Is there a benefit of 131I-MIBG therapy in the treatment of children with stage 4 neuroblastoma?

M. Schmidt; T. Simon; B. Hero; W. Eschner; M. Dietlein; F. Sudbrock; R. Bongartz; F. Berthold; H. Schicha

doi:10.1055/s-0038-1625111

Nuklearmedizin - NuclearMedicine, Inhaltsverzeichnis

Nuklearmedizin 2006; 45(04): 145-151
DOI: 10.1055/s-0038-1625111

Original Articles

Schattauer GmbH

Is there a benefit of ¹³¹I-MIBG therapy in the treatment of children with stage 4 neuroblastoma?

A retrospective evaluation of The German Neuroblastoma Trial NB97 and implications for the The German Neuroblastoma Trial NB2004Gibt es einen Nutzen durch die ¹³¹I-MIBG-Therapie bei der Behandlung von Kindern mit Neuroblastom Stadium 4?Eine retrospektive Datenanalyse der Deutschen Neuroblastom- Studie NB97 und Auswirkungen auf die Nachfolgestudie NB2004

M. Schmidt

¹Department of Nuclear Medicine

,

T. Simon

²Children’s Hospital

,

B. Hero

²Children’s Hospital

,

W. Eschner

¹Department of Nuclear Medicine

,

M. Dietlein

¹Department of Nuclear Medicine

,

F. Sudbrock

¹Department of Nuclear Medicine

,

R. Bongartz

³Department of Radiotherapy University of Cologne, Germany

,

F. Berthold

²Children’s Hospital

,

H. Schicha

¹Department of Nuclear Medicine

› Institutsangaben

Abstract

Summary

Aim: ¹³¹I-meta-iodobenzylguanidine (¹³¹I-MIBG) therapy has been used in neuroblastoma treatment for many years but its value in high intensive first line treatment protocols is not exactly known. Patients, methods: Stage 4 neuroblastoma patients >1 year with ¹²³I-MIBG positive residual disease (primary tumour and/or metastasis) after complete induction chemotherapy according to the German neuroblastoma trial NB97 were retrospectively analyzed. Results: One-hundred-eleven patients had ¹²³I-MIBG positive residual disease after complete induction chemotherapy. Forty patients received ¹³¹I-MIBG therapy using a median activity of 0.44 GBq/kg body weight. By univariate analysis, patients who underwent ¹³¹I-MIBG therapy had a better 3-year event free survival (3-y-EFS 46±8%) and 3-year overall survival (3-y-OS 58±9%) than 71 patients without ¹³¹I-MIBG therapy (3-y-EFS 19±5%, p=0.003; 3-y-OS 43±6%, p=0.037). However, subgroup analysis of 66 patients who underwent high dose chemotherapy with autologous stem cell transplantation (ASCT) during treatment found a very similar outcome with ¹³¹I-MIBG therapy (3-y-EFS 49±9%, 3-y-OS 59±10%) and without ¹³¹I-MIBG therapy (3-y-EFS 33±9%, p=0.171; 3-y-OS 59±9%, p=0.285) due to the dominating effect of ASCT. By multivariate analysis, ¹³¹I-MIBG therapy had no impact on EFS (p=0.494) and OS (p=0.891). Only ASCT, external beam radiation therapy and MYCN amplification were important for EFS and OS. Conclusions: An independent advantage of I-131-MIBG therapy could not be proven in this retrospective analysis. The ongoing German Neuroblastoma Trial NB2004 will address the influence of ¹³¹I-MIBG therapy with emphasis on tumour dosimetry.

