"Proton beam cancer therapy 'effective with fewer side effects'," BBC News reports. A US study found the technique caused fewer side effects than conventional radiotherapy.
Proton beam therapy hit the headlines in 2014 due to the Ashya King case – with his parents removing him from hospital without the knowledge of staff to receive this treatment abroad. The technique is an alternative to standard radiotherapy. In this study, it was used to treat a malignant brain tumour called medulloblastoma in 59 children.
Medulloblastomas can be cured with a combination of surgery, chemotherapy and radiotherapy. However, standard "photon" radiotherapy is associated with a risk of long-term complications for the child, including hearing problems and cognitive (brain function) impairment.
Photon beam therapy uses beams of protons (sub-atomic particles) to destroy cancerous cells. Unlike conventional radiotherapy, the beam of protons stops once it "hits" the cancerous cells. This results in much less damage to surrounding tissue.
In this study, 16% of the children had serious hearing loss five years after proton beam therapy. This compares favourably with standard radiotherapy, where about 25% have hearing loss. Cognitive impairment was also slightly less – 1.5 intelligence points (IQ) lost per year, compared with 1.9 in studies of standard radiotherapy. Overall survival was reported to be similar to standard radiotherapy. The main limitation is that this was not a randomised controlled trial directly comparing the two forms of radiotherapy – the researchers said this would be unethical.
The results seem promising and the researchers hope their study will pave the way for other studies examining safety and survival outcomes of proton beam radiotherapy in other cancers.
The study was carried out by researchers from Massachusetts General Hospital, Brigham and Women’s Hospital in Boston, and Winship Cancer Institute of Emory University in Atlanta, US. The study was funded by the US National Cancer Institute and Massachusetts General Hospital, and published in the peer-reviewed medical journal The Lancet Oncology.
The partner of the lead author of the study is reported as having stock options in ProCare, a private medical company that provides proton beam therapy.
The UK media's reporting of the study was accurate and, as would be expected, referenced the Ashya King case, which was one of the bigger news stories of 2014.
This was a prospective phase II trial aiming to look at the side effects and survival outcomes of using proton radiotherapy to treat children and young people (aged 3 to 21 years) with medulloblastoma.
Medulloblastoma is a type of brain tumour that starts in the cerebellum – an area found at the base of the brain. It is the most common malignant (cancerous) brain tumour in children. Although it can be cured with a combination of surgery, radiotherapy and chemotherapy, the treatment often leads to long-term complications, such as cognitive and hearing impairment, hormonal problems and risk of other cancers. The researchers say that survivors often have a poorer quality of life than their peers, with complications being greatest for the youngest children.
Proton beam therapy (also known as proton radiotherapy) seems promising in being able to be given at a lower and more targeted dose than standard (photon) radiotherapy, and is increasingly used to minimise side effects of treatment.
A phase II trial primarily aims to see whether a possible new treatment is safe, and also start to get an idea of whether it might be effective and at what doses. This phase II trial was non-randomised and open label (unblinded) – meaning that all people were receiving the same treatment and knew what treatment they were receiving.
Ideally, if the results of phase II trials are promising, they then progress into larger phase III randomised controlled trials which examine effectiveness and safety in a larger number of people with the condition, compared to inactive placebo or other treatments usually used for the condition. However, the researchers say that in this case, randomising children to different forms of radiotherapy would be unethical.
Despite this being a non-comparative trial, the fact that it was set up prospectively to monitor the effects of this treatment means the data is more likely to be reliable than studies where researchers just look back at people's routine medical notes to see what happened to them.
The study recruited children and young people (aged 3 to 21 years) with medulloblastoma, all of whom initially received surgery to remove the tumour. Further diagnosis and staging was then based on laboratory analysis of the tumour and imaging results. Of the 59 participants included, 39 were classified as having standard-risk disease (according to Children's Oncology Group criteria), six with intermediate-risk disease, and 14 with high-risk disease. Their average age was 6.6 years.
