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Particle Therapy Co-operative Oncology Group (PTCOG 40) Meeting, Institute Curie 2004

¹ Department of Clinical Oncology, Queen Elizabeth University Hospital Cancer Centre, Birmingham B15 2TH and ² Department of Radiotherapy Physics, Meyerstein Institute of Oncology, University College London Hospitals, London, UK

	Introduction

Top Introduction Techniques Treatment results Paediatric cancers Orsay site visit Radiobiology Discussion Conclusions References

 
The question of whether the UK should commission a new high-energy cyclotron or synchrocyclotron in order to be at the cutting edge of radiation therapy cancer research remains unanswered. At present the only such UK facility, situated at Clatterbridge on the Wirral peninsula, has sufficient energy to treat cancers of the eye; deeper situated targets are not accessible to such sophisticated treatment. This report has been written in order to inform British Oncologists, Physicists, the administrators of the Research Councils and other relevant funding bodies about the latest research and development in particle radiotherapy. Some British children and young adults are referred to the proton therapy Centre in Orsay, near Paris: this fact and the probable increase in future demand for proton and ion beam treatments abroad should also be of interest to our Department of Health.

Over 30 000 patients have by now received proton therapy for cancer, with 3000 treated in the last year. The growth in centres and patients treated follow linear and exponential rates, respectively. There are now 21 treatment centres, with the largest throughput of over 1000 patients per year at the University of Loma Linda facility and nearly 500 patients per year at Massachusetts General Hospital (MGH), where many new techniques are being developed particularly for cancers in children. Dr Janet Sisterson (MGH) presented these facts at the opening of PTCOG40 (Particle Therapy Cooperative Oncology Group) held in Paris (June 16–18, 2004) under the auspices of the Institute Curie. PTCOG has now held two meetings per year for the last 20 years for persons in all disciplines relating to particle therapy. Their website (http://ptcog.web.psi.ch/index.html) lists the worldwide proton and light ion centres with updated figures of patients treated. Further details of the PTCOG40 meeting such as speakers and their institutions will become available in the newsletter section of the website, entitled "Particles".

The pioneering efforts of those involved in particle therapies have provided conventional radiotherapy with many of its more advanced techniques, e.g. three-dimensional (3D) treatment planning, respiratory gating, equivalent uniform dose, etc. In parallel with the increased clinical activity, there are now seven industrial companies that manufacture "turn-key" cyclotron centres capable of treating 2000–3000 patients per year in 3–5 treatment rooms. There was a pictorial exhibition of these products at the meeting and it is apparent that installation costs are falling due to the increased competition.

Proton therapy initially developed as radiosurgery and evolved into fractionated therapy for rare cancers that were considered incurable using conventional radiotherapy. At present, an increasing range of common cancers over a wide range of TNM staging are being successfully treated with resultant higher control rates and/or reduced normal tissue complication probabilities. This is possible owing to the excellent dose localization properties of the Bragg peak characteristic of energetic charged particles. A further recent development is the emergence of carbon ion therapies, with participating centres in some cases using mixtures of conventional therapy, in the intensity-modulated radiotherapy (IMRT) mode, and ions. The application of these treatments could not have occurred without the recent improvements in tumour imaging, so that far safer dose escalation and improved patient selection for radical treatment is now possible. Positron emission tomography (PET) imaging has also been used to define patients with minimal numbers of metastatic deposits for treatment by proton or ion extracranial radiosurgery.

	Techniques

Top Introduction Techniques Treatment results Paediatric cancers Orsay site visit Radiobiology Discussion Conclusions References

 
The technical improvements described at PTCOG40 include: standards of particle dosimetry; fast analytical planning software, for example using Moliere's theory of charged particles and various Monte Carlo programmes all with good fits to measured dose [1]; improved immobilization; analysis of the influence of patient movement [2] and of varying tissue inhomogeneities; detailed and impressive analyses of reliability and accuracy in the entire clinical setting were presented.

Various methods of treatment delivery were discussed, from uniform passively scattered fields with spread out Bragg peaks, modulated using mechanical range shifters and compensators, to individual pencil beams that can "dose paint" a cancer target, using scanning "wobbler" magnets [3]. There are several methods of dose painting such as lateral edge tracking, which is forgiving of uncertainties in Bragg peak position. A technique called double parallel scanning is being developed in Switzerland. Confirmation of regional dose deposition within the patient is possible by PET scanning of beam auto-activation products [4]. Various additional devices such as robotic treatment couches have been utilized to improve the accuracy of patient positioning while maintaining efficiency.

