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Raymond Hutchinson, M.D.,
Professor of Pediatrics
Clinical Director, Pediatric BMT Program
Children rarely develop cancer, but when they do, treatment
often is successful. That, indeed, is good news. Unfortunately,
several childhood cancers remain highly lethal; metastatic
neuroblastoma is one of the most deadly.
Approximately half of the children diagnosed with neuroblastoma
have metastases at the time of diagnosis (1). Furthermore,
in half of all children who are diagnosed with neuroblastoma
by their second birthday, the impact upon families and society
is greater than first impressions might suggest. Only one
in five children older than one year of age with metastatic
neuroblastoma survives (1).
Stem Cell Transplants
The use of high-dose chemo-radiotherapy followed by autologous
bone marrow infusion has gained wide acceptance in the treatment
of newly diagnosed patients with chemotherapy-sensitive, metastatic
neuroblastoma and in patients with disease recurrence following
initial chemotherapy (2,3). A trial recently completed by
the ChildrenŐs Cancer Group (in which the University of MichiganŐs
Pediatric Oncology Program participated) demonstrated improved
disease-free survival for children with advanced neuroblastoma
after high-dose chemo-radiotherapy and autologous bone marrow
transplant versus children continuing on standard-dose chemotherapy
Pediatric oncologists and bone marrow transplant physicians
at the University of Michigan Cancer Center (UMCC) are applying
this promising technology to the unfortunate children afflicted
by advanced neuroblastoma. A total of 28 autologous stem cell
transplants have been performed for children with advanced
neuroblastoma; disease-free survival at four years is 30%
(see Figure 1).
Because there is plenty of room for improvement, innovative
treatment approaches are being developed at UMCC. Dr. Greg
Yanik recently initiated a transplant trial in which a tumor-targeted
radiotherapeutic agent, 131I-metaiodobenzylguanidine (131I-MIBG),
is used to deliver radiation therapy in place of standard
total body irradiation. This agent concentrates selectively
in tissues of adrenergic origin (e.g., the adrenal medulla)
and in tumors that arise in such tissues (e.g., neuroblastoma).
Prior phase I and II trials of 131I-MIBG at the University
of Michigan and elsewhere have demonstrated the safety and
the therapeutic activity of this treatment modality (5,6).
Dr. Yanik and his colleagues hope that the 131I-MIBG will
effectively deliver radiation therapy to the tumor sites,
while sparing the non-involved surrounding tissues. If proven
effective, Dr. Yanik's approach will increase the therapeutic
index of autologous transplant for advanced neuroblastoma.
This trial is currently accruing patients at the first of
three planned dose levels of 131I-MIBG.
In a related area, my colleague Jim Geiger, M.D., and I are
conducting a phase I trial of tumor cell vaccination for children
with refractory neuroblastoma. Similar trials conducted at
other medical centers indicate that tumor immunization strategies
can produce anti-tumor effects (7-9). The UMCC trial utilizes
autologous tumor and autologous antigen presenting cells (dendritic
cells) to promote and augment in vivo anti-neuroblastoma immune
response. A series of three intradermal immunizations at two-week
intervals is completed for each patient, monitoring for adverse
reactions and for anti-tumor efficacy. This trial is in an
early stage as well and is currently accruing patients. Eventually,
this approach may be used following stem cell transplant to
treat minimal residual disease, thereby hopefully increasing
the percentage of patients with long-term, disease-free survival.
Through the combined efforts of UMCC investigators, new avenues
to treat neuroblastoma are being explored. Hopes are high
that new inroads will be made into the successful treatment
of this dreaded disease.
To refer a patient to one of the above protocols, please call
- Brodeur GM, Castleberry RP, et al. Neuroblastoma, in
Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric
Oncology (2nd ed.). Philadelphia, PA. J.B. Lippincotte Co.,
p 739, 1993.
- Philip T, Ladenstein R, Zucker JM, et al. Double megatherapy
and autologous bone marrow transplantation for advanced
neuroblastoma: the LMCE2 study. Br J Cancer. 67:119, 1993.
- Graham-Pole J, Casper J, Elfenbein G, et al. High-dose
chemoradiotherapy supported by marrow infusions for advanced
neuroblastoma: a Pediatric Oncology Group study. J Clin
Oncol. 9:152, 1991.
- Matthay KK, Harris R, Reyolds CP, et al. Improved event-free
survival (EFS) for autologous bone marrow transplantation
(ABMT) vs. chemotherapy in neuroblastoma: a phase III randomized
Children's Cancer Group (CCG) study. Proc Am Soc Clin Oncol.
- Sisson JC, Shapiro B, Hutchinson RJ, Carey JE, Zasadny
KR, Zempel SA, Normolle DP. Predictors of toxicity in treating
patients with neuroblastoma by radiolabeled metaiodobenzylguanidine.
Eur J Nucl Med. 21:46, 1994.
- Hutchinson RJ, Sisson JC, Shapiro B, Miser JS, Normolle
D, Shulkin BL, Francis IR, Zasadny K, Carey JE, Johnson
JW, Mallette SA, Mudgette B. 131-1-Metaiodobenzylguanidine
treatment in patients with refractory advanced neuroblastoma.
Am J Clin Oncol. (CCT). 15(3): 226, 1992.
- Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients
with B-cell lymphoma using autologous antigen-pulsed dendritic
cells. Nat Med. 2:52, 1996.
- Hsu FJ, Caspar CB, Czerwinski D, et al. Tumor-specific
idiotype vaccines in the treatment of patients with B-cell
lymphoma: long-term results of a clinical trial. Blood.
- Reichardt VL, Okada CY, Liso A, et al. Idiotype vaccination
using dendritic cells after autologous peripheral blood
stem cell transplantation for multiple myeloma: a feasibility
study. Blood. 93:2411, 1999.
Figure 1. Disease-free survival (patients alive without
recurrence) of 28 patients with advanced neuroblastoma following
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