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Proton therapy in chordoma of the base of the skull: a systematic review


Chordoma is a rare, slow-growing, locally aggressive, primary bone tumor that arises from the skull base region in approximately 25–35% of cases. The therapeutic approach to chordoma has traditionally been surgery, followed by radiation therapy. The advent of charged particle radiotherapy has let us consider protons as the postoperative treatment of choice, but no controlled studies have yet confirmed the superiority of protons over photons. During January 2008, two independent researchers conducted a systematic review of the current data on the treatment of base of the skull chordoma C with proton therapy (PT) and, for comparison, with other irradiation techniques (conventional radiation therapy, ion therapy, fractionated stereotactic radiation therapy, and radiosurgery). Two hundred and ten reports in total were retrieved (81 concerning PT). According to the inclusion criteria, 47 articles were considered in the analysis. There were no prospective trials (randomized or nonrandomized) but just seven uncontrolled single-arm studies for PT, providing clinical outcomes for 416 patients in total; these reports were mainly related to advanced inoperable or incompletely resected tumors. The therapeutic approach to chordoma of the base of the skull has traditionally relied on surgical control. Radiation therapy has demonstrated to be a valuable modality for local control in the postoperative setting, particularly with the advent of charged particle radiotherapy. The use of protons has shown better results in comparison to the use of conventional photon irradiation, resulting in the best long-term (10 years) outcome for this tumor with relatively few significant complications considering the high doses delivered with this therapeutic modality.

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Correspondence to Maurizio Amichetti.

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Ladislau Steiner, Chun-Po Yen, Charlottesville, USA

Amichetti et al. conducted a systematic review of the current data on the treatment of skull base chordomas with proton therapy and compared the imaging and clinical outcomes to those following fractionated photon radiation, ion therapy, fractionated stereotactic photon therapy, and radiosurgery.

The Medline literature search was restricted to articles published in English between January 1980 and January 2008. Of 210 reports, 81 addressed proton treatment. Using the guidelines of the National Institute of Health for systematic reviews of research on effectiveness, 47 articles were selected according to the following criteria (1) series with at least ten patients and (2) at least 24 months of follow-up. Twenty articles with data that were updated in later versions were eliminated leaving 27 articles for final analysis.

Selected series were: (1) seven proton therapy articles with a total of 416 patients; these were all retrospective and no randomized phase I or II studies; the largest series was from the Francis Burr Therapy Center at Massachusetts General Hospital, Boston with 169 patients; (2) ten studies with 141 patients undergoing conventional fractionated photon radiotherapy; (3) one publication on stereotactic fractionated radiation therapy with 45 patients; (4) five studies on radiosurgery with a total of 109 patients; (5) a total of 206 patients in four studies on ion therapy.

The authors meticulously assessed the content of the reviewed articles; however, their tables are difficult to read. Commenting the results of the different treatment modalities, they emphasized the inherent bias of retrospective analysis of small number of patients treated over many years and the fact that some patients were treated before the advent of megavoltage linear accelerators and/or the introduction of the CT scan. They insisted on the pitfalls when discussing cases with various treatment policies that sometimes there were no tissue diagnosis and/or sufficient details on radiotherapy techniques. They also warned of flaws in comparing relatively large series of proton therapy with long track record to small series of other kind of radiations with shorter periods of follow-up. They emphasized that mostly uncontrolled evidence supports the clinical advantages of proton as compared to conventional photon therapy and that, in order to evaluate the long-term efficacy of proton treatment in chordomas, it should be kept in mind that only Munzenrider et al. reported on long-term survival in 10 years of follow-up. Furthermore, superiority in terms of local control using proton has been demonstrated versus conventional photon therapy only.

It is pertinent to the authors' observation that a great part of the data in proton therapy included patients referred to treatment using cyclotrons in physics departments with suboptimal techniques as compared to the technology in today's proton units dedicated to treatment of patients.

Mentioning as a drawback the absence of cell repair during radiosurgery, Amichetti et al. failed to explain that not cell repair during sublethal dose delivery but the radiological effects induced by the steep dose gradients at the edge of the target defines the advantages of radiosurgery.

The advantage of proton due to its characteristic high-dose region at the end of the particle range (Bragg peak) is common knowledge. However, the statements of Amichetti et al. that the planning technique of the proton therapy is superior to that used in gamma knife procedures and that in irregular-shaped tumors the proton treatment plan is more conformal than that achieved with gamma knife may be taken with a grain of salt. Concerning the advantage of the proton treatment in large chordomas, there is a consensus today that, without radical surgery resulting in small tumor residuals, no radiation modality can successfully manage a chordoma. Or, if this is the case, it is not relevant whether a method may cover larger tumor volumes as compared to other radiation modalities.

Finally, illustrations of one case of chordoma treated by us at the Lars Leksell Center for gamma surgery in the Department of Neurosurgery, University of Virginia, may serve as a caveat against hasty conclusions before mature data are available.


A. R. a 45-year-old gentleman with skull base chordoma was treated with gamma surgery on October 19, 1994. The size of the tumor progressively decreased. However, after 5 years, recurrence occurred. At the time of retreatment with gamma surgery, the tumor measured 3 cm3 on enhanced T1-weighted magnetic resonance imaging (MRI; A). It did shrink progressively and, after close to 9 years, measured 0.1 cm3 (90% decrease) on enhanced T1-weighted MRI (B).

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Amichetti, M., Cianchetti, M., Amelio, D. et al. Proton therapy in chordoma of the base of the skull: a systematic review. Neurosurg Rev 32, 403 (2009).

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  • Systematic review
  • Chordoma
  • Base of the skull
  • Proton therapy