Proton therapy of esthesioneuroblastoma

Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 14, 2011

Presenter: Robert Malyapa MD, PhD
Presenter's Affiliation: University of Florida


  • Esthesioneuroblastoma, also know as olfactory neuroblastoma, is a rare malignancy originating from the olfactory epithelium in the roof of the nasal cavity.
  • About 4 per 10 million cases are reported, only 1200 have been diagnosed since 1924, and the entity represents about 2-5% of all sinonasal cancers.
  • They are typically found in the vault of the nasal cavity or the lateral wall adjacent to the ethmoid sinuses.
  • A bimodal age distribution exists with patients typically presenting in the 2nd and 6th decade of life.
  • Staging and survival by stage are as follows:

Kadish Stage (Cancer, 1976)

Extent of Disease

5-year Survival


Confined to nasal cavity



Extends to paranasal sinuses



Extends beyond nasal cavity or paranasal sinuses


(Chao, H&N, 2001)

Lymph node involvement or distant metastasis





  • Surgery is often the primary modality of treatment. There is evidence suggesting that post-operative radiation therapy or chemoradiation improves local control, especially for advanced disease.
  • General guidelines suggest that small, low grade tumors may be treated by surgery or radiation therapy alone to 65-70 Gy, while larger tumors warrant surgical treatment with either pre-operative radiation therapy to 50 Gy, or post-operative chemoradiation to 60 Gy.
  • Treatment planning is challenging given the complex tumor shape in close proximity to critical structures. In spite of advances in IMRT technique, sparing of the medial retina, optic nerves, optic chiasm, and brainstem are difficult with high-dose photon radiation plans.
  • Protons present an attractive alternative because of the physical dose distribution, or spread-out Bragg peak. Proton therapy offers potential to reduce the morbidity of treatment while maintaining the high doses needed to eradicate microscopic disease.

Materials and Methods

  • Between January 2008 and April 2011, 30 patients with esthesioneuroblastoma were treated post-operatively with protons on a clinical research protocol at the University of Florida.
  • Study design: non-randomized, prospective data collection
  • The treatment regimen was one of hyperfractionation, or delivery of a smaller dose per fraction delivered multiple times per day. 
  • Patients were treated with 1.2 Gy(RBE) twice a day for a total dose of 64.8-69.6 Gy(RBE) if post-operative margins were negative, or 74.4 Gy(RBE) if post-operative margins were positive.
  • The rational for hyperfractionation was based on the large experience with photon hyperfractionation at University of Florida, and also data suggesting that the risk of radiation-induced optic neuropathy is minimized in a hyperfractionated schedule
  • The lower neck was treated with a matched photon field.
  • Weekly chemotherapy with a cisplatin-based regimen of dose 30 mg/m2 was concurrently administered.
  • Immobilization included a base of skull frame with a tongue depressor.
  • CT (with and without contrast) and MRI were obtained at the time of simulation; images were co-registered for segmentation of target and critical structures.
  • Proton technique was passive, double scattering with on-board image guidance
  • Range uncertainty was 1.5% and largely composed of proximal margin and distal range uncertainty, small misalignments from compensator smearing, and aperture margin.
  • Each field was treated twice daily.


  • The median patient age was 54 yrs with a range from 15 to 81 yrs.
  • The majority of patients were Kadish stage C (n=7), with the remainder Kadish B (n=5) and Kadish A (n=1).
  • Mean follow-up was 21.5 months with a range from 10 to 36 months.
  • Of the 13 patients in the cohort, 10 are alive at 36 months. One patient died from metastatic disease to the liver at 12 months post-treatment. Another patient died of a brain lesion at 11 months post-treatment. Both patients were Kadish C at presentation. The cause of death for the third patient was not discussed.
  • Acute toxicity included skin reaction, which resolved in 4 weeks for most patients.
  • No ocular toxicity was seen in any patient.
  • One in-field recurrence occurred, which was successfully salvaged.

Author’s Conclusions

  • Conformal proton therapy for esthesioneuroblatoma is well tolerated.
  • The use of proton therapy permitted doses of 64.8 to 74.4 Gy(RBE) without exceeding tolerance of adjacent structures.

Clinical Implications

  • This study describes the University of Florida experience with proton beam radiation for esthesioneuroblastoma.
  • The findings suggest that proton radiation may be a treatment technique offering improved dosimetry in a difficult location with acceptable local control and reasonable acute toxicities.
  • Other studies using proton plans or combined photon/proton plans show similarly high local control rates and diminished toxicity, particularly through minimizing risk of damage to the visual apparatus.
  • This study was unique in that all patients were treated post-operatively and a hyperfractionation schedule was used.
  • If proton radiation can minimize damage to normal structures, it may someday replace surgery as a first-line treatment for this rare malignancy. Surgery may be reserved for patients who do no respond to proton beam therapy.
  • Skin toxicity is a major concern with twice daily treatment of all fields with proton therapy. The results of this study suggest that skin toxicity is temporary and manageable. This may lead to use of hyperfractionation in other disease sites with proton therapy.
  • Prospective randomized trials are needed to further evaluate the role of proton therapy in esthesioneuroblastoma.