One of the advantages of particle beam therapy is that only one particle source, such as a central cyclotron, is required for treatments in several (e.g. 3–5) treatment rooms. The beam can be diverted or "switched" between rooms by the operation of bending magnets. This means that large numbers of patients can be treated from a single source, which is economically advantageous. Throughput issues were discussed, such as the logistics of efficient treatment set-ups using adjacent rooms, with rapid transfer of patients to the actual treatment position. Fast beam switching from room to room is being improved: at Orsay this is now achieved in only 10–20 s. Gantry design is critical – these weigh around 100 tonnes for protons and up to 600 tonnes for carbon ions and need to be able to rotate while keeping to an accuracy of below 1 mm. The use of bending magnets placed at the mouth of the collimator of a fixed horizontal beam, combined with robotic motion of the patient support couch, may reduce costs and tonnage, yet cover 85% of treatment geometries.

Confirmation of the regional dose deposition within a patient is possible by PET scanning of beam auto-activation products.

A separate forum was held for physicians and considered target volume determination and treatment planning exercises for difficult cases of recurrent chordomas and other paraspinal tumours; this successful new development will hopefully be repeated in future meetings.

	Treatment results

Top Introduction Techniques Treatment results Paediatric cancers Orsay site visit Radiobiology Discussion Conclusions References

 
Protons
Many centres presented descriptions of techniques and of phase 1 and 2 dose escalation studies with outcomes. There is a dearth of phase 3 randomized controlled trials in this area, but these are anticipated when optimum techniques and dose levels have been agreed. For protons, the highlights included head and neck oropharyngeal cancers, where tumour control rates and disease-free survival rates were 84% and 65%, respectively. Re-treatment of nasopharyngeal cancers provides a survival of 50% at 2 years with no brain necrosis to date. Adenoid cystic and other radioresistant cancers such as melanoma are also well controlled. Techniques were also described for acoustic neuromas, T1N0M0 breast cancers, olfactory neuroblastoma, benign meningiomas and lachrymal gland cancers. There were no detailed updates of the base of skull proton therapy experience in the MGH Boston apart from a statement that the 10 year control rate is 98% for chondrosarcomas and 44% for chordomas. Recruitment to the MGH randomized dose escalation trial for chordomas is expected to be complete towards the end of 2004.

The majority of patients treated to date have received proton therapy to the eye using relatively low energy beams. These treatments have become increasingly sophisticated due to the refinement of the indications to include certain sizes of melanoma [6] and hamartomas. A reduction in the usual tumour margins from 2.5 mm to 1 mm where tumours are close to critical structures such as the optic nerve and macula has not been associated with an increased recurrence rate, as correctly predicted by Chauvel and colleagues [7], although some opthalmologists use additional laser therapy if treatment margins are small.

Carbon ions
In the case of carbon ions, very impressive results were presented from Germany and Japan, particularly from the HIMAC centre (National Radiological Sciences Institute) where nearly 1800 patients have been treated with meticulous attention to detail. Despite a relative biological effect (RBE) of three in the spread out Bragg peaks, the safety of therapy is well confirmed with impressive local control rates, although in some instances X-ray IMRT is given as a first phase to minimize potential ion beam over-dosage due to organ movement and in the case of large treatment volumes. Examples include large inoperable high-grade osteosarcomas of the pelvis in young adults [8]. Control rates of 77% and survival rates of 45% at 5 years were described after 73.6 Gy eq. in 16 fractions over 1 month, with no neurological or other severe adverse late effects. Small peripheral non-small-cell lung cancers are highly curable [9] without long-term loss of lung function (measured by gas transfer factor) and only minor short-term changes in forced expiratory volume in 1 s (FEV₁) [10]. In such cases single fractions of 28 Gy eq. have recently been found to give the same results as higher doses given in 15–17 fractions (around 60% survival at 5 years with no serious complications). Thus for small cancers, the prospects of carefully conducted radiosurgery is feasible, without the complications that follow radical surgery. Hypofractionation of prostate cancer (stages T1–T3) to 66 Gy in 20 fractions with hormone therapy gives high control rates (79% at 5 years for initial prostate specific antigen (PSA) levels above 20) [11]. Of 201 recently analysed patients, only 2 had rectal bleeding and 6% had grade 2 bladder side effects: the technique continues to be refined. Other applications include pre-sacral rectal recurrences (78.4% control at 2 years) and inoperable melanomas with concomitant chemotherapy. Large hepatic cell cancers are now treated to a dose of 52.8 Gy eq. in only 4 fractions, without significant toxicity and with a local control rate of 90%, a 5 year survival equivalent to surgery but without the attendant morbidity.

