Carbon Ion Radiotherapy for Head and Neck Tumors Invading the Skull Base

Reviewer: Geoffrey Geiger MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 14, 2009

Presenter: A. Hasegawa, J. E. Mizoe, K. Jingu, H. Bessho, T. Kamada, H. Tsujii
Presenter's Affiliation: Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan
Type of Session: Scientific


  • A limiting factor in the treatment of malignancies of the skull base is the proximity to critical structures, such as the brainstem, optic nerves/chiasm, and the spinal cord.
  • Compared to more readily available modalities of radiation, carbon ions interact more densely with tissue, result in a greater degree of ionization per unit volume, and have a higher radiobiological effect (RBE) than photons or protons.
  • Charged particle beam therapy with carbon ions, therefore, allows the delivery of higher doses of conformal radiation due to the dose characteristics of particle beam radiotherapy, including finite range and steep dose fall off beyond the Bragg peak.
  • Because of their superior conformality and higher radiobiological effectiveness, charged particle radiation therapy is expected to deliver biologically equivalent doses with superior precision and with less radiation-induced morbidity than conventional radiation therapy.
  • Particle therapy using protons or carbon ions, therefore, has the potential to be of benefit in treatment for head and neck tumors of the skull base.
  • Historically, resection has been the primary treatment modality for most skull base tumors, although complete resection is often not possible, frequently necessitating postoperative radiation.
  • Conventional treatment using conformal photon beam irradiation is often limited by higher than desired doses to organs at risk (OARs); this study examines the efficacy and toxicities of carbon ion radiotherapy for tumors with skull base or intracranial invasion.

Materials and Methods

  • The data presented here are prospective, single institution data from a phase II trial of 278 patients treated between April 1997 and March 2007, of which 93 were analyzed with tumors invading the skull base, intracranial regions, or cerebrum.
  • All had head and neck tumors were treated with carbon ion radiotherapy.
  • Eligibility criteria included:
    • Age 15-80 years.
    • Measureable and histologically proven tumor.
    • Expected prognosis of at least six months.
    • No prior history of radiation therapy and an interval of at least 4 weeks since the most recent cycle of systemic therapy.
    • All of these patients had neither regional lymph node nor distant metastasis prior to carbon ion radiotherapy.
  • The prescribed tumor doses were 57.6 or 64.0 CGE (centi Gray equivalents) in 16 fractions delivered over four weeks.


  • The patients consisted of 51 males and 42 females aged from 23-78 with an average age of 55.4 years.
  • Histologically, tumors were classified as follows:
    • 43 were adenoid cystic carcinoma,
    • 23 were malignant mucosal melanoma,
    • 22 were adenocarcinomas, and
    • 5 were other histological types.
  • The clinical target volume (CTV) ranged from 53.6 to 670.1 mL, with a median treated volume of 190 mL.
  • Of analyzed patients, 76 were treated with 57.6 CGE and 17 with 64 CGE.
  • The median follow-up time was 32.5 months (range, 2.6–143 months).
  • Outcome: The 5-year local control and overall survival rates were 75% and 46%, respectively. There were no significant differences in local control rates between histological types.
    • In total, 56 patients died: 30 had distant metastasis, 7 had in-field recurrences, 7 had marginal recurrences, and 2 had meningeal dissemination. Ten deaths were due to other causes not associated with tumors.
    • Fourteen of 23 malignant melanoma patients died due to distant metastasis, and the 3- and 5-year overall survival rates for mucosal malignant melanoma were 32% and 7%, respectively.
    • Patients were divided into two groups according to intracranial involvement; group A was made up of 44 patients whose tumors abutted the cranial fossa, group B consisted of 49 patients whose tumors displaced or invaded the frontal or temporal lobe.
    • The 5-year local control rates were 74% for group A and 75% for group B.
    • The 5-year overall survival rates were 43% for group A and 39% for group B. There was no significant difference in outcome between the two groups.
  • Toxicity: although acute grade 3 skin and mucosal reactions appeared in 4 patients (4%) and 9 patients (10%), respectively, the late skin and mucosal reactions were all grade 1 or less.
    • Only one patient developed a late grade 2 mucosal reaction.
    • In regard to brain toxicity, 12 patients (13%) developed late grade 2 brain reactions, which necessitated steroid administration, and all of which subsequently resolved.

Author's Conclusions

  • The set of patients analyzed in this retrospective analysis all had locally advanced non-squamous cell  skull base tumors not amenable to surgical resection.
  • These patients were considered excellent candidates for definitive carbon ion therapy.
  • At the median follow-up, most patients treated with carbon ion radiotherapy demonstrated a durable therapeutic response.
  • The overall survival rate for malignant melanoma with respect to systemic control was not considered acceptable, and patients were enrolled into a subsequent phase II clinical study incorporating systemic therapy beginning in 2001.

Clinical/Scientific Implications

  • For tumors requiring high doses of radiation for acceptable local control, adequate doses are traditionally limited by the ability to avoid unacceptable doses to OARs.
  • Particle therapy has a well-established history with tumors of several histologies, and carbon ion RT combines the physical advantages of a particle beam together with distinct biological features that potentially lead to higher RBE in the tumor than in the surrounding normal tissue.
  • By using the physical properties of particle therapy, further local dose escalation is possible based on the physical properties of the Bragg peak and the finite range of carbon ion beams, even for tumors closely surrounded by critical structures.
  • Complete tumor resection can rarely be achieved in skull base lesions, and long-term control was historically achieved only when patients were treated with cautious and complete resection; therefore, high-dose postoperative radiation has historically been recommended, and this analysis demonstrates good rates of local control at 5-years for non-squamous tumor histologies with acceptable long-term toxicity.
  • Overall, the data presented here appear interesting and promising, with potentially improved results as compared to historical data with the use of photon and proton/photon irradiation; however, the small sample size and relatively short follow-up time presented preclude making statements regarding effectiveness.
  • The data presented here demonstrate that delivery of adequate dose to skull base tumors is feasible and tolerable with carbon ions, and continued study with reports including longer follow up are warranted.