Radiotherapy for the future
http://www.100md.com
《英国医生杂志》
Protons and ions hold much promise
Charged particle beams (CPB), consisting of protons or carbon ions produced in a cyclotron or synchrotron, are an important development in radiotherapy.1 w1 Compared with conventional x rays, charged particle beams produce excellent dose distributions to tumours and reduced doses to normal tissues. They thus hold out the promise of enhanced treatments for cancer and improved quality of life for patients being treated.
All the major technical advances in radiotherapy, such as increasing x ray energies and better target localisation have improved accuracy and outcomes,w2 w3 without direct evidence from randomised clinical trials. The one modern exception, conformal radiotherapy (using better shaped x ray beams to conform with tumour geometry), was tested in a randomised trial only in the United Kingdom: the reduction in serious morbidity found has led to extensive use.w4
Treatment with charged particle beams marks a more radical change from incremental improvements in x ray based therapy. Its safe implementation has been made possible by improved tumour and normal tissue imaging using spiral computed tomography and magnetic resonance imaging, rapid three dimensional dose plan computing, and the industrial manufacture of entire CPB treatment centres.
Carbon ions cause denser ionisation than protons and x rays. They theoretically offer better prospects for radio resistant tumours. Like conventional x rays, CPB cause DNA damage, but they deposit energy more selectively. As particle velocity decreases through tissue, ionisation becomes maximal at the "Bragg peak,"w5 with none a few millimetres further beyond that peak. So, compared with a single x ray beam, charged particle beams deliver a reduced proximal dose, an equivalent or higher tumour dose, and either none or a greatly reduced dose distally. For multiple charged particle beams, the advantageous dose distributions are further increased than with the most sophisticated x ray techniques, resulting in a reduced average dose to normal tissues by around 50% or more. Safer dose distributions are obtainable from a smaller number of beams and fewer treatments can be given.2-5 w6 These features should result in fewer normal tissues side effects and, if dose escalation is used, increased tumour control: thus, the finely balanced therapeutic ratio in radiotherapy is expected to improve.
The evidence so far is limited to phase I and II dose escalation studies using charged particle beams in a limited range of cancers where conventional radiotherapy results in disappointing tumour control or because of dose limitations imposed by closely situated critical tissues, as in the case of chordomas, paraspinal tumours, air sinus and orbital cancers, bone and many soft tissue sarcomas. Intracranial vascular malformations, acoustic neuromas, and meningiomas have also been treated.1 6-8. There is early clinical experience, with high local tumour control rates, in locally advanced head and neck, oesophageal, lung, rectal, cervix, and prostate cancers.1 w7
In cancers for which direct comparisons with existing treatments can be made, cure rates for small T1N0M0 peripheral lung cancers are comparable with those after surgery, but with relatively minor changes in pulmonary physiology. Typical results are 60% survival at five years without deterioration in standard lung function tests such as vital capacity and gas transfer factor after proton therapy in 10 patients, a deterioration of less than 8% in lung function in the first cohort of 81 patients treated with carbon ions, and 15-20% reductions where x rays were combined with protons for larger stage 1-111 cancers9-12. For primary liver cancer, the control rates after 15w8 or four1 carbon ion exposures are equivalent to radical surgery (92% local control rates and a 25% five year overall survival in 24 patients with accompanying liver cirrhosis), but without the serious morbidity associated with hepatic resection. Children represent a special case: the risk of radiation induced malignancy, based on standard radiation protection data, is predicted to reduce by 10-15 fold.w9. A theoretical reduced cancer induction risk is also possible in irradiated adults. In addition, older patients with metallic prostheses, such as hip replacements, can have treatment of bladder, prostate and uterine cancers to more reliable central pelvic doses using charged particle beams.w1
The only proton facility in the UK is at Clatterbridge (Wirral), where a cyclotron capable of producing proton energies of 60 mega-electron volts (MeV) is used to successfully treat choroidal melanomas.w10 The penetration depth of charged particle beams is proportional to their energy: 60 MeV produce Bragg peaks at around 3 cm depth, sufficient for eye cancers. For depths of up to 20 cm, which are necessary for thoracic, abdominal, and pelvic cancers, over 200 MeV is required.
