|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5321-5324 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.3331
Successful Antiangiogenic Therapy for Neuroblastoma With ThalidomideDepartment of Bone Marrow Transplantation & Cancer Immunotherapy, Hadassah University Hospital, Jerusalem, Israel
Department of Pediatric Hematology & Oncology, Soroka Medical Center, Beersheba, Israel
Department of Bone Marrow Transplantation & Cancer Immunotherapy, Hadassah University Hospital, Jerusalem, Israel
Children's Hospital and Harvard Medical School, Boston, MA
A previously healthy 5-year-old boy presented with bone pain and limping at a tertiary hospital, and was referred to our care with a tentative diagnosis of acute leukemia. In our hospital, stage IV neuroblastoma (NB) arising from the left adrenal gland was diagnosed, with bone marrow involvement. Evaluation included favorable histology according to the Shimada classification. N-myc was not amplified and no 1p(–) deletion was found. Urine catecholamines were 8 ng/mL (normal, 0 to 4 ng/mL). Angiogenesis-specific immunostainings showed high vascularity in the tumor tissue. To differentiate established or mature vessels from immature and growing ones in the initial biopsy of our patient, we used antibodies to CD34+ to demonstrate the endothelial cells of the blood vessels, and
NB, originating from the neural crest, is the most common extracranial solid tumor found in children.1 Age and staging at diagnosis are the most important clinical variables predictive of disease outcome. High-risk disease groups are International Neuroblastoma Staging System stage IV older than 1 year at diagnosis; any stage III with amplified N-myc or unfavorable Shimada pathology; stage II with amplified N-myc and unfavorable Shimada pathology; and stage IV S (special) with amplified N-myc in children younger than 1 year old which have different biological features and often good prognosis without treatment. Historically, high-risk NB patients have a poor long-term survival rate of less than 15%.2 The prognosis improved significantly over the years3 due to the introduction of intensive induction chemotherapy4 especially with high platinum agents,5 followed by myeloablative consolidation therapy with stem cell rescue,6 and targeted therapy with 13-cis-retinoic acid for MRD.7 Retrospective analysis of various induction regimens in national trials showed a correlation between cumulative drug doses and response rate.8 Currently, high-risk NB patients treated with intensive chemotherapy, radiotherapy, autologous stem-cell rescue and 13-cis-retinoic acid have a 3-year event-free survival rate of 34%.9 However, limiting factors for intensive induction therapy are acute and long-term toxicity as well as the development of secondary neoplasias.10 Thus, the overall outcome for high-risk refractory or recurrent NB patients remains extremely poor. Recent research focuses on novel cytotoxic agents, targeted delivery of radionuclides, specific antibodies,11 new retinoid compounds, and immune-mediated therapy. Angiogenic research12 yielded important insights into tumor biology,13,14 resulting in various clinical applications.15 We report a unique case of high-risk refractory stage IV NB that responded to oral thalidomide. Possible future directions for NB treatment with adjuvant antiangiogenic agents are discussed. A child with primary NB stage IV arising from the adrenal was a high-risk patient whose disease had run an aggressive clinical course. Intensive and prolonged chemotherapy including etoposide, irinothecan, and topothecan, followed by autologous peripheral stem-cell transplantation, 13-cis-retinoic acid, and radiation with iodine-132–metaiodobenzylguanidine failed to induce complete remission. These massive therapies are known to have significant short- and long-term adverse effects including the development of secondary neoplasias. Thalidomide, a known antiangiogenic agent16 used successfully, inter alia, for the treatment of multiple myeloma,17 was given experimentally to our highly pretreated patient with refractory NB. He responded very well to the drug, achieving complete remission. It was AML, most probably a secondary neoplasia due to prolonged etoposide treatment,10 which determined the fatal outcome of this patient. NB is an extremely vascular tumor, and high vascularity is known to correlate with poor outcome.19 The inhibitory effect of antiangiogenic agents, such as TNP-470, given continuously at a low dose, has been shown in vivo on NB cells,20 especially in the setting of subclinical disease.21 Thalidomide, a hypnotic agent that was introduced in Europe in the 1960s, caused rare and mild adverse effects like constipation, nausea, drowsiness, dizziness, headache, and dermatological hypersensitivity. Phocomelia, a rare malformation of the extremities, with peripheral neuropathy, when taken early in the course of pregnancy, occurs due to the suppression of blood vessel proliferation by the metabolites of thalidomide,22 an effect that is now being exploited in oncology. This case report demonstrates the remarkable effect of an antiangiogenic agent on metastatic NB. To the best of our knowledge, our patient is the first clinical case of successful treatment of stage IV NB with thalidomide. He had previously failed many protocols, including etoposide, which most probably induced the secondary AML leading finally to his death. The unique clinical course of this patient supports the concept of