Proton Beam Therapy for Patients with Malignancies of The Nasal Cavity, Para-nasal Sinuses, and/or Involving the Skull Base: The Analysis of Late Toxicity

Reporter: Abigail Berman Milby, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 4, 2011

Presenting Author: S. Zenda
Presenter's Affiliation: National Cancer Center Hospital East, Chiba, Japan


  • Proton beam radiotherapy (PBT), with its characteristic spread out Bragg peak (SOBP), permits sharp fall off distally and laterally to the beam.
  • Surgical resection for tumors of the nasal cavity and para-nasal sinus are often complicated and associated with high rates of serious complications and residual gross disease.
    • Radiotherapy is an excellent alternative to surgery, although achieving high enough doses for tumor control is difficult due to the organs-at-risk in close proximity.
  • Several investigators reported PBT as a promising alternative treatment to surgery or radiotherapy for malignancies of the nasal cavity and para-nasal sinuses:
    • A study by Nishimura et al. showed the effective use of PBT in olfactory neuroblastoma with a 5-year progression free survival (PFS) of 84% and overall survival (OS) of 93% (IJROBP, 2007).
    • This group presented their experience with T4 (unresectable) tumors of the nasal cavity and para-nasal sinus, finding a 3-year PFS of 49.1% and OS of 59.3% (Zanda et al., IJROBP, in press). PBT has been used as a feasible and effective treatment modality which has the possibility to provide curative high-dose irradiation to the tumor volume without increasing normal tissue toxicity.
  • This study reports a retrospective analysis of patients treated with PBT to the nasal cavity, para-nasal sinuses to quantify and qualify the late toxicity profile.

Materials and Methods

  • Eligible patients had the following features:
    • malignancies of the nasal cavity, para-nasal sinuses, or head and neck malignancy with intra-cranial extension
    • treatment with definitive or postoperative PBT (>50GyE)
    • > 1 year of observation after the PBT
  • Toxicities were graded according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE ver. 3.0).


  • From January 1999 through November 2008, there were 91 patients identified.
  • The most common primary site was nasal cavity (n=63), followed by maxillary sinus (18), ethmoid sinus (8), sphenoid sinus (5), or other (2).
  • The most common histology was olfactory neuroblastoma (27), followed by squamous cell carcinoma (18), adenoid cystic carcinoma (15), melanoma (14), or other (17).
  • Median age was 57 years (range 17-84) and the number of males/females was 53/38.
  • T stage of the patients were as follows: T1 (Kadish A)=4, T2 (Kadish B)=17, T3=8, T4 (Kadish C)=77, or recurrent =7.
  • Post-operative PBT/definitive PBT was given in 16/75 patients, respectively.
  • 21 patients received induction chemotherapy and 11 received chemotherapy concurrent with PBT.
  • Dose schedule was as follows: 66-70 GyE(10), 65 GyE/25fx(62), 60 GyE/15 fx(17), and 50-60 GyE (2).
  • Gross tumor volume (GTV) was defined by pretreatment CT/MRI and PET. Clinical target volume (CTV) was defined as the region around the GTV and adjacent sinuses, and planning target volume was defined as CTV plus a 3-mm margin with fine-tuning with consideration of organs-at-risk.
  • Dose constraints were as follows:
    • For 2.0-2.5 GyE/fx and 4.0 GyE/fx, respectively (all numbers in GyE): surface of brainstem 60 and 45, center of brainstem 50 and 33, optic nerves 54 and 42, optic chiasm 54 and 42, and optic lens 15 and 13.
  • Median observation periods were 45.9 months (range 4-138) and 29 patients (31.9%) were observed more than 5 years.
  • Median time to onset of a > Grade 2 late toxicity was 39.7 months (range 2.7-115).
  • Grade 3 late toxicities occurred in 6 patients (7.7%) with 10 events (hearing loss 1, cataract 4, CNS-V disorder 1, brain necrosis 1, soft tissue necrosis 1, and bone necrosis 2).
  • Grade 4 late toxicities occurred in 7 patients (7.7%) with 7 events as follows:
    • CSF leakage (2)
    • decreased visual acuity (5)
      • 4 patients with T4 disease and one with Kadish A
      • Treatment doses 60-65 GyE
      • 4 patients alive without disease and one dead of disease
      • Time of onset between 1 year, 5 months and 6 years, 6 months
  • There were 2 treatment-related deaths, caused by CSF leakage (2.2%).

Author's Conclusions

  • PBT appears to have an acceptable safety profile in patients with the nasal cavity, para-nasal sinuses, however there is still room to decrease side effects further with improvements in technology.
  • Late toxicity can occur beyond 5 years of the treatment, and further long-term follow-up is necessary in this study.

Clinical Implications

  • Due to location near critical normal structures, these tumors can be difficult to treat with conventional therapy.
  • The authors state that PBT has an acceptable safety profile in these patients, however there was still a 7.7% risk of grade 4 toxicity. This reinforces the need for radiation oncologists to go over in detail with patients the risk of serious toxicity, in particular vision loss, and use further technological advances to decrease the toxicity profile.
  • These patients were treated with double scatter proton technology (DSPT); intensity modulated proton therapy (IMPT) will theoretically improve the ability to conform the dose distribution to the irregularly shaped volume. Studies examining the long-term toxicity of IMPT versus DSPT will be important in this patient population.
    • In addition, Monte-Carlo simulation may improve PBT technology.
  • It would be interesting to see the beam arrangement used in these proton beam plans. There is significant distal edge uncertainty in PBT and therefore this may have contributed to some of the long-term toxicity.
  • Additional studies that would add to the literature for para-nasal sinus and nasal cavity tumors include:
    • A matched-pair analysis comparing the late toxicity of PBT and intensity modulated radiation therapy (IMRT) which is currently the most common modality used.
    • A correlation study of acute toxicity and late toxicity with PBT.