Radiotherapy using charged particle beams shows great promise, and many high energy facilities are already being developed across Europe, the United States, and the Far East.1 w1 Yet that promise needs to be researched thoroughly, to establish efficacy and cost effectiveness, with full UK participation. Although the UK tends to implement new radiotherapy technologies slowlyw11 w12, it has a good reputation in conducting clinical trials of efficacyw4. At least one high energy UK facility should be established to conduct phase III trials, with equitable patient referral via the cancer networks. In that way the UK can contribute to establishing the evidence base for charged particle beam therapy and British patients will not lag behind in receiving the potential benefits. According to estimates, 10-20% of patients receiving radiotherapy might benefit from charged particle beams,9 w3 w7 w13 so the decision to build a major proton facility is an important one for the British government to make.
Bleddyn Jones, professor in clinical oncology
(b.jones.1@bham.ac.uk) Department of Clinical Oncology, Queen Elizabeth University Hospital, Birmingham B45 8TB
Neil Burnet, lecturer in clinical oncology
University of Cambridge Department of Oncology, Oncology Centre, Addenbrookes Hospital, Cambridge CB2 2QQ
Additional references w1-w13 are on bmj.com
Competing interest: BJ and NB are members of the Engineering and Physics Research Council (UK) funded Medical Applications of Ion Beams Network. BJ is a trustee of the Cyclotron Trust (UK Charity).
References
Jones B, Rosenberg I. Commentary: Particle Therapy Co-operative Oncology Group (PTCOG 40) Meeting, Institute Curie 2004. Br J Radiol 2005;78: 94-7.
Baumert BG, Norton IA, Lomax AJ, Davis JB. Dose conformation of intensity-modulated stereotactic photon beams, proton beams, and intensity-modulated proton beams for intracranial lesions. Int J Radiat Oncol Biol Physics. 2004;60: 1314-24.
Lomax AJ, Cella L, Weber D, Kurtz JM, Miralbell R. Potential role of intensity-modulated photons and protons in the treatment of the breast and regional nodes. Int J Radiat Oncol Biol Physics 2003;55: 785-92.
Lomax AJ, Goitein M, Adams J. Intensity modulation in radiotherapy: photons versus protons in the paranasal sinus. Radiotherapy Oncology 2003;66: 11-8.
Cozzi L, Fogliata A, Lomax A, Bolsi A. A treatment planning comparison of 3D conformal therapy, intensity modulated photon therapy and proton therapy for treatment of advanced head and neck tumours. Radiother Oncology 2001;61: 287-97.
Schulz-Ertner D, Nikoghosyan A, Thilmann C, Haberer T, Jakel O, Karger C, et al. Results of carbon ion radiotherapy in 152 patients. Int J Radiat Oncol Biol Physics 2004;58: 631-40.
Kamada T, Tsujii H, Tsuji H, Yanagi T, Mizoe JE, et al. Efficacy of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin. Oncology 2002;20: 4466-71.
Breuer H, Smit BJ. Proton therapy and radiosurgery. Berlin: Springer, 1999.
Bush DA, Slater JD, Bonnet R, Cheek GA, Dunbar RD, Moyers M, et al. Proton-beam radiotherapy for early-stage lung cancer. Chest 1999;16: 1313-9.
Bonnet RB, Bush D, Cheek GA, Slater JD, Panossian D, Franke C, et al. Effects of proton and combined proton/photon beam radiation on pulmonary function in patients with resectable but medically inoperable non-small cell lung cancer. Chest 2001;120: 1803-10.
Miyamoto T, Yanamoto N, Nishimura H, Koto M, Tsujii H, et al. Carbon ion radiotherapy for stage 1 non-small cell lung cancer. Radiother Oncol 2003;66: 127-40.
Kadono K, Homma T, Kamahara K, Nakayama M, Satoh H, Sekizawa K, et al. Effect of heavy-ion radiotherapy on pulmonary function in stage I non-small cell lung cancer patients. Chest 2002;122: 1925-32.
