Impact of Radiotherapy for High-Risk Neuroblastoma: A Children's Cancer Group Study

Reviewer: Jeffrey C. Haynes, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 9, 2006

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Authors: Haas Kogan DA, Swift PS, Selch M, et al.
Source: Oncology Biol. Phys. , Vol. 56, pp. 28-39, 2003.

Background

  • Neuroblastoma strikes 650 children per year in the US
  • Survival at 5 years remains <30% for high-risk tumors in children >1 year old
  • Local recurrence is a major issue
    • Surgery is frequently difficult
    • 17%-74% of patient have a local recurrence
  • Radiation therapy could reduce local recurrences
  • Optimal radiation indications and dosage have not been determined

Methods: CCG-3891

  • 539 patients age 1-18 years with high-risk neuroblastoma
    • 453 Stage IV patients
    • 72 Stage III patients with N-MYC gene amplification, unfavorable histology, or serum ferritin level >=143
  • Induction chemotherapy
    • Cisplatin, doxorubicin, etoposide, and cyclophosphamide
    • 5 cycles at 28 day intervals
  • Evaluation of response
  • Surgery in those without progression
    • Attempted gross total resection of primary and metastases larger than 3 cm
  • External beam radiation to gross residual disease
    • Dose
      • 10 Gy to mediastinal and intra-abdominal tumors
      • 20 Gy to extra-abdominal tumors
      • 2 Gy daily fractions
    • Target
      • Gross residual disease as determined by physical exam, operative reports, and imaging 2 weeks after surgery (CT, MRI, and MIBG scan)
      • 1-2 cm margin
  • Randomization
    • Randomized following third cycle of induction chemotherapy
    • Continuation of chemotherapy (CC) following completion of induction chemotherapy and local treatment
        • Cisplatin, doxorubicin, etoposide, ifosfamide, and mesna
        • 3 cycles
    • Autologous bone marrow transplant (ABMT) following completion of induction chemotherapy and local treatment
      • Carboplatin, etoposide, and melphalan followed by total body irradiation (TBI) consisting of 3.33 Gy daily for 3 days

Results

  • 66 month median follow-up (range 2-114 months)
  • Event-free survival at 5 years: 25%
  • Overall survival at 5 years: 35%
  • Local recurrence was common
    • 349 total recurrences among the 539 patients
    • 31 isolated to the primary site
    • 148 with simultaneous local and distant recurrences
  • Patients in the ABMT arm with significantly fewer local recurrences
    • 33% vs. 51% at 5 years (p = 0.004)
    • More pronounced among patients with N-MYC amplified tumors: 25% vs. 70% (p = 0.001)
    • Partly explained by the higher proportion whose resection was complete in the ABMT arm (68% vs. 59%)
    • Additional radiation from ABMT may have contributed to difference between groups
    • Higher doses appear to be helpful among the 36 patients with extra-abdominal primary tumors
      • No local relapses among the 6 patients who received 20 Gy to the primary site vs. 44% local relapses among the 30 patients who did not receive radiation (2 within the first group and 10 within the second group received TBI)
  • No significant improvement in time to local recurrence or event-free survival was observed when comparing patients who received radiation to the primary site versus those who did not
    • Slight but consistent trend towards improved EFS among patients who received primary site radiation across nearly all subgroups
    • Trend more impressive in light of the fact that radiation was given based upon the presence of gross residual disease, rather than randomly
  • Only slightly worse toxicity among patients receiving radiation to the primary site
    • More frequently required parenteral nutrition: 55% vs. 44% (p = 0.05)
    • Increased but non-significant veno-occlusive disease of the liver: 14% vs. 7% (p = 0.26)

Discussion/Clinical Implications

The authors suggest that these data support improved local recurrence with increased radiation dose, but it is impossible to draw conclusions from them. Furthermore, higher doses have been clearly shown to increase morbidity in the young children undergoing treatment for neuroblastoma. In any case, distant recurrence remains a much greater problem than local recurrence. While the authors make the best of data that have limited usefulness, it would be imprudent to base clinical decisions upon the results of this study.



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