	Paediatric cancers

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For cancer in children, a European Proton Therapy Group is being established and proton therapy is now approved within American paediatric research protocols. It is already evident from Boston that chemo-proton radiotherapy is very well tolerated in children, and the Massachusetts General retain reserved treatment slots for treating children at short notice. For example, in the treatment of orbital rhabdomyosarcoma 88% eye retention has been found after doses of 40–55 Gy in 20–25 fractions. In France, the optimization of posterior fossa radiotherapy in children with medulloblastomas is designed to reduce deafness. In Boston they aim to virtually eliminate the dose to a substantial portion of the vertebral bodies and all other anterior structures during cranio-spinal therapy, in order to reduce growth disorders and the occurrence of second malignancies in later life.

	Orsay site visit

Top Introduction Techniques Treatment results Paediatric cancers Orsay site visit Radiobiology Discussion Conclusions References

 
The conference included a visit to the Centre de Protontherapie Orsay (CPO) situated on the outskirts of Paris at the University of Orsay campus, where proton therapy is provided for a large range of sites including children and adults with skull base cancers (including some British patients). The last PTCOG meeting held there was in 1993 and the present authors have noted a marked improvement in the general facilities for patients, although the surrounding environment is not that of a hospital. The majority of the treatment is actually given by conventional radiotherapy at the central Paris hospitals, with protons used as a boost. This has all been made possible due to a highly motivated cooperative group of physicians in various Paris hospitals. There is considerable central government support via the Commissariat à l'Energy Atomique, which also supports radiotherapy research. There are already plans to extend the facility and possibly to open another centre in central Paris, as well as the ambitious Etoile project at Lyon [12], which aims to treat 2000 patients per year with carbon ions.

	Radiobiology

Top Introduction Techniques Treatment results Paediatric cancers Orsay site visit Radiobiology Discussion Conclusions References

 
The radiobiology content was relatively sparse, but included some high linear energy transfer (LET) bio-effect modelling incorporated into treatment planning [13], and unpublished work on the different apoptotic responses in three glioma lines exposed to protons at Clatterbridge. There was an interesting poster follow-up of some recently published work [14] on proton irradiation of DNA plasmids loaded with platinum atoms, which showed that the high ionization cross section of platinum caused more efficient double strand breaks during proton irradiation than for X-rays. This suggests a role for concurrent or sequential chemoradiation in tumours that take up platinum avidly. Only one oral presentation, from Cape Town South Africa, presented their doses as biological effective dose (BED) and concluded that the / ratio for acoustic neuromas treated by stereotactic proton therapy is around 1.7 Gy. Surprisingly, there were no presentations of radiobiological comparisons of particle beams situated at different international centres. Such research can provide important quality assurance, although funding across national boundaries can be a restrictive issue.

	Discussion

Top Introduction Techniques Treatment results Paediatric cancers Orsay site visit Radiobiology Discussion Conclusions References

 
PTCOG meetings consider the highest possible ideals in radiation oncology and we would encourage greater UK participation for a variety of reasons. For the UK to adapt to the inevitable demand for particle therapy abroad [15, 16], it would be sensible to have a rational plan based on the existing Cancer Networks. Designated specialists (clinical oncologists and physicists) could advise patients and their relatives as to the relative merits or unsuitability of therapy abroad. For this to occur, it will be necessary for at least some centres in the UK to obtain appropriate treatment planning software and for the specialists concerned to develop and maintain an interest in this subject. It would be preferable for the UK to possess its own service, based initially on one large facility with equity of access controlled via the existing Cancer Networks.

It is anticipated that very high intensity lasers targeted through plasma at thin metallic foils will eventually allow proton facilities to be located in a single room at relatively low cost [17, 18]. With such methods, we envisage that most of the largest cancer centres in the UK could provide proton therapy. However, as yet there is no such prototype for clinical or biological use, so that such an expansion is at least a decade or more away. In the meantime, a large National Centre with multiple treatment rooms and based on existing cyclotron technology needs to be commissioned so that considerable experience can be acquired before an eventual expansion of smaller units can occur.

Future PTCOG meetings are planned for Bloomington, Indiana (October 2004), Japan (spring 2005) and Munich (October 2005). After 2007 there will only be one such meeting per year. We would encourage specialists not only to attend these meetings but also to visit proton centres abroad: a reasonable start would be to visit the Clatterbridge Cyclotron, used only for eye treatments.

Recent Austrian estimates conclude that around 14% of all radiotherapy treatments would have improved outcomes if given using protons rather than X-rays: this represents a challenge to us all. The UK needs the equivalent of the French Commissariat à l'Energy Atomique or the National Radiological Sciences Institute in Japan, as there seems to be no single arm of the UK Government that can represent the interests of different departments about radiation research and development. Should a UK proton facility either be funded for the delivery of healthcare by the Department of Health or, in order to answer important medical, physics and associated engineering research questions, should funding originate from the two relevant Research Councils, the MRC and EPSRC? The main UK cancer research charity (CRUK) is highly focused and dedicated to improve the control of cancer by biochemical means, with scant resource allocation to radiation research. In the meantime, perhaps the new National Cancer Research Institute should take the lead in this important area and bring the relevant stakeholders together? The UK radiation oncology community could undoubtedly rationalize the indications for particle therapy by performing randomized control trials that compare the best available treatments such as IMRT with protons, and test the use of protons as part of mixed schedules. The prospectus for research alongside such projects is vast and extends into the molecular and genetic fields as well as experimental and clinical radiobiology.