Zusammenfassung

Ziel: Die Therapie mit ¹³¹I-Metaiodbenzylguanidin (¹³¹I-MIBG) wird seit Jahren zur Behandlung des Neuroblastoms praktiziert. Der Wert dieses Therapieelements im Rahmen einer hochintensiven Erstbehandlung ist nicht geklärt. Patienten, Methoden: Stadium-4-Neuroblastompatienten im Alter >1 Jahr, die am Ende der kompletten Induktionschemotherapie der Deutschen Neuroblastom- Studie NB97 noch ¹²³I-MIBG-positives residuelles Tumorgewebe (Primärtumor und/oder Metastasen) hatten, wurden retrospektiv ausgewertet. Ergebnisse: 111 Patienten hatten ¹²³I-MIBG-positives residuelles Tumorgewebe nach abgeschlossener Induktionschemotherapie. 40 Patienten erhielten eine ¹³¹I-MIBG-Therapie unter Verwendung einer medianen Aktivität von 0,44 GBq/kg Körpergewicht. Die univariate Analyse zeigte eine bessere 3-Jahres-Rate für das krankheitsfreie Überleben (3-y-EFS 46±8%) und für das Gesamtüberleben (3-y-OS 58±9%) für die Patienten mit ¹³¹I-MIBG-Therapie verglichen mit 71 Patienten ohne ¹³¹I-MIBG-Therapie (3-y-EFS 19±5%, p=0.003; 3-y-OS 43±6%, p=0.037). Die Subgruppenanalyse der 66 Patienten, die eine Hochdosischemotherapie mit autologer Stammzelltransplantation (ASCT) erhalten hatten, zeigten jedoch eine vergleichbares Überleben mit ¹³¹I-MIBGTherapie (3-y-EFS 49±9%, 3-y-OS 59±10%) und ohne ¹³¹I-MIBG-Therapie (3-y-EFS 33±9%, p=0.171; 3-y-OS 59±9%, p=0.285) wegen des dominierenden Effekts der ASCT. In der multivariaten Analyse hatte ¹³¹I-MIBG keinen Einfluss auf das EFS (p=0,494) oder das OS (p=0,891), wichtig waren ASCT, externe Strahlentherapie und MYCN-Amplifikation. Schlussfolgerungen: Ein unabhängiger Vorteil der ¹³¹I-MIBG-Therapie konnte in dieser retrospektiven Analyse nicht bewiesen werden. Die laufende Deutsche Neuroblastom-Studie NB2004 wird den Einfluss der ¹³¹I-MIBG-Therapie untersuchen, wobei der Tumordosimetrie ein besonderer Stellenwert zukommt.