Within 35 days of surgery, all participants received proton radiotherapy delivered to the brain and spinal cord. This was given at a total dose of 18-36 Gy radiobiological equivalents (GyRBE) delivered at 1.8 GyRBE per fraction followed by a boost dose (GyRBE is a measure of the amount of radiation delivered to an area of human tissue). All trial participants received the proton radiotherapy at an average (median) dose of 23.4 GyRBE and a boost dose of 54.0 GyRBE.
All participants also received chemotherapy, which could be given before, during or after radiotherapy.
The average follow-up of participants was seven years. The main (primary) outcome examined was grade 3 or 4 hearing loss at three years after radiotherapy. This level of hearing loss is serious and would mean the child would need treatment such as hearing aids in at least one ear, or cochlear implants, as well as speech-language related services.
The researchers also looked for cognitive (brain function) impairment (assessed at 1, 3, 5 and 7-8 years), and hormonal effects, which were assessed by annual measurements of height, weight and blood hormone levels. They also looked at the proportion of children surviving without their disease progressing (progression-free survival) at three years, and overall survival.
Overall, hearing in participants was significantly poorer at follow-up than it had been before treatment. Of 45 children with complete hearing assessments available at three years, 12% had grade 3-4 hearing loss. By five years, grade 3-4 hearing loss had risen to 16%. Four children experienced this hearing loss in both ears, and three in one ear (one of the latter group had improved hearing later on).
Looking at cognitive impairment, IQ decreased by an average of 1.5 points (95% confidence interval [CI] 0.9 to 2.1) per year five years after treatment. The main areas of impairment were information processing speed and verbal comprehension. Just over half of children (55%) had hormonal problems five years after treatment, with low levels of growth hormone being most common. There was no toxicity reported for the heart, lungs or gastrointestinal system.
Looking at effectiveness, 83% of children were alive and their disease had not progressed at three years, and 80% at five years. Overall, at five-year follow up, 83% of children were alive.
The researchers conclude: "Proton radiotherapy resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments."
This phase II study looked at the long-term side effects of using proton radiotherapy as part of the treatment of children with medulloblastoma. The treatment was used alongside standard surgical removal and chemotherapy. The current study is reported to be the longest prospective follow-up study available on this treatment for medulloblastoma.
Overall, 12% of the study's participants had severe hearing loss three years after proton radiotherapy, and 16% at five years. This was reported by the authors to be less than the equivalent 23 Gy dose of standard (photon) radiotherapy, which was said to cause hearing loss in about a quarter (25%) of those receiving it. However, as the researchers say, these comparisons are not completely reliable because of the different doses used.
Cognitive impairment was also slightly less than has been observed with standard radiotherapy – 1.5 IQ points in this study, and 1.9 with photon radiotherapy in other studies. Again, the researchers caution over the differences in radiation doses used and population treated.
Progression-free and overall survival rates in this study were reported to be much the same as those using standard radiotherapy. There was also a lack of reported toxic effects to the heart, lungs or digestive system.
Overall, the results seem positive. The difficulty is that this is a non-comparative trial. All children received proton radiotherapy. There was no randomised comparison group with similar characteristics in terms of tumour type, stage, surgery and chemotherapy treatment who instead received standard radiotherapy, to directly compare complications and survival outcomes. Ideally, a large number of children randomised to the same dose schedule of the two forms of radiotherapy would be needed to give the best comparative information on effectiveness and safety.
However, the researchers say: "Although a randomised trial is the best way to obtain a proper comparison cohort, both clinical leaders in the UK and the US deem randomised trials of proton and photon radiotherapy in children to be both unethical and not feasible". This means that such trials are unlikely to be carried out, and this type of prospective non-comparative study is likely to be the best evidence available.
The researchers suggest their findings of an acceptable toxicity profile and similar survival outcomes of proton compared to standard radiotherapy mean, "This study could serve as a template for other outcomes-based studies in different populations to better define the role of proton radiotherapy for the treatment of other cancers."