	Conclusions

Top Introduction Techniques Treatment results Paediatric cancers Orsay site visit Radiobiology Discussion Conclusions References

 
Protons and light ions should not be seen as competitors to existing conventional treatments, but as a complementary force in the fight against cancer. Their precise roles remain to be fully defined, but it is inevitable that there will be increasing indications for their use in cancer therapy here in the UK, either by increased referral of patients abroad or by investment in particle treatment facilities for the eventual benefit of a larger number of UK cancer patients; they deserve the best treatment.

	Acknowledgments

 
The authors are grateful for the financial support of The Cyclotron Trust, their respective NHS Hospital Trusts and NHS endowment funds in order to attend PTCOG40. Owing to space constraints we regret not being able to mention the names and affiliations of all the many excellent speakers that contributed to this meeting.

Received for publication July 5, 2004. Revision received September 15, 2004. Accepted for publication October 4, 2004.

	References

Top Introduction Techniques Treatment results Paediatric cancers Orsay site visit Radiobiology Discussion Conclusions References

 

1. Paganetti H, Gottshalk B. Test of Geant3 and Geant4 nuclear models for 160 MeV protons stopping in CH2. Med Phys 2003;30:1926–31.[Medline]
2. Paganetti H. Four dimensional Monte Carlo simulation of time dependent geometries. Phys Med Biol 2004;49:N75–N81.[Medline]
3. Kohno R, Kanenatsu N, Yusa K, Kanai T. Experimental evaluation of analytical penumbra calculation model for wobbled beams. Med Phys 2004;31:1153–7.[Medline]
4. Hishikawa Y, Kagawa K, Murakami M, Sakai H, Akagi T, Abe M. Usefulness of positron emission tomographic images after proton therapy. Int J Radiat Oncol Biol Phys 2002;53:1388–91.[Medline]
5. Pedroni E, Bearpark R, Bohringer T, Coray A, Duppich E, et al. The PSI gantry 2: a second generation proton scanning gantry. Z Med Phys 2004;14:25–34.[Medline]
6. Domato B, Lecvonak K. Conservation of eyes with choroidal melanoma by a multimodality approach to treaatment: an audit of 1632 patients. Opthalmology 2004;111:977–83.
7. Courdi A, Caufolle JP, Grange JD, Diallo-Rosier L, Sahel J, et al. Results of proton therapy of uveal melanomas treated in Nice. Int J Radiat Oncol Biol Phys 1999;45:5–11.[Medline]
8. 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 Oncol 2002;20:4466–71.[Abstract/Free Full Text]
9. 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.[CrossRef][Medline]
10. 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.[Abstract/Free Full Text]
11. Akakura K, Tsujii H, Morita S, Tsuji H, Yagishita T, et al. Phase I/II clinical trials of carbon ion therapy for prostate cancer. Prostate 2004;58:252–8.[CrossRef][Medline]
12. Pommier P, Balosso J, Bolla M, Gerard JP. The French project ETOILE: review of clinical data for light ion hadrontherapy. Cancer Radiother 2002;6:369–78.[Medline]
13. Wilkens JJ, Oelfke U. A phenomenological model for the relative biological effectiveness in therapeutic proton beams. Phys Med Biol 2004;49:2811–25.[Medline]
14. Lacombe S, Le Sech C, Esaulov V. DNA strand breaks induced by low keV energy heavy ions. Phys Med Biol 2004;49:N65–N73.[Medline]
15. Suit H, Goldberg S, Niemerko A, Trofimov A, Adams J, et al. Proton beams to replace photon beams in radical dose treatments. Acta Oncologica 2003;42:800–8.[CrossRef][Medline]
16. Jagsi R, DeLaney TF, Donelan K, Tarbell NJ. Real time rationing of scarce resources: the Northwest proton Therapy experience. J Clin Oncology 2004;22:2246–50.[Free Full Text]
17. Malka V, Fritzler S, Lefebvre E, Aleonard M-M, Burgy F, et al. Electron acceleration by a Wake Field forced by an intense ultra short laser pulse. Science 2002;298:1596–600.[Abstract/Free Full Text]
18. Fourkal E, Li JS, Ding M, Tajina T, Ma CM. Particle selection for laser accelerated proton therapy feasibility study. Med Phys 2003;30:1660.[Medline]

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