Keywords

High risk neuroblastoma - stage 4 neuroblastoma - ¹³¹I-MIBG therapy

Schlüsselwörter

Hochrisiko-Neuroblastom - Neuroblastom Stadium 4 - ¹³¹I-MIBG-Therapie

Volltext

Referenzen

References
1 Berthold F, Hero B. Neuroblastoma: current drug therapy recommendations as part of the total treatment approach. Drugs 2000; 59: 1261-77.
2 Berthold F, Hero B, Kremens B. et al. Long-term results and risk profiles of patients in five consecutive trials (1979–1997) with stage 4 neur- oblastoma over 1 year of age. Cancer Lett 2003; 197: 11-7.
3 Berthold F, Boos J, Burdach S. et al. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 2005; 6: 649-58.
4 Biermann M, Pixberg MK, Schuck A. et al. Multicenter trial differentiated thyroid carcinoma (MSDS): diminished acceptance of adjuvant external beam radiotherapy. Nuklearmedizin 2003; 42: 244-50.
5 Brodeur GM, Prichard J, Berthold F. et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993; 11: 1466-77.
6 Collett D. Strategy for model selection. In: Modelling survival data in medical research. London: Chapman and Hall; 1994: 78-83.
7 DuBois SG, Messina J, Maris JM. et al. Hematologic toxicity of high-dose iodine-131-metaiodobenzylguanidine therapy for advanced neuroblastoma. J Clin Oncol 2004; 22: 2452-60.
8 Franzius C, Lang K, Wormanns D. et al. PET/CT und PET – Einsatz in der pädiatrischen Onkologie. Der Nuklearmediziner 2004; 27: 315-23.
9 Franzius C, Riemann B, Vormoor J. et al. Metastatic neuroblastoma demonstrated by wholebody PET-CT using 11C-HED. Nuklearmedizin 2005; 44: N4-5.
10 Garaventa A, Guerra P, Arrighini A. et al. Treatment of advanced neuroblastoma with ¹³¹I-metaiodobenzylguanidine. Cancer 1991; 67: 922-8.
11 Garaventa A, Bellagamba O, Lo Piccolo MS. et al. ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) therapy for residual neuroblastoma: a mono-institutional experience with 43 patients. Br J Cancer 1999; 81: 1378-84.
12 Hoefnagel CA, Voûte PA, de Kraker J. et al. ¹³¹I-metaiodobenzylguanidine therapy after conventional therapy for neuroblastoma. J Nucl Biol Med 1991; 35: 202-6.
13 Hoefnagel CA, Lewington VJ. MIBG therapy. In: Ell PJ, Gambhir SS. (eds). Nuclear medicine in clinical diagnosis and treatment. Edinburgh, London, New York: Churchill Livingstone; 2004: 445-57.
14 Kaatsch P, Spix C. Annual report 2003. Mainz, German Childhood Cancer Registry 2004; 72.
15 Kang TI, Brophy P, Hickeson 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.
16 Klingebiel T, Bader P, Bares R. et al. Treatment of neuroblastoma stage 4 with ¹³¹I-meta-iodobenzylguanidine, high-dose chemotherapy and immunotherapy. A pilot trial. Eur J Cancer 1998; 34: 1398-402.
17 Klingebiel T, Berthold F, Treuner J. Metabenzylguanidin (MIBG) in treatment of 47 patients with neuroblastoma: results of the German Neuroblastoma Trial. Med Ped Oncol 1991; 19: 84-8.
18 Klingebiel T, Treuner J, Ehninger G. et al. ¹³¹I-metaiodobenzylguanidine in the treatment of metastatic neuroblastoma. Clinical, pharmacological and dosimetric aspects. Cancer Chemother Pharmacol 1989; 25: 143-8.
19 Knickmeier M, Matheja P, Wichter T. et al. Clinical evaluation of no-carrier-added meta-¹²³I-iodobenzylguanidine for myocardial scintigraphy. Eur J Nucl Med 2000; 27: 302-7.
20 Knickmeier M, Schäfers M, Schober O. Two years’ experience using no-carrier-added meta-¹²³I-iodobenzylguanidine in clinical studies. Eur J Nucl Med 2001; 28: 1437.
21 Lashford LS, Lewis IJ, Fielding SL. et al. Phase I/II trial of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom Children’s Cancer Trial Group investigation. J Clin Oncol 1992; 10: 1889-96.
22 Matthay KK. Intensification of therapy using hematopoietic stem-cell support for high-risk neuroblastoma. Pediatr Transplant 1999; 3 (Suppl. 01) 72-7.
23 Matthay KK, DeSantes K, Hasegawa B. et al. Phase I dose escalation of ¹³¹I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. J Clin Oncol 1998; 16: 229-36.
24 Miano M, Garaventa A, Pizzitola MR. et al. Megatherapy combining ¹³¹I metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma. Bone Marrow Transplant 2001; 27: 571-4.
25 Özer S, Dobrozemsky G, Kienast O. et al. Value of combined XCT/SPECT technology for avoiding false positive planar ¹²³I-MIBG scintigraphy. Nuklearmedizin 2004; 43: 164-70.
26 Oliver P, Colarinha P, Fettich J. et al. Guidelines for radioiodinated MIBG scintigraphy in children. Eur J Nucl Med Mol Imaging 2003; 30: BP45-50.
27 Sisson JC, Frager MS, Valk TW. et al. Scintigraphic localization of pheochromocytoma. N Engl J Med 1981; 305: 12-7.
28 Sisson JC, Shapiro B, Hutchinson RJ. et al. Survival of patients with neuroblastoma treated with 125I MIBG. Am J Clin Oncol 1996; 19: 144-8.
29 Staak JO, Dietlein M, Engert A. et al. Hodgkin´s lymphoma in nuclear medicine: diagnostic and therapeutic aspects. Nuklearmedizin 2003; 42: 19-24.
30 Troncone L, Rufini V, Montemaggi P. et al. The diagnostic and therapeutic utility of radioiodinated metaiodobenzylguanidine (MIBG). 5 years experience. Eur J Nucl Med 1990; 16: 325-35.
31 Yanik GA, Levine JE, Matthay KK. et al. Pilot trial of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. J Clin Oncol 2002; 20: 2142-9.