Neuroblastoma – Stem Cell Transplantation – pro

Lay Summary: Neuroblastoma is the only PNET in which the value of stem cell transpalntation in certain situations has been proven.

Primitive neuroepithelial tumors include medulloblastoma, neuroblastoma arising in the central nervous system, ependymoblastoma, or pineoblastoma. All show a similar histology and are principally distinguished by their site of origin. Essentially, medulloblastoma may be considered a cerebellar or posterior fossa PNET while pineoblastoma may be considered a PNET arising in the pineal gland, and neuroblastomas may be considered a central PNET.

High-dose myeloablative therapy in conjunction with either autologous or allogeneic bone marrow transplantation for the treatment of neuroblastoma has been used since the early 1980s in a variety of investigative settings. The first randomized trial by the European Neuroblastoma Study Group showed better progression-free survival for children with transplantation; however, the study was small and the controls received no continuing therapy. Subsequent phase I/II trials indicated that increased disease-free survival (DFS) and progression-free survival (PFS) were achieved with autologous transplant compared with historical controls or groups that had received more standard chemotherapy regimens. Interpretation and comparison of the studies is difficult due to the variety of regimens tested and whether time to progression was calculated from the start of induction therapy or from the date of transplant. Comparison with historical controls is also complicated by the addition of platinum regimens in 1982, which improved PFS and overall survival (OS) results for standard chemotherapy.

A Phase II Study (protocol number CCG-3891) by the Children’s Cancer Group (CCG) investigated tandem autologous stem cell transplantation in high risk neuroblastoma patients (Grupp, 2000). The study enrolled 39 participants but only 37 patients completed the first autologous stem cell transplant and 33 (89%) completed the second autologous stem cell transplant. With a median follow-up of 22 months, 26 (67%) patients remained event free, with a 3 year estimated event free survival (EFS) of 58%. The rate of death due to toxicity 8% was comparable to the mortality rate of a single-cycle autologous stem cell transplant.

In an update of 97 patients treated between 1994 and 2002, George and colleagues (2006) reported encouraging long term survival with tandem autologous stem cell transplants for patients with high risk neuroblastoma.  Patients underwent induction therapy with five cycles of standard agents, resection of the primary tumor and local radiation followed by two consecutive courses of myeloablative therapy along with total-body irradiation and peripheral blood stem cell rescue. The study reported progression-free survival (PFS) at 5 and 7 years of 47% and 45%, and an overall survival (OS) rate at 5 and 7 years was 60% and 53%, respectively.

Tandem autologous transplant regimens have yet to be tested in a randomized controlled trial for other pediatric solid tumors. There is an ongoing, open label, non-randomized clinical trial studying tandem transplants in gliomas which include PNET. Other investigational approaches for advanced solid tumors include novel chemotherapy regimens, multiple HDC/stem cell cycles, differentiating agents, monoclonal antibodies, and genetic manipulations.

No randomized controlled trials of autologous bone marrow transplantation have been published to date for other high risk pediatric solid tumors other than neuroblastoma. Several small phase I/ II or case control studies have been performed. Most of these studies include different tumor types, multiple prior treatments, and even different bone marrow transplant regimens, making conclusions and comparisons quite difficult. While some studies have hinted at a benefit for transplant, other trials have found no difference. For neurobalstome, recurrent or high risk, stem cell transplantation is considered medically necessary. Tandem transplants may be better for neuroblastoma. Several case series demonstrated significantly better outcomes for individuals with high-risk disease who received tandem autologous transplantation compared with single autologous transplantation. Three-year overall survival (OS) rates ranged from 57–79%.

The Shimada index is a histopathologic classification system, widely used for neuroblastoma, developed by H. Shimada. Using the Shimada criteria, kids with neuroblastoma can be grouped into a favorable or unfavorable category. It’s based on the presence or absence of cell stroma, the degree of differentiation, and the mitosis-karyorrhexis index. Another researcher, Joshi, has simplified Shimada’s classification system. Now both these researchers, along with others, are working to combine the predictive abilities of both into a simple and comprehensive system.

Histology refers to the actual tumor pathology. The best method for classifying histology is the Shimada index. It reads:


  • stroma rich, all ages, no nodular pattern
  • stroma poor, age 1.5-5 yr, differentiated, MKI < 100
  • stroma poor, age <1.5 yr, MKI < 200


  • stroma rich, all ages, nodular pattern
  • stroma poor, age >5 yr
  • stroma poor, age 1.5-5 yr, undifferentiated
  • stroma poor, age < 1.5 yr, MKI > 200

MKI is the mitosis-karyorrhexis index (number of mitoses and karyorrhexis per 5,000 cells)

The risk of progression of the tumor causing morbidity and mortality is gauged based on the stage of the tumor, the age of the child at diagnosis, and tumor biology. The biological features considered are the Shimada classification, amplification of the MYCN gene, and the number of chromosomes in tumor cells. Besides histology, there are other factors that are important when determining prognostic significance. Of course, the age at diagnosis is important, with children under the age of 1 year having the best overall prognosis. Here are some other important factors:

  • neuron-specific enolase: normal level (1- 100 ng/ml) > abnormal (> 100 ng/ml)
  • ferritin level: normal level (0- 150 ng/ml) > abnormal (> 150 ng/ml)
  • VMA/HVA ratio: high (> 1) > low (< 1)
  • stage: I or II or IVs > III > IV
  • site of primary tumor: neck/ posterior mediastinum/ pelvis > abdominal primaries
  • gallium uptake by tumor: absent > present
  • n-myc amplification: 1 n-myc copy > greater than 1 n-myc copy
  • P-glycoprotein levels in tumor cells at dx: expression before treatment may be of some prognostic significance.
  • expression of neural growth factor receptor (TRK) gene: high levels of messenger RNA of TRK gene in tumor cells strongly predicts good outcome.
  • lower LDH levels (< 1500 u/ml) > high LDH levels (> 1500 u/ml)
  • Ha-ras p21 expression: aggressive tumors have low expression of Ha-ras p51. High Ha-ras p21 correlates with better disease-free survival.
  • chromosome 1p deletion is associated with poor survival.

American Society for Blood and Bone Marrow Transplantation. Policy Statements, Guidelines and Reviews. Available at:

Barrett D, Fish JD, Grupp SA. Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors. Pediatr Clin North Am. 2010 Feb;57(1):47-66.

Dome JF, Rodriquez-Galindo Cl Spunt SL, Santana VM. Pediatric solid tumors. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, editors. Clinical Oncology, 4th ed. New York: Churchill Livingstone; 2008.

Helman LJ, Malkin D. Cancers of childhood. In: Devita, Jr. VT, Lawrence TS, Rosenberg SA, editors. Devita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008.

Justyna Kanold, MD et al, Long-term results of CD34+ cell transplantation in children with neuroblastoma  Medical and Pediatric Oncology, Volume 35, Issue 1 , Pages 1 – 7

Bertuzzi A, Castagna L, Nozza A et al. High-dose chemotherapy in poor-prognosis adult small round-cell tumors: Clinical and molecular results from a prospective study. J Clin Oncol 2002;20(8):2181-2188

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