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The use and effects of proton beam therapy, which affects less normal tissue when targeting a tumour than traditional radiotherapy, are addressed in a paper published in The Lancet Oncology journal. The authors report similar survival levels as conventional radiotherapy as well as “acceptable toxicity”.
Prof. Kevin Harrington, Joint Head of Radiotherapy and Imaging, The Institute of Cancer Research, said
“This is an important set of observations that highlights the need to properly evaluate proton beam radiotherapy in the clinic. The reductions in toxicity suggested by the study are important, but this is an observational series of cases, not a prospective clinical trial – and while the results look promising, there remains a lack of data about the side-effects of proton beam radiotherapy in children.
“Soon the UK will have three research centres at which proton beam therapy will be available, in a context that will allow further studies to be performed in a carefully controlled fashion. The ICR will be leading a national network of research on advanced radiotherapy technologies, including protons, with the aim of conducting trials to bring the latest treatment approaches to patients.”
Prof. Gillies McKenna, Head of the Department of Oncology & Director of the CRUK/MRC Institute for Radiation Oncology, University of Oxford, said:
“This study reported by Dr Yock and her colleagues is not a randomized trial, because many people believe that randomized trials of such treatments in children are unethical, and place an unnecessary strain on the families. What she has done is closely follow a series of 59 patients treated between 2003 and 2009 where we can compare the outcomes to other published series of similar patients who had been treated with conventional X-ray treatment. The good news is that the outcomes in terms of cure were at least as good as we see with X-rays, and many of the side effects are indeed dramatically reduced. There were no side effects seen in the heart and lungs and gastrointestinal tract, which are almost always seen with X-rays, and no secondary cancers were seen at a time when we would have expected to see then in X-ray treated patients.
“Side effects were not completely eliminated. Hearing problems were seen, because parts of the inner ear did receive some radiation dose, and decreases in IQ were seen because this is a cancer of the brain and treating the brain with radiation in children does cause some damage. Nevertheless, the results were sufficiently better than conventional treatment that we can confidently say that for many children this may be a better treatment, and we can expect the results to continue to improve.
“Methods for delivering proton treatment have been improved since this study was initiated to reduce, for example, the dose to the inner ear. Furthermore, we understand much more about the underlying mutations and genetic changes that cause this disease that may allow us to create more targeted and less toxic treatments, including in the chemotherapy portion of treatment.”
Dr Martin English, Consultant Paediatric Oncologist, Birmingham Children’s Hospital, said:
“This is an interesting paper and the authors’ report that 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. I agree with their conclusion.
“Radiotherapy is used for a number of cancers and brain tumours occurring in childhood. Medulloblastoma is the commonest malignant brain tumour of childhood accounting for 15-20% of all cases of brain tumours and 60-80 cases per year in the UK in children under the age of 16. Proton beam therapy is relatively new in paediatric practice and as fortunately childhood tumours are rare there is not a lot of information about the long-term outcome of treatment.
“This study starts to fill in some of the gaps in knowledge, but it is a preliminary work, not the final word. It is a phase II study which is one designed to show if there is effectiveness. The authors have done this and their published survival is similar to cases where conventional radiotherapy has been used. It does not provide evidence of a better chance of cure than with conventional radiotherapy, nor would one be expected unless the dose of radiation delivered to the brain was increased.
“The authors do report damage to hormones produced in the brain and that is also seen with conventional radiotherapy. They had patients with different degrees of risk and therefore different doses of radiation. The incidence of hormone damage is not higher than with conventional radiotherapy, but it is not possible to say that it is significantly lower.
“They also report hearing loss in some patients. The organ of hearing in the inner ear, the cochlea, is sensitive both to radiation and to cisplatin, one of the commonly used chemotherapy drugs for medulloblastoma. Again the severity of hearing damage is not excessive. Children are carefully monitored during treatment and if hearing loss is developing then the cisplatin dose is modified. This hearing loss is not more than would be expected in children treated with conventional radiotherapy. Further studies are necessary to prove if it can reduce the hearing damage seen.
“The authors note that their patients had an average reduction in IQ of 1.5 points per year and that other authors have reported higher loss. However they rightly point out that other factors may also be involved and it cannot be said from their study that proton beam radiotherapy reduces the rate of fall in IQ. That will require different trials to answer the question in the future.
“The authors do not note any significant damage to heart, lungs or chest wall, but did not do specific tests to investigate for these. One would not normally expect to see clinically apparent damage to these organs and structures after conventional radiotherapy for medulloblastoma. Some authors have found abnormalities when they do detailed tests of heart and lung function, but the papers quoted in this publication are more than 20 years old and conventional radiotherapy has also been significantly improved over the past few decades.
“In the future specific studies need to be designed to prove if there is a reduction in damage to distant sites such as heart or lungs after proton beam radiation as opposed to conventional radiotherapy. The UK will be well placed to design such investigations in the future when the two national centres open.”
Further background information from Dr Martin English:
“Conventional radiotherapy, sometimes described as ‘photon’ radiotherapy uses X-rays to treat the patient. Proton beam radiotherapy uses beams of protons which are sub-atomic particles. In each case the beams are directed at the patient from different directions and sometimes shaped by shielding part of the beam so a high dose of radiation is achieved in the area targeted. In both cases normal tissue receives a dose of radiation as the beam enters the body. In the case of conventional radiotherapy the X-rays may also give a dose of radiation to normal tissue on the way out of the body. However the proton beam radiation does not give a significant exit dose of radiation. Both treatments apply the same amount of radiation to the target tissue and should have equal biological effectiveness in killing tumour cells.
“Medulloblastoma is the commonest of a group of childhood brain tumours where it is important not just to give a high dose of radiation to the tumour, but to also treat the entire brain and spinal cord with radiation. This is because there is likely to be microscopic cells travelling in the fluid surrounding the brain and spinal cord and so the whole of the compartment containing the central nervous system needs to receive radiation.
“At the moment children with localised brain tumours such as ependymoma (30-40 cases per year) or low grade glioma (figures are harder to say but around 30 cases per year requiring radiotherapy)and a mumber of rarer tumours may be referred to the United States for treatment with proton beam radiotherapy if they require radiotherapy as part of their treatment. Depending on the position of the tumour not every case benefits from proton treatment.
“The pathway is different for medulloblastoma. Children with standard risk disease, which is those over 3 years of age with a near total removal of the tumour and no evidence of spread of disease, should start radiotherapy within 4-6 weeks of the surgery diagnosing the tumour. This is major surgery and in the best cases children will be hospital in-patients for 1-2 weeks and longer stays are common. Radiotherapy planning is a complex process that may take over a week and children need to be fit enough to travel to the centre providing the treatment. For this reason UK specialists in childhood brain tumours do not usually recommend proton beam radiotherapy for children with medulloblastoma. This is mainly because of concern that the chance of cure will be reduced if there is any delay.
“Once proton beam radiotherapy is available in the UK it will be part of the treatment options available to children with medulloblastoma where it is felt there will be benefit to the child.”
‘Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study’ by Yock et al. published in The Lancet Oncology on Friday 29th January.
Declared interests
Prof. Kevin Harrington: No declared interests
Prof. Gillies McKenna: None declared
Dr Martin English: All comments are Dr English’s alone, not of any organisations he is a member of. He is a Consultant paediatric Oncologist at Birmingham Children’s Hospital specialising in brain tumours and the late effects of treatment for childhood cancer. He is a member of the UK Children’s Cancer and Leukaemia Group and a member of the NHS England Clinical Reference Group for Children’s Cancer. He has been instructed as an expert witness in medico-legal cases to comment on the late effects of treatment received by children with cancer.