Proton radiation therapy versus conventional radiation treatment (i.e. photon radiation) for the treatment of chordoma

What is the issue?
Chordoma is a rare tumour that can grow at any location in the spine. Because some of the locations are difficult to reach, some of the tumour may be left behind, even after aggressive surgery. When this happens, radiation to the postoperative area can help reduce the chance of the tumour coming back. Given the closeness to the spinal cord and other important organs, special radiation techniques are required to maximise tumour control, while minimising harm to normal tissues in the body.

Why is this review important?
At the time of this review, there is a lack of evidence to confirm a benefit with proton therapy compared to conventional photon radiation treatment. However, it is important to note that this review found a number of delivery techniques for both proton and photon therapy. As evidence comparing the latest techniques for proton and photon therapy emerges, we will update this review.

The aim of the review:
The aim of this Cochrane Review was to find out whether proton therapy is more effective than photon therapy for improving local control, and reducing mortality, recurrence, and treatment-related toxicity. We collected and analysed all relevant studies to answer this question.

What are the main findings?
We included six studies that enrolled 187 adults with chordoma, four of which we included in a meta-analysis. We are uncertain whether proton radiation therapy compared to conventional photon radiation treatment improves local control, because our confidence in the evidence was very low (2 observational studies, 39 participants). We are uncertain whether proton therapy compared to photon therapy reduces mortality (4 observational studies, 65 participants), recurrence (4 observational studies, 94 participants), or treatment-related toxicity (1 observational study, 33 participants).

Quality of the Evidence:
We found very low-certainty evidence for all outcomes due to high risk of bias in all the included observational studies, very small sample sizes, and varying ranges in the duration of participants' follow-up period between studies.

Authors' conclusions:
From the currently available evidence, we do not know if proton therapy, used for adults with chordoma, is associated with clinically appreciable benefits and acceptable harms.

The existing research on this question is solely of non‐randomised design, and is underpowered, with substantial imprecision. Any estimates of effect based on the existing insufficient evidence is very uncertain and is likely to change with future research.

Authors' conclusions: 

There is a lack of published evidence to confirm a clinical difference in effect with either proton or photon therapy for the treatment of chordoma. As radiation techniques evolve, multi-institutional data should be collected prospectively and published, to help identify persons that would most benefit from the available radiation treatment techniques.

Read the full abstract...

Chordoma is a rare primary bone tumour with a high propensity for local recurrence. Surgical resection is the mainstay of treatment, but complete resection is often morbid due to tumour location. Similarly, the dose of radiotherapy (RT) that surrounding healthy organs can tolerate is frequently below that required to provide effective tumour control. Therefore, clinicians have investigated different radiation delivery techniques, often in combination with surgery, aimed to improve the therapeutic ratio.


To assess the effects and toxicity of proton and photon adjuvant radiotherapy (RT) in people with biopsy-confirmed chordoma.

Search strategy: 

We searched CENTRAL (2021, Issue 4); MEDLINE Ovid (1946 to April 2021); Embase Ovid (1980 to April 2021) and online registers of clinical trials, and abstracts of scientific meetings up until April 2021.

Selection criteria: 

We included adults with pathologically confirmed primary chordoma, who were irradiated with curative intent, with protons or photons in the form of fractionated RT, SRS (stereotactic radiosurgery), SBRT (stereotactic body radiotherapy), or IMRT (intensity modulated radiation therapy). We limited analysis to studies that included outcomes of participants treated with both protons and photons.

Data collection and analysis: 

The primary outcomes were local control, mortality, recurrence, and treatment-related toxicity. We followed current standard Cochrane methodological procedures for data extraction, management, and analysis. We used the ROBINS-I tool to assess risk of bias, and GRADE to assess the certainty of the evidence.

Main results: 

We included six observational studies with 187 adult participants. We judged all studies to be at high risk of bias. Four studies were included in meta-analysis.

We are uncertain if proton compared to photon therapy worsens or has no effect on local control (hazard ratio (HR) 5.34, 95% confidence interval (CI) 0.66 to 43.43; 2 observational studies, 39 participants; very low-certainty evidence).

Median survival time ranged between 45.5 months and 66 months. We are uncertain if proton compared to photon therapy reduces or has no effect on mortality (HR 0.44, 95% CI 0.13 to 1.57; 4 observational studies, 65 participants; very low-certainty evidence).

Median recurrence-free survival ranged between 3 and 10 years. We are uncertain whether proton compared to photon therapy reduces or has no effect on recurrence (HR 0.34, 95% CI 0.10 to 1.17; 4 observational studies, 94 participants; very low-certainty evidence).

One study assessed treatment-related toxicity and reported that four participants on proton therapy developed radiation-induced necrosis in the temporal bone, radiation-induced damage to the brainstem, and chronic mastoiditis; one participant on photon therapy developed hearing loss, worsening of the seventh cranial nerve paresis, and ulcerative keratitis (risk ratio (RR) 1.28, 95% CI 0.17 to 9.86; 1 observational study, 33 participants; very low-certainty evidence). There is no evidence that protons led to reduced toxicity.

There is very low-certainty evidence to show an advantage for proton therapy in comparison to photon therapy with respect to local control, mortality, recurrence, and treatment related toxicity.