starting adjuvant antiangiogenic treatment with thalidomide early in the therapeutic plan, as such treatment might have cured this patient of NB and would have avoided the use of etoposide. The child's outstanding clinical improvement after administration of thalidomide was documented by CT studies performed before and after treatment (Fig 2). The good response of our patient to thalidomide suggests that initial adjuvant protocols containing continuous low-dose antiangiogenic agents constitute an optimally effective therapeutic modality for high-risk NB. The concept of antiangiogenic treatment for highly vascular tumors is also supported by the use of bortezomib, a new proteasome inhibitor that has proven successful in the treatment of adult tumors in the preclinical and clinical settings, and has demonstrated an antiangiogenic effect on NB cells as well.23 Long-term administration of antiangiogenic agents appears to be crucial for an antitumor effect and there is no known interference with cytotoxic treatment. Due to its well-known analgetic effect, thalidomide or more recent related drugs seem to us also ethically acceptable for patients with refractory, end-stage NB with an extremely poor prognosis. Long-term administration of antiangiogenic agents may constitute a new therapeutic modality that makes it possible to reduce or replace aggressive cytotoxic chemoradiotherapy, which induces toxicity and secondary neoplasms. Future clinical research in randomized trials should be carried out to evaluate the efficacy, benefits, and hazards of antiangiogenic treatment of pediatric high-risk NB, with the aim of improving its currently poor outcome. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS We thank J. Folkman (Children's Hospital, Harvard Medical School, Boston, MA) for his comments; and Lilly Schaechter, Einat Budowski, and Jacob Bar (Hadassah, Jerusalem, Israel) for their help in the preparation of this manuscript. REFERENCES
1. Maris JM, Matthay KK: Molecular biology of neuroblastoma. J Clin Oncol 17:2264-2279, 1999 2. Finklestein JZ, Klemperer MR, Evans A, et al: Multiagent chemotherapy for children with metastatic neuroblastoma: A report from Childrens' Cancer Study Group. Med Ped Oncol 6:179-188, 1979[CrossRef][Medline] 3. Weinstein JL, Katzenstein HM, Cohn SL: Advances in the diagnosis and treatment of neuroblastoma. Oncologist 8:278-292, 2003 4. Castleberry RP, Cantor AB, Green AA, et al: Phase II investigational window using carboplatin, ioroplatin, ifosfamide, and iepirubicin in children with untreatee disseminated neuroblastoma: A Pediatric Oncology Group study. J Clin Oncol 12:1616-1620, 1994 5. Cheung NV, Heller G: Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. J Clin Oncol 9:1050-1058, 1991[Abstract] 6. Ladenstein R, Philip T, Lasset C, et al: Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: A report from the European Bone Marrow Transplantation Solid Tumor Registry. J Clin Oncol 16:953-965, 1998[Abstract] 7. Keshelava N, Seeger RC, Groshen S, et al: Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res 58:5396-5405, 1998 8. Hartmann O, Berthold F: Treatment of advanced neuroblastoma: The European Experience, in Brodeur GM, Sawada T, Tsuchida Y, et al (eds): Neuroblastoma. Amsterdam, the Netherlands, Elsevier Science, 2000, pp 437-452 9. Matthay KK, Villablanca JG, Seeger RC, 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 341:1165-1173, 1999 10. Kushner BH, Cheung NK, Kramer K, et al: Neuroblastoma and treatment-related myelodysplasia/leukemia: The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 16:3880-3889, 1998 11. Brignole C, Marimpietri D, Pastorino F, et al: Effect of bortezomib on human neuroblastoma cell growth, apoptosis and angiogenesis. J Natl Cancer Inst 98:1142-1157, 2006 12. Folkman J: Tumor angiogenesis: Therapeutic implications. N Engl J Med 285:1182-1186, 1971[Medline] 13. Ribatti D, Vacca A, Dammacco F: The role of the vascular phase in solid tumor growth: A historical review. Neoplasia 1:293-302, 1999[CrossRef][Medline] 14. Kerbel RS: Tumor angiogenesis: Past, present and the near future. Carcinogenesis 21:505-515, 2000 15. Rajkumar SV, Mesa R, Tefferi A: A review of angiogenesis and anti-angiogenic therapy in hematologic malignancies. J Hematother Stem Cell Res 11:33-47, 2002[CrossRef][Medline] 16. D'Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082-4085, 1994 17. Weber D, Rankin K, Gavino M, et al: Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21:16-19, 2003 19. Meitar D, Crawford SE, Rademaker AW, et al: Tumor angiogenesis correlates with metastatic disease, N-myc amplification, and poor outcome in human neuroblastoma. J Clin Oncol 14:405-414, 1996 20. Katzenstein HM, Salwen HR, Nguyen NN, et al: Antiangiogenic therapy inhibitis human neuroblastoma growth. Med Pediatr Oncol 36:190-193, 2001[CrossRef][Medline] 21. Shusterman S, Grupp SA, Barr R, et al: The angiogenesis inhibitor TPN-470 effectively inhibits human neuroblastoma xenograft growth, especially in the setting of subclinical disease. Clin Cancer Res 7:977-984, 2001 22. Avramovich Y, Amit T, Youdim MB: Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein. J Biol Chem 277:31466-31473, 2002 23. Brignole C, Marimpietri D, Pastorino F, et al: Bortezomib on human neuroblastoma cell growth, apoptosis and angiogenesis. J Natl Cancer Inst 98:1142-1157, 2006
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
-smooth muscle actin antibodies to stain mature vessels supported by pericytes (