Charged particle beams (CPB), consisting of protons or carbon ions produced in a cyclotron or synchrotron, are an important development in radiotherapy.1 w1 Compared with conventional x rays, charged particle beams produce excellent dose distributions to tumours and reduced doses to normal tissues. They thus hold out the promise of enhanced treatments for cancer and improved quality of life for patients being treated.
All the major technical advances in radiotherapy, such as increasing x ray energies and better target localisation have improved accuracy and outcomes,w2 w3 without direct evidence from randomised clinical trials. The one modern exception, conformal radiotherapy (using better shaped x ray beams to conform with tumour geometry), was tested in a randomised trial only in the United Kingdom: the reduction in serious morbidity found has led to extensive use.w4
Treatment with charged particle beams marks a more radical change from incremental improvements in x ray based therapy. Its safe implementation has been made possible by improved tumour and normal tissue imaging using spiral computed tomography and magnetic resonance imaging, rapid three dimensional dose plan computing, and the industrial manufacture of entire CPB treatment centres.
Carbon ions cause denser ionisation than protons and x rays. They theoretically offer better prospects for radio resistant tumours. Like conventional x rays, CPB cause DNA damage, but they deposit energy more selectively. As particle velocity decreases through tissue, ionisation becomes maximal at the "Bragg peak,"w5 with none a few millimetres further beyond that peak. So, compared with a single x ray beam, charged particle beams deliver a reduced proximal dose, an equivalent or higher tumour dose, and either none or a greatly reduced dose distally. For multiple charged particle beams, the advantageous dose distributions are further increased than with the most sophisticated x ray techniques, resulting in a reduced average dose to normal tissues by around 50% or more. Safer dose distributions are obtainable from a smaller number of beams and fewer treatments can be given.2-5 w6 These features should result in fewer normal tissues side effects and, if dose escalation is used, increased tumour control: thus, the finely balanced therapeutic ratio in radiotherapy is expected to improve.
The evidence so far is limited to phase I and II dose escalation studies using charged particle beams in a limited range of cancers where conventional radiotherapy results in disappointing tumour control or because of dose limitations imposed by closely situated critical tissues, as in the case of chordomas, paraspinal tumours, air sinus and orbital cancers, bone and many soft tissue sarcomas. Intracranial vascular malformations, acoustic neuromas, and meningiomas have also been treated.1 6-8. There is early clinical experience, with high local tumour control rates, in locally advanced head and neck, oesophageal, lung, rectal, cervix, and prostate cancers.1 w7
In cancers for which direct comparisons with existing treatments can be made, cure rates for small T1N0M0 peripheral lung cancers are comparable with those after surgery, but with relatively minor changes in pulmonary physiology. Typical results are 60% survival at five years without deterioration in standard lung function tests such as vital capacity and gas transfer factor after proton therapy in 10 patients, a deterioration of less than 8% in lung function in the first cohort of 81 patients treated with carbon ions, and 15-20% reductions where x rays were combined with protons for larger stage 1-111 cancers9-12. For primary liver cancer, the control rates after 15w8 or four1 carbon ion exposures are equivalent to radical surgery (92% local control rates and a 25% five year overall survival in 24 patients with accompanying liver cirrhosis), but without the serious morbidity associated with hepatic resection. Children represent a special case: the risk of radiation induced malignancy, based on standard radiation protection data, is predicted to reduce by 10-15 fold.w9. A theoretical reduced cancer induction risk is also possible in irradiated adults. In addition, older patients with metallic prostheses, such as hip replacements, can have treatment of bladder, prostate and uterine cancers to more reliable central pelvic doses using charged particle beams.w1
The only proton facility in the UK is at Clatterbridge (Wirral), where a cyclotron capable of producing proton energies of 60 mega-electron volts (MeV) is used to successfully treat choroidal melanomas.w10 The penetration depth of charged particle beams is proportional to their energy: 60 MeV produce Bragg peaks at around 3 cm depth, sufficient for eye cancers. For depths of up to 20 cm, which are necessary for thoracic, abdominal, and pelvic cancers, over 200 MeV is required.
