Seidl C, Senekowitsch-Schmidtke R (2008) Treatment of diffuse-type gastric cancer cells using 213Bi-radioimmunoconjugates in vitro and in vivo following intraperitoneal dissemination. Curr Radiopharm 1:215–224CrossRefGoogle Scholar
  50. Seidl C, Zöckler C, Beck R, Quintanilla-Martinez L, Bruchertseifer F, Senekowitsch-Schmidtke R (2011) 177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi. Eur J Nucl Med Mol Imaging 38:312–322PubMedCrossRefGoogle Scholar
  51. Senekowitsch-Schmidtke R, Schuhmacher C, Becker KF, Nikula TK, Seidl C, Becker I, Miederer M, Apostolidis C, Adam C, Huber R, Kremmer E, Fischer K, Schwaiger M (2001) Highly specific tumor binding of a 213Bi-labeled monoclonal antibody against mutant E-cadherin suggests its usefulness for locoregional alpha-radioimmunotherapy of diffuse-type gastric cancer. Cancer Res 61:2804–2808PubMedGoogle Scholar
  52. Sgouros G, Hobbs RF, Song H (2011) Modelling and dosimetry for alpha-particle therapy. Curr Radiopharm 4:261–265PubMedCrossRefGoogle Scholar
  53. Sharkey RM, Goldenberg DM (2006) Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA Cancer J Clin 56:226–243PubMedCrossRefGoogle Scholar
  54. Song EY, Qu CF, Rizvi SM, Raja C, Beretov J, Morgenstern A, Apostolidis C, Bruchertseifer F, Perkins A, Allen BJ (2008) Bismuth-213 radioimmunotherapy with C595 anti-MUC1 monoclonal antibody in an ovarian cancer ascites model. Cancer Biol Ther 7:76–80PubMedCrossRefGoogle Scholar
  55. Stewart JS, Hird V, Sullivan M, Snook D, Epenetos AA (1989) Intraperitoneal radioimmunotherapy for ovarian cancer. Br J Obstet Gynaecol 96:529–536PubMedCrossRefGoogle Scholar
  56. Street HH, Goris ML, Fisher GA, Wessels BW, Cho C, Hernandez C, Zhu HJ, Zhang Y, Nangiana JS, Shan JS, Roberts K, Knox SJ (2006) Phase I study of 131I-chimeric(ch) TNT-1/B monoclonal antibody for the treatment of advanced colon cancer. Cancer Biother Radiopharm 21:243–256PubMedCrossRefGoogle Scholar
  57. Verheijen RH, Massuger LF, Benigno BB, Epenetos AA, Lopes A, Soper JT, Markowska J, Vyzula R, Jobling T, Stamp G, Spiegel G, Thurston D, Falke T, Lambert J, Seiden MV (2006) Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol 24:571–578PubMedCrossRefGoogle Scholar
  58. Verwaal VJ, van Tinteren H, Ruth SV, Zoetmulder FA (2004) Toxicity of cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy. J Surg Oncol 85:61–67PubMedCrossRefGoogle Scholar
  59. Yin BW, Kiyamova R, Chua R, Caballero OL, Gout I, Gryshkova V, Bhaskaran N, Souchelnytskyi S, Hellman U, Filonenko V, Jungbluth AA, Odunsi K, Lloyd KO, Old LJ, Ritter G (2008) Monoclonal antibody MX35 detects the membrane transporter NaPi2b (SLC34A2) in human carcinomas. Cancer Immun 8:3PubMedCentralPubMedGoogle Scholar
  60. Yong KJ, Milenic DE, Baidoo KE, Brechbiel MW (2012) 212Pb-radioimmunotherapy induces G2 cell-cycle arrest and delays DNA damage repair in tumor xenografts in a model for disseminated intraperitoneal disease. Mol Cancer Ther 11:639–648PubMedCentralPubMedCrossRefGoogle Scholar
  61. Zalutsky MR, Reardon DA, Pozzi OR, Vaidyanathan G, Bigner DD (2007) Targeted alpha-particle radiotherapy with 211At-labeled monoclonal antibodies. Nucl Med Biol 34:779–785PubMedCentralPubMedCrossRefGoogle Scholar
  62. Zielinska B, Apostolidis C, Bruchertseifer F, Morgenstern A (2007) An improved method for the production of Ac-225/Bi-213 from Th-229 for targeted alpha therapy. Solvent Extr Ion Exch 25:339–349CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Christof Seidl
    • 1
  • Reingard Senekowitsch-Schmidtke
    • 1
  1. 1.Department of Nuclear MedicineTechnische Universität MünchenMunichGermany

Personalised recommendations