Radiotherapy using charged particle beams shows great promise, and many high energy facilities are already being developed across Europe, the United States, and the Far East.1 w1 Yet that promise needs to be researched thoroughly, to establish efficacy and cost effectiveness, with full UK participation. Although the UK tends to implement new radiotherapy technologies slowlyw11 w12, it has a good reputation in conducting clinical trials of efficacyw4. At least one high energy UK facility should be established to conduct phase III trials, with equitable patient referral via the cancer networks. In that way the UK can contribute to establishing the evidence base for charged particle beam therapy and British patients will not lag behind in receiving the potential benefits. According to estimates, 10-20% of patients receiving radiotherapy might benefit from charged particle beams,9 w3 w7 w13 so the decision to build a major proton facility is an important one for the British government to make.
Bleddyn Jones, professor in clinical oncology
(b.jones.1@bham.ac.uk) Department of Clinical Oncology, Queen Elizabeth University Hospital, Birmingham B45 8TB
Neil Burnet, lecturer in clinical oncology
University of Cambridge Department of Oncology, Oncology Centre, Addenbrookes Hospital, Cambridge CB2 2QQ
Additional references w1-w13 are on bmj.com
Competing interest: BJ and NB are members of the Engineering and Physics Research Council (UK) funded Medical Applications of Ion Beams Network. BJ is a trustee of the Cyclotron Trust (UK Charity).
References
Jones B, Rosenberg I. Commentary: Particle Therapy Co-operative Oncology Group (PTCOG 40) Meeting, Institute Curie 2004. Br J Radiol 2005;78: 94-7.
Baumert BG, Norton IA, Lomax AJ, Davis JB. Dose conformation of intensity-modulated stereotactic photon beams, proton beams, and intensity-modulated proton beams for intracranial lesions. Int J Radiat Oncol Biol Physics. 2004;60: 1314-24.
Lomax AJ, Cella L, Weber D, Kurtz JM, Miralbell R. Potential role of intensity-modulated photons and protons in the treatment of the breast and regional nodes. Int J Radiat Oncol Biol Physics 2003;55: 785-92.
Lomax AJ, Goitein M, Adams J. Intensity modulation in radiotherapy: photons versus protons in the paranasal sinus. Radiotherapy Oncology 2003;66: 11-8.
Cozzi L, Fogliata A, Lomax A, Bolsi A. A treatment planning comparison of 3D conformal therapy, intensity modulated photon therapy and proton therapy for treatment of advanced head and neck tumours. Radiother Oncology 2001;61: 287-97.
Schulz-Ertner D, Nikoghosyan A, Thilmann C, Haberer T, Jakel O, Karger C, et al. Results of carbon ion radiotherapy in 152 patients. Int J Radiat Oncol Biol Physics 2004;58: 631-40.
Kamada T, Tsujii H, Tsuji H, Yanagi T, Mizoe JE, et al. Efficacy of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin. Oncology 2002;20: 4466-71.
Breuer H, Smit BJ. Proton therapy and radiosurgery. Berlin: Springer, 1999.
Bush DA, Slater JD, Bonnet R, Cheek GA, Dunbar RD, Moyers M, et al. Proton-beam radiotherapy for early-stage lung cancer. Chest 1999;16: 1313-9.
Bonnet RB, Bush D, Cheek GA, Slater JD, Panossian D, Franke C, et al. Effects of proton and combined proton/photon beam radiation on pulmonary function in patients with resectable but medically inoperable non-small cell lung cancer. Chest 2001;120: 1803-10.
Miyamoto T, Yanamoto N, Nishimura H, Koto M, Tsujii H, et al. Carbon ion radiotherapy for stage 1 non-small cell lung cancer. Radiother Oncol 2003;66: 127-40.
Kadono K, Homma T, Kamahara K, Nakayama M, Satoh H, Sekizawa K, et al. Effect of heavy-ion radiotherapy on pulmonary function in stage I non-small cell lung cancer patients. Chest 2002;122